VOGL ANNETTE (DE)
SCHMITT SASKIA (DE)
MAI ISABELLE (DE)
HERTERICH SARAH (DE)
SCHUMACHER DOMINIK (DE)
KASPER MARC-ANDRÉ (DE)
CYPRYS PHILIPP (DE)
| WO2020073131A1 | 2020-04-16 | |||
| WO2021202984A1 | 2021-10-07 | |||
| WO2022235636A1 | 2022-11-10 | |||
| WO2018041985A1 | 2018-03-08 | |||
| WO2004010957A2 | 2004-02-05 | |||
| WO2019236954A1 | 2019-12-12 | |||
| WO2018041985A1 | 2018-03-08 | |||
| WO2019170710A2 | 2019-09-12 |
| US20210301031A1 | 2021-09-30 | |||
| US20210220477A1 | 2021-07-22 | |||
| US11407825B2 | 2022-08-09 | |||
| EP23172910A | 2023-05-11 | |||
| EP0401384A1 | 1990-12-12 | |||
| US5757078A | 1998-05-26 | |||
| US5672662A | 1997-09-30 | |||
| US6077939A | 2000-06-20 | |||
| US20090274713A1 | 2009-11-05 | |||
| EP0495432A1 | 1992-07-22 |
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| WHAT IS CLAIMED IS: 1. An antibody drug conjugate (ADC) comprising an anti-NaPi2b antibody (e.g., an antibody against NPT2B_HUMAN Sodium-dependent phosphate transport protein 2B, e.g., having UniProt Accession Number: O95436 or SEQ ID NO: 1 and/or an antibody against NPT2B_RAT Sodium-dependent phosphate transport protein 2B, e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2), wherein said NaPi2b antibody is capable of the following: a) binding to human Napi2b (e.g., SEQ ID NO: 1) and/or rat Napi2b (e.g., SEQ ID NO: 2), preferably said binding to said human Napi2b and said rat Napi2b having about the same KD, further preferably said binding to said human Napi2b and said rat Napi2b is the binding to endogenous Napi2b (e.g., located on cell surface), most preferably said antibody is selected from the group consisting of: AV-25, AV-15, AV- 18, AV-21 and AV-29 antibody), further most preferably said about same KD having up to 50% difference (e.g., up to 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 7%, 5%, 4%, 3%, 2% or 1% difference); b) cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2), preferably by the means of the antigen-mediated antibody internalization; further preferably said internalization is improved (e.g., by at least 10%, e.g., 15%) compared to the corresponding internalization of the parental antibody (e.g., comprising SEQ ID NOs: 54 and 55, e.g., as shown in Figure 1); c) cross-reactivity with cynomolgus monkey (e.g., Macaca fascicularis) Napi2b (e.g., having UniProtKB Accession Number: A0A2K5UHY1 or SEQ ID NO: 3; d) internalization, preferably by the means of the antigen-mediated antibody internalization; e) not having a dipeptide deamidation site in a heavy chain variable region’s (VH) CDR2, preferably said absent dipeptide deamidation site is NG (Asn-Gly) in VH CDR2; wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) cytotoxic moieties (e.g., cytotoxic payloads, e.g., Tubulin disrupting agents, e.g., Topoisomerase-I inhibitor/s, e.g., Auristatins or camptothecin, e.g., MMAE (monomethyl auristatin E) or MMAF (monomethyl auristatin F), e.g., Exatecan), preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. 2. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody not having a dipeptide deamidation site in a heavy chain variable region’s (VH) CDR2, preferably said absent dipeptide deamidation site is NG (Asn-Gly) in VH CDR2. 3. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties, preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. 4. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) Exatecan cytotoxic moieties via one or more linkers, preferably via one or more phosphonamidate linkers. 5. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties via an ethynylphosphonamidate-linker/s conjugation (e.g., to all eight interchain-cysteine residues), preferably each phosphonamidate linker carries at least one PEG24 moiety (e.g., to prevent aggregation of the ADC), further preferably said ADC carries up to said eight linker payload moieties and eight PEG24 moieties. 6. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said ADC comprising a humanized monoclonal NaPi2b-specific IgG1 antibody conjugated to a cytotoxic payload: a) wherein the cytotoxic pyload is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof; and/or b) wherein cytotoxic payload is a camptothecin moiety C selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan, and gimatecan; and/or c) wherein the cytotoxic pyload is conjugated via a cleavable linker (L), preferably wherein the linker L is cleavable by a protease, a glucuronidase, a sulfatase, a phosphatase, an esterase, or by disulfide reduction, more preferably wherein the linker is cleavable by a protease, preferably by a cathepsin such as cathepsin B; and/or d) wherein the linker L comprises a valine-citrulline-PAB moiety or a valine-alanine- PAB moiety; and/or e) wherein cytotoxic payload is Exatecan, conjugated via a chemical valine-citrulline- PAB or a valine-alanine-PAB release unit, wherein said release unit is cleavable by a protease. 7. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein: a) said anti-NaPi2b monoclonal antibody is capable of specifically recognizing human Napi2b (e.g., SEQ ID NO: 1) and/or rat Napi2b (e.g., SEQ ID NO: 2) overexpressed on cancer cell/s; and (b) upon binding of said ADC to said NaPi2b overexpressed on cancer cells said ADC is capable of being internalized by the cells and trafficked into the lysosomal compartment, in which preferably a lysosomal protease (e.g., Cathepsin B) is capable of releasing said cytotoxic payload from the said ADC. 8. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said ADC having one or more of the following characteristics: a) said ADC is hydrophilic; b) said ADC having a retention time of less than 10.12 minutes, preferably said retention time is from about 9.73 minutes to about 10.06 minutes; c) said ADC having IC50 cytotoxicity of less than 30 ng/mL, preferably less than 16.7 ng/mL (e.g., in OVCAR-3 cancer cells e.g., HTB-161#, ATCC), further preferably said IC50 cytotoxicity is from about 13.0 to about 15.5 ng/mL. 9. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody is an antibody comprising: a) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 4 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 5; preferably said anti-NaPi2b antibody is the AV25 antibody comprising:a light chain comprising SEQ ID NO: 6 and a heavy chain comprising SEQ ID NO: 7; b) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 8 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 9; preferably said anti-NaPi2b antibody is the AV-15 antibody comprising: a light chain comprising SEQ ID NO: 10 and a heavy chain comprising SEQ ID NO: 11; c) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 12 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 13; preferably said anti-NaPi2b antibody is the AV-18 antibody comprising: a light chain comprising SEQ ID NO: 14 and a heavy chain comprising SEQ ID NO: 15; d) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 16 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 17; preferably said anti-NaPi2b antibody is the AV-21 antibody comprising: a light chain comprising comprising SEQ ID NO: 18 and a heavy chain comprising comprising SEQ ID NO: 19; e) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 20 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 21; preferably said anti-NaPi2b antibody is the AV-29 antibody comprising: a light chain comprising comprising SEQ ID NO: 22 and and a heavy chain comprising comprising SEQ ID NO: 23. 10. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody is: a) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 24, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 25, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 26 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; b) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 30, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 31, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 32 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 33, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 34, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 35; c) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 36, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 37, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 38 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 39, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 40, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 41; d) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 42, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 43, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 44 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 45, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 46, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 47; e) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 48, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 49, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 50 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 51, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 52, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 53. 1. The antibody drug conjugate (ADC) according to any one of the preceding claims, wherein said anti-NaPi2b antibody has one or more of the following characteristics: a) a monoclonal antibody; b) a chimeric antibody and/or humanized anbibody; c) specifically recognizes Napi2b overexpressed on cancer cells; d) human IgG antibody, preferably a human IgG1 antibody; e) comprising kappa (κ) light chain; f) comprising lambda (λ) light chain; g) comprising Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA mutations), wherein said LALA mutations are capable of reducing immunocell effector function/s; h) capable of being internalized by target cells (e.g., cancer cells) expressing Napi2b; preferably said internalized antibody is directed to lysosomes; i) a tumor-selective antibody, preferably said tumor is a liquid and/or solid tumor; j) a malignant-cell selective antibody; k) binding to said human and/or rat Napi2b in a glycosylation-dependent manner, wherein said antibody binds to a glycosylated form of said Napi2b protein; l) having KD to an endogenously expressed human Napi2b in the range from about 0.01 to about 10 nmol/L, preferably in the range from about 1 to about 10 nmol/L, further preferably from about 1 to about 7 nmol/L, further preferably from about 1 to about 4 nmol/L (e.g., in OVCAR-3 cells (e.g., HTB-161#, ATCC) endogenously expressing Napi2b), further preferably said KD is measured by the means of a FACS assay, further most preferably having said KD in the range from about 2.661 to about 6.644 nmol/L; m) optionally, having KD in the range from about 0.01 to about 10 nmol/L to an immobilized exogenous full-length Napi2b and/or one or more fragments thereof, preferably said one or more fragments comprising at least one extracellular domain (ECD) of said Napi2b (e.g., said ECD comprising amino acids 122-135 and/or amino acids 235-361 and/or 429-485 and/or amino acids 547-552 of the human Napi2b having SEQ ID NO: 1) and/or one or more fragments of said ECD (e.g., having length from about 15 to about 30 amino acids), wherein said full-length Napi2b and/or one or more fragments thereof are fused or not fused to one or more protein tags (e.g., 6 x His-tags, FLAG, HA, V5, Fc-fusion, MBP, SUMO, TEV, GFP, TST), preferably preferably said KD is measured by the means of an ELISA assay, preferably from about 0.05 to about 0.2 nmol/L, further preferably having said KD in the range from about 0.071 to about 0.147 nmol/L; n) cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2); and/or m) not having a dipeptide deamidation site in a heavy chain variable region’s (VH) CDR2, preferably said absent dipeptide deamidation site is NG (Asn-Gly) in VH CDR2. 12. The antibody drug conjugate (ADC) according to any one of claims 1 to 11, in particular of claim 1, having the formula (I): , or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-Na2Pi2b antibody as defined in any one of the preceding claims; is a double bond; or V is absent when is a double bond; or V is H or (C1- when is a bond; X is R3 C when is a double bond; or R4 X is R3 C when is a bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; m is an integer ranging from 1 to 10; and n is an integer ranging from 1 to 20. 13. The antibody drug conjugate (ADC) according to claim 12, wherein is a double bond; V is absent; X is R3 C ; and R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R3 is H or (C1-C8)alkyl; more preferably R3 is H. 14. The antibody drug conjugate (ADC) according to claim 12 or 13, wherein Y is NH. 15. The antibody drug conjugate (ADC) according to any one of claims 12 to 14, wherein the connector unit CU is cleavable. 16. The antibody drug conjugate (ADC) according to claim 15, wherein the connector unit CU is cleavable by a protease, a glucuronidase, a sulfatase, a phosphatase, an esterase, or by disulfide reduction. 17. The antibody drug conjugate (ADC) according to claim 16, wherein the connector unit CU is cleavable by a protease, preferably by a cathepsin such as cathepsin B. 18. The antibody drug conjugate (ADC) according to any one of claims 12 to 17, wherein the connector unit CU comprises a valine-citrulline moiety or a valine-alanine moiety. 19. The antibody drug conjugate (ADC) according to claim 18, wherein the connector unit CU is: O O O O * H N N N H H O # O N NH H 2 , wherein # indicates the attachment point to the Y and * indicates the attachment point to the cytotoxic moiety CM. 20. The antibody drug conjugate (ADC) according to claim 18, wherein the connector unit CU is: ## * , wherein * indicates the attachment point to the Y and ## indicates the attachment point to the cytotoxic moiety CM. 21. The antibody drug conjugate (ADC) according to any one of claims 12 to 20, wherein R1 is: KF o , wherein indicates the position of the O; KF is selected from the group consisting of -H, -PO3H, -(C1-C10)alkyl, -(C1-C10)alkyl- SO3H, -(C2-C10)alkyl-CO2H, -(C2-C10)alkyl-OH, -(C2-C10)alkyl-NH2, -(C2-C10)alkyl- NH(C1-C3)alkyl and -(C2-C10)alkyl-N((C1-C3)alkyl)2; and o is an integer ranging from 1 to 100. 22. The antibody drug conjugate (ADC) according to claim 21, wherein KF is H. 23. The antibody drug conjugate (ADC) according claim 21 or 22, wherein o ranges from 8 to 30. 24. The antibody drug conjugate (ADC) according to claim 23, wherein o ranges from 20 to 28. 25. The antibody drug conjugate (ADC) according to claim 24, wherein o is 22, 23, 24, 25 or 26. 26. The antibody drug conjugate (ADC) according to claim 23, wherein o ranges from 8 to 16. 27. The antibody drug conjugate (ADC) according to claim 26, wherein o is 10, 11, 12, 13 or 14. 28. The antibody drug conjugate (ADC) according to any one of claims 12 to 27, wherein the cytotoxic moiety CM is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. 29. The antibody drug conjugate (ADC) according to claim 28, wherein the cytotoxic moiety CM is a camptothecin moiety. 30. The antibody drug conjugate (ADC) according to claim 29, wherein the camptothecin moiety is selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan, and gimatecan. 31. The antibody drug conjugate (ADC) according to claim 30, wherein the cytotoxic moiety CM is exatecan having the formula: NH2 O N F N O HO O . 32. The antibody drug conjugate (ADC) according to claim 31, wherein the cytotoxic moiety CM is exatecan having the formula: O O . 33. The antibody drug conjugate (ADC) according to claim 31 or 32, wherein the exatecan is bound to the connector unit CU via the amino group. 34. The antibody drug conjugate (ADC) according to any one of claims 28 to 33, wherein: Ab is an anti-NaPi2b antibody as defined in any one of the preceding claims; is a double bond; or V is absent when is a double bond; or V is H when is a bond; X is R3 C when is a double bond; or R4 X is R3 C when is a bond; Y is NH; R1 is a polyethylene glycol unit having the structure: KF o , wherein: indicates the position of the O; KF is H; and o is an integer ranging from 8 to 30; R3 is H; R4 is H; CU is a connector unit having the following structure: * H 2 , wherein # indicates the attachment point to the Y and * indicates the attachment point to the camptothecin moiety (CM); CM is a camptothecin moiety; m is 1; and n is an integer ranging from 1 to 10. 35. The antibody drug conjugate (ADC) according to claim 34, wherein is a double bond; V is absent; X is R3 C ; and R3 is H. 36. The antibody drug conjugate (ADC) according to claim 34 or 35, wherein the camptothecin moiety CM is exatecan having the formula: O O . 37. The antibody drug conjugate (ADC) according to claim 36, wherein the exatecan is bound to the connector unit CU via the amino group. 38. The antibody drug conjugate (ADC) according to claim 37, wherein o ranges from 20 to 28. 39. The antibody drug conjugate (ADC) according to claim 38, wherein o is 22, 23, 24, 25 or 26. 40. The antibody drug conjugate (ADC) according to any one of claims 34 to 39, wherein n ranges from 2 to 10, preferably wherein n is 4 or 8. 41. The antibody drug conjugate (ADC) according to claim 40 having the following formula (Ia): F O O O O N H H N N O N N H H Ab S P O N O N O H O O OH N NH OH 23 H O O 8 (Ia), wherein Ab is an anti-NaPi2b antibody as defined in any one of the preceding claims. 42. The antibody drug conjugate (ADC) according to claim 28, wherein the cytotoxic moiety CM is an auristatin. 43. The antibody drug conjugate (ADC) according to claim 42, wherein the cytotoxic moiety is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). 44. The antibody drug conjugate (ADC) according to claim 43, wherein the cytotoxic moiety is monomethyl auristatin E (MMAE). 45. A method of producing an antibody drug conjugate (ADC), said method comprising: conjugating the antibody according to any one of the preceding claims to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) cytotoxic moieties (e.g., cytotoxic payloads, e.g. Tubulin disrupting agents, e.g., Topoisomerase-I inhibitor/s, e.g., Auristatins or camptothecin, e.g., MMAE (monomethyl auristatin E) or MMAF (monomethyl auristatin F), e.g., Exatecan), preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. 46. The method according to claim 45, said method comprising: reacting a compound of formula (II) O X P CU Y CMm OR1 V (II), or a pharmaceutically acceptable salt or solvate thereof; wherein: is a triple bond; or is a double V is absent when is or V is H or (C1- is a double bond; X is R3 C when is a triple bond; or R4 X is R3 C when is a double bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; and m is an integer ranging from 1 to 10; with a thiol-containing molecule of formula (III) Ab SH n (III), wherein Ab is an anti-NaPi2b antibody as defined in any one of the preceding claims; and n is an integer ranging from 1 to 20; resulting in an antibody drug conjugate (ADC) of formula (I) , or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-NaPi2b as defined in any one of the preceding claims; is a double bond when in a of formula is a bond; or V is absent when is a double bond; or V is H or (C1- when is a bond; X is R3 C when is a double bond; or R4 X is R3 C when is a bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; m is an integer ranging from 1 to 10; and n is an integer ranging from 1 to 20. 47. The method according to claim 46, further comprising reducing at least one disulfide bridge of the antibody in the presence of a reducing agent to form a thiol group (SH). 48. An antibody drug conjugate (ADC) produced by the method according to any one of the preceding claims. 49. A composition or kit comprising an antibody drug conjugate (ADC) according to any one of the preceding claims. 50. The composition according to any one of the preceding claims, wherein said composition is a pharmaceutical and/or diagnostic composition. 51. A method for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non- small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer and fallopian tube cancer, said method comprising: administering a therapeutically or prophylactically effective amount of the antibody drug conjugate (ADC), composition or kit according to any one of the preceding claims. 52. The antibody drug conjugate (ADC), composition or kit according to any one of the preceding claims, for use as a medicament and/or in therapy. 53. The antibody drug conjugate (ADC), composition or kit according to any one of the preceding claims, for use in one or more of the following methods: (a) method for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non-small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer and fallopian tube cancer; (b) method for monitoring development of cancer and/or for assessing the efficacy of cancer therapy; (c) method for screening a candidate compound for anti-cancer activity; (d) method for altering resistance of cancer cells to chemotherapy; (e) method for sensitizing cancer cells to chemotherapy; (f) method for inhibiting the growth of cancer cell expressing NaPi2b; (g) method for production or preparation of an antibody; (h) method for immunizing a non-human animal; (i) method for preparation of a hybridoma; (j) method according to any one of the preceding claims; (k) method according to any one of (a)-(j), wherein said method is an in vivo, in vitro, or ex vivo method. 54. Use of the antibody drug conjugate (ADC), composition or kit according to any one of the preceding claims, for one or more of the following: (a) for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non-small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer. uterus cancer, ureter cancer, bladder cancer and fallopian tube cancer; (b) for monitoring development of cancer and/or for assessing the efficacy of cancer herapy; (c) for screening a candidate compound for anti-cancer activity; (d) for altering resistance of cancer cells to chemotherapy; (e) for sensitizing cancer cells to chemotherapy; (f) for inhibiting the growth of cancer cell expressing NaPi2b; (g) for production or preparation of an antibody; (h) for immunizing a non-human animal; (i) for preparation of a hybridoma; (j) in a method according to any one of the preceding claims; (k) use according to any one of (a)-(j), wherein said use is an in vivo, in vitro, or ex vivo use. |
. [00253] Exemplary amino acid units include, but are not limited to, units of formula (VII) where: R20 is benzyl and R21 is -(CH ) NH (Phe-Lys); R20 i 21 2 4 2 s isopropyl and R is -(CH 2 ) 4 NH 2 (Val- Lys); R20 is isopropyl and R21 is -(CH2)3NHCONH2 (Val-Cit). [00254] Useful -Ww- units can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease. In one embodiment, a -W w - unit is that whose cleavage is catalyzed by cathepsin B, C and/or D, or a plasmin protease (“tumor-associated proteases”). Preferably, the -W w - unit is cleaved by cathepsin B. Suitable linkers, which can be cleaved by a protease, are described, e.g., in G.M. Dubowchik et al., “Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates; Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity”, Bioconjugate Chem., Vol. 13, No. 4, 2002, 855-869; S.C. Jeffrey et al., “Dipeptide-based highly potent doxorubicin antibody conjugate”, Bioorg. Med. Chem. Lett. 16 (2006), 358-362; and M.S. Kung Sutherland et al., “SGN-CD33A: a novel CD33-targeting antibody- drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML”, Blood, 22 August 2013, volume 122, number 8, 1455-1463. [00255] When R19, R20 or R21 is other than hydrogen, the carbon atom to which R19, R20 or R21 is attached is chiral. Each carbon atom to which R19, R20 or R21 is attached may be independently in the (S) or (R) configuration. Preferably, each carbon atom to which R19, R20 or R21 is attached, when chiral, is in the (S) configuration. [00256] In one preferred embodiment, the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). In another preferred embodiment, the amino acid unit is valine-alanine (i.e. Val-Ala or VA). In another preferred embodiment, the amino acid unit is alanine-alanine (i.e. Ala-Ala or AA). In another preferred embodiment, the amino acid unit is phenylalanine-lysine (i.e. Phe-Lys or FK). Such connector units are illustrative examples for a connector unit which can be cleaved by a protease, such as e.g. cathepsin B. [00257] The notation of peptides used herein throughout this specification follows the conventional nomenclature. Accordingly, the N-terminus of a peptide is written on the left, and the C-terminus of the peptide is written on the right. As an illustrative but non-limiting example, in the dipeptide valine-citrulline (i.e. Val-Cit or VC), the valine has the N-terminus, and the citrulline has the C-terminus. Preferably, in any one of the embodiments described herein, when a second spacer unit (-A-) is present, the N-terminus of a peptide, such as e.g. of a dipeptide (as illustrative non-limiting example: Val-Cit), is bound to the second spacer unit (-A-), more preferably via a carbonyl group of the second spacer unit, and the C-terminus of the peptide is bound to a first spacer unit (-B-), in case a first spacer unit (-B-) is present, or to the camptothecin moiety (-C) in case a first spacer unit (-B-) is absent. [00258] In yet another embodiment, the amino acid unit is N-methylvaline-citrulline. In yet another embodiment, the amino acid unit is selected from the group consisting of 5-aminovaleric acid, homophenylalanine-lysine, tetraisoquinolinecarboxylate-lysine, cyclohexylalanine-lysine, isonepecotic acid-lysine, betaalanine-lysine, and isonepecotic acid. [00259] Preferably, the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe-Lys or FK). More preferably, the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). [00260] In some embodiments, the amino acid unit is selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine- glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). Preferably, the amino acid unit is selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine- glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). More preferably, the amino acid unit is valine-glutamine (i.e. Val-Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). Connector units which comprise amino acid units according to these embodiments can be illustrative examples for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). The amino acid unjts of these embodiments and further suitable amino acid units are disclosed, e.g., in Salomon et al., “Optimizing Lysosomal Activation of Antibody-Drug Conjugates (ADCs) by Incorporation of Novel Cleavable Dipeptide Linkers”, Mol. Pharmaceutics 2019, 16, 12, 4817–4825. [00261] The first spacer unit (B), when present, may link an amino acid unit (Ww) to the cytotoxic moiety when an amino acid unit is present. Alternatively, the first spacer unit (B) may link the second spacer unit (A) to the cytotoxic moiety (CM) when the amino acid unit is absent. The first spacer unit may link the cytotoxic moiety to the Y when both the amino acid unit and second spacer unit are absent. [00262] The integer b may be 0 or 1. In preferred embodiments, the integer b is 1. Alternatively, in other embodiments, the integer b is 0, and the first spacer unit is absent. [00263] The first spacer unit (–B–) may be of two general types: self-immolative and non- self-immolative. A non-self-immolative first spacer unit is one in which part or all of the first spacer unit remains bound to the cytotoxic moiety (CM) after cleavage, particularly enzymatic, of an amino acid unit (–W w –) of the linker (L). Alternatively, an exemplary compound containing a self- immolative first spacer unit can release a cytotoxic moiety -CM without the need for a separate hydrolysis step. In an exemplary embodiment, a self-immolative first spacer unit is a PAB group that is linked to -W w - via the amino nitrogen atom of the PAB group, and connected directly to -CM via a carbonate, carbamate or ether group. Without being bound by any particular theory or mechanism, Scheme 2 depicts a possible mechanism of drug release of a PAB group which is attached directly to a drug moiety –D, via a carbamate or carbonate group espoused by Toki et al. (2002) J Org. Chem.67:1866-1872. Herein, the drug moiety D is also denoted as cytotoxic moiety CM. , wherein Q is -(C 1 -C 8 )alkyl, -O-(C 1 -C 8 )alkyl, -halogen, -nitro or -cyano; m is an integer ranging from 0 to 4, preferably m is 0, 1 or 2, more preferably m is 0 or 1, still more preferably m is 0; and p ranges from 1 to 20. [00264] Without being bound by any particular theory or mechanism, Scheme 3 depicts a possible mechanism of drug release of a PAB group which is attached directly to a drug moiety -D via an ether or amine linkage. Herein, the drug moiety D is also denoted as cytotoxic moiety CM. wherein Q is -(C 1 -C 8 )alkyl, -O-(C 1 -C 8 )alkyl, -halogen,- nitro or -cyano; m is an integer ranging from 0 to 4, preferably m is 0, 1 or 2, more preferably m is 0 or 1, still more preferably m is 0; and p ranges from 1 to 20. [00265] Other examples of self-immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group such as 2-aminoimidazol-5-methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho or para- aminobenzylacetals. Spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm, et al., J. Amer. Chem. Soc., 1972, 94, 5815) and 2-aminophenylpropionic acid amides (Amsberry, et al., J. Org. Chem., 1990, 55, 5867). Elimination of amine-containing drugs that are substituted at the alpha-position of glycine (Kingsbury, et al., J. Med. Chem., 1984, 27, 1447) are also examples of self-immolative spacer useful in exemplary compounds. [00266] In one embodiment, the first spacer unit is a branched bis(hydroxymethyl)styrene (BHMS) unit as depicted in Scheme 4, which can be used to incorporate and release multiple drugs (D). Herein, the drug moiety D is also denoted as cytotoxic moiety CM.
wherein Q is -(C 1 -C 8 )alkyl, -O-(C 1 -C 8 )alkyl, -halogen, -nitro or -cyano; m is an integer ranging from 0 to 4; preferably m is 0, 1 or 2; more preferably m is 0 or 1; still more preferably m is 0; and p ranges from 1 to 10; n is 0 or 1; and p ranges from 1 to 20. [00267] In preferred embodiments, the first spacer unit is represented by formula (X): wherein Q is -(C 1 -C 8 )alkyl, -O-(C 1 -C 8 )alkyl, -halogen, -nitro or -cyano; and m is an integer ranging from 0 to 4; preferably m is 0, 1 or 2; more preferably m is 0 or 1; in very preferred embodiments m is 0. Preferably, when an amino acid unit is present, in formula (X), the NH group is bound to a C- terminus of the amino acid unit. Preferably, in formula (X), the C(O) group is bound to the cytotoxic moiety (CM), such as, for example, a camptothecin moiety. [00268] In very preferred embodiments, the first spacer unit is a PAB group having the following structure: H . Preferably, when an amino acid unit is present, the NH group is bound to an amino acid unit (-W w - ), more preferably to a C-terminus of the amino acid unit. Preferably, the C(O) group is bound to the cytotoxic moiety (CM), such as, for example, a camptothecin moiety. [00269] In some embodiments, the first spacer group (-B-) is a heterocyclic “self-immolating moiety” of Formulas I, II or III bound to the cytotoxic moiety and incorporates an amide group that upon hydrolysis by an intracellular protease initiates a reaction that ultimately cleaves the first spacer unit (-B-) from the cytotoxic moiety such that the cytotoxic moiety is released from the conjugate in an active form. The connector unit further comprises an amino acid unit (-W w -) adjacent to the first spacer group (-B-) that is a substrate for an intracellular enzyme, for example an intracellular protease such as a cathepsin (e.g., cathepsin B), that cleaves the peptide at the amide bond shared with the first spacer group (-B-). Heterocyclic self-immolating moieties are described, e.g., in WO 2019/236954. [00270] In some embodiments, the first spacer unit (-B-) is a heterocyclic self-immolating group selected from Formulas I, II and III: I , wherein the wavy lines indicate the covalent attachment sites to the amino acid unit -W w - and the cytotoxic moiety CM, and wherein U is O, S or NR6; Q is CR4 or N; V1 , V2 and V3 are independently CR4 or N provided that for formula II and III at least one of Q, V1 and V2 is N; T may be O pending from a cytotoxic moiety (-CM); R1 , R2 , R3 and R4 are independently selected from the group consisting of H, F, Cl, Br, I, OH, -N(R5) 5 + 2, -N(R ) 3 , -(C 1 -C 8 )alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, -SO R5, -S(=O)R5, -SR5, -SO N(R5) , -C( 5 5 5 2 2 2 =O)R , -CO 2 R , -C(=O)N(R ) 2 , -CN, - N 3 , -NO 2 , -(C 1 -C 8 )alkoxy, -(C 1 -C 8 )halosubstituted alkyl, polyethyleneoxy, phosphonate, phosphate, -(C 1 -C 8 )alkyl, -(C 1 -C 8 )substituted alkyl, -(C 2 -C 8 )alkenyl, -(C 2 -C 8 )substituted alkenyl, -(C 2 -C 8 )alkynyl, -(C 2 -C 8 )substituted alkynyl, -(C 6 -C 20 )aryl, -(C 6 -C 20 )substituted aryl, -(C 3 -C 20 )heterocycle, and -(C 3 - C )substituted heterocycle; 2 3 20 or when taken together, R and R form a carbonyl (=O), or spiro carbocyclic ring of 3 to 7 carbon atoms; and R5 and R6 are independently selected from H, -(C1- C 8 )alkyl, -(C 1 -C 8 )substituted alkyl, -(C 2 -C 8 )alkenyl, -(C 2 -C 8 )substituted alkenyl, -(C 2 -C 8 )alkynyl, -(C 2 - C8)substituted alkynyl, -(C6-C20)aryl, -(C6-C20)substituted aryl, -(C3-C20)heterocycle, and -(C3- C20)substituted heterocycle; wherein -(C1-C8)substituted alkyl, -(C2-C8) substituted alkenyl, -(C2- C 8 )substituted alkynyl, -(C 6 -C 20 )substituted aryl, and -(C 3 -C 20 )substituted heterocycle are independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, -N(R5) 2 , -N(R5) + 3 , -(C 1 -C 8 )alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, -(C 1 - C 8 )alkylsulfonate, -(C 1 -C 8 )alkylamino, 4-dialkylaminopyridinium, -(C 1 -C 8 )alkylhydroxyl, -(C 1 - C 8 )alkylthiol, -SO 2 R5, -S(=O)R5, -SR5, -SO 2 N(R5) 2 , -C(=O)R5, -CO 2 R5, -C(=O)N(R5) 2 , -CN, -N 3 , - NO 2 , -(C 1 -C 8 )alkoxy, -(C 1 -C 8 )trifluoroalkyl, -(C 1 -C 8 )alkyl, -(C 3 -C 12 )carbocycle, -(C 6 -C 20 )aryl, -(C 3 - C 20 )heterocycle, polyethyleneoxy, phosphonate, and phosphate. [00271] The antibody drug conjugate (ADC) comprising a heterocyclic self-immolative moiety is stable extracellularly, or in the absence of an enzyme capable of cleaving the amide bond of the self-immolative moiety. However, upon entry into a cell, or exposure to a suitable enzyme, an amide bond is cleaved initiating a spontaneous self-immolative reaction resulting in the cleavage of the bond covalently linking the self-immolative moiety to the camptothecin moiety, to thereby effect release of the drug in its underivatized or pharmacologically active form. [00272] The self-immolative moiety in conjugates either incorporates one or more heteroatoms and thereby may provide improved solubility, may improve the rate of cleavage and/or may decrease propensity for aggregation of the antibody drug conjugate (ADC). Thus, the heterocyclic self-immolative connector unit constructs in some instances may result in increased efficacy, decreased toxicity, and/or desirable pharmacokinetic and/or pharmacodynamic properties. [00273] When the cytotoxic moiety CM is a camptothecin moiety, it is understood that T in formulae I-III may be for example O, as it can be derived from the tertiary hydroxyl (-OH) on the lactone ring portion of a camptothecin moiety. When the cytotoxic moiety CM is a camptothecin moiety, it is also possible that T in formulae I-III may be for example NH, as it can be be derived from an amino group (-NH 2 ) of a camptothecin moiety, e.g. of exatecan. [00274] Not to be limited by theory or any particular mechanism, the presence of electron- withdrawing groups on the heterocyclic ring of formula I, II or III may moderate the rate of cleavage. [00275] In one embodiment, the self-immolative moiety is the group of formula I in which Q is N, and U is O or S. Such a group has a non-linearity structural feature which improves solubility of the conjugates. In this context R is sometimes H, methyl, nitro, or CF 3 . In one embodiment, Q is N and U is O thereby forming an oxazole ring and R is H. In another embodiment, Q is N and U is S thereby forming a thiazole ring optionally substituted at R with an Me or CF3 group. [00276] In another exemplary embodiment, the self-immolative moiety is the group of formula II in which Q is N and V1 and V2 are independently N or CH. In another embodiment, Q, V1 and V2 are each N. In another embodiment, Q and V1 are N while V2 is CH. In another embodiment, Q and V2 are N while V1 is CH. In another embodiment, Q and V1 are both CH and V2 is N. In another embodiment, Q is N while V1 and V2 are both CH. [00277] In another embodiment, the self-immolative moiety is the group of formula III in which Q, V1 , V2 and V3 are each independently N or CH. In another embodiment Q is N while V1 , V2 and V3 are each N. In another embodiment, Q, V1 , and V2 are each CH while V3 is N. In another embodiment Q, V2 and V3 are each CH while V1 is N. In another embodiment, Q, V1 and V3 are each CH while V2 is N. In another embodiment, Q and V2 are both N while V1 and V3 are both CH. In another embodiment Q and V2 are both CH while V1 and V3 are both N. In another embodiment, Q and V3 are both N while V1 and V2 are both CH. [00278] Preferably, the connector unit (CU) has the formula: *–A ## a–W w –B b – , wherein the integer a is 1, the integer b is 1, and the integer w is 2, 3 or 4, more preferably the integer w is 2 or 3; in very preferred embodiments the integer w is 2; and -A-, each -W- and -B- are as defined herein; * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (CM). [00279] Preferably, the connector unit (CU) has the following structure: *–A ## a–W w –B b – , wherein -A- is a second spacer unit as described herein; a is an integer as described herein; preferably a is 1; -B- is a first spacer unit as described herein; b is an integer as described herein; preferably b is 1; * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM); -W w - is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine- alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe- Lys or FK). Preferably, in these embodiments the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). Alternatively, in these embodiments, the amino acid unit -W w - may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine-glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). In these embodiments, the amino acid unit may be a dipeptide selected from the group consisting of valine- glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). In these embodiments, the amino acid unit may be valine-glutamine (i.e. Val- Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). Connector units (CU) according to these embodiments can be illustrative examples for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00280] ## O , wherein -A- is a second spacer unit as described herein; a is an integer as described herein; preferably a is 1; -W w - is an amino acid unit as described herein; w is an integer as described herein; preferably w is 2, 3 or 4 (i.e. preferably -W w - is a dipeptide, a tripeptide or a tetrapeptide), more preferably w is 2 or 3 (i.e. more preferably -W w - is a dipeptide or a tripeptide), e.g. w may be 1 or 2; in very preferred embodiments w is 2 (i.e. still more preferably -W w - is a dipeptide); Q is as defined herein; m is an integer as defined herein, preferably m is 0; * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Preferably, in these embodiments, the amino acid unit -W w - is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe-Lys or FK). More preferably, in these embodiments the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). Alternatively, in these embodiments, the amino acid unit -W w - may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine- glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). In these embodiments, the amino acid unit may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). In these embodiments, the amino acid unit may be valine-glutamine (i.e. Val-Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). Connector units (CU) according to these embodiments can be illustrative examples for a connector unit (CU) which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00281] More preferably, the connector unit CU has the following structure: O H N Q m W w * O ## O , is as defined herein; * denotes the attachment point to the Y; and # denotes the attachment point to the amino acid unit -W w -, when present, or to the NH group; -W w - is an amino acid unit as described herein; w is an integer as described herein, preferably w is 2, 3 or 4 (i.e. preferably -W w - is a dipeptide, a tripeptide or a tetrapeptide), more preferably w is 2 or 3 (i.e. more preferably -W w - is a dipeptide or a tripeptide), in very preferred embodiments w is 2 (i.e. still more preferably -W w - is a dipeptide); Q is as defined herein; m is an integer as defined herein, preferably m is 0; * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Preferably, in these embodiments, the amino acid unit -W w - is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe-Lys or FK). More preferably, in these embodiments the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). Alternatively, in these embodiments, the amino acid unit -W w - may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine- glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). In these embodiments, the amino acid unit may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). In these embodiments, the amino acid unit may be valine-glutamine (i.e. Val-Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). Connector units (CU) according to these embodiments can be illustrative examples for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00282] Still more preferably, the connector unit CU has the following structure: ## O , wherein: -W w - is an amino acid unit as described herein; w is an integer as described herein, preferably w is 2, 3 or 4 (i.e. preferably -W w - is a dipeptide, a tripeptide or a tetrapeptide), more preferably w is 2 or 3 (i.e. more preferably -W w - is a dipeptide or a tripeptide), in very preferred embodiments w is 2 (i.e. still more preferably -W w - is a dipeptide); * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Preferably, in these embodiments, the amino acid unit -W w - is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe-Lys or FK). More preferably, in these embodiments the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). Alternatively, in these embodiments, the amino acid unit -W w - may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine- glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). In these embodiments, the amino acid unit may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). In these embodiments, the amino acid unit may be valine-glutamine (i.e. Val-Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). Connector units (CU) according to these embodiments can be illustrative examples for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00283] In a preferred embodiment, the connector unit CU has the following structure: O O O O ## H N N N H H O O * N NH H 2 , which comprises the dipeptide valine-citrullin as the amino acid unit -W w -; and wherein * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Such connector unit is an illustrative example for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00284] In another preferred embodiment, the connector unit CU has the following structure: ## * , which comprises the dipeptide valine-alanine as the amino acid unit -W w -; and wherein * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Such connector unit (CU) is an illustrative example for a connector unit which is cleavable, in particular by a protease, such as e.g. a cathepsin (e.g., cathepsin B). [00285] The connector unit CU may have the following structure: ## , wherein: O # * is as defined herein; * denotes the attachment point to the Y; and # denotes the attachment point to the amino acid unit -W w -; -W w - is an amino acid unit as described herein; w is an integer as described herein, preferably w is 2, 3 or 4 (i.e. preferably -W w - is a dipeptide, a tripeptide or a tetrapeptide), more preferably the integer w is 2 or 3 (i.e. more preferably -W w - is a dipeptide or a tripeptide), still more preferably w is 2 (i.e. still more preferably -W w - is a dipeptide); * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). Preferably, in these embodiments, the amino acid unit -W w - is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), alanine-alanine (i.e. Ala-Ala or AA) and phenylalanine-lysine (i.e. Phe-Lys or FK). More preferably, in these embodiments the amino acid unit is a dipeptide selected from the group consisting of valine-citrulline (i.e. Val-Cit or VC), valine-alanine (i.e. Val-Ala or VA), and phenylalanine-lysine (i.e. Phe-Lys or FK). Still more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC) or valine-alanine (i.e. Val-Ala or VA). Even more preferably, in these embodiments the amino acid unit is valine-citrulline (i.e. Val-Cit or VC). Alternatively, in these embodiments, the amino acid unit -W w - may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), phenylalanine- glutamin (i.e. Phe-Gln or FQ) and threonine-threonine (i.e. Thr-Thr or TT). In these embodiments, the amino acid unit may be a dipeptide selected from the group consisting of valine-glutamine (i.e. Val-Gln or VQ), leucine-glutamine (i.e. Leu-Gln or LQ), and phenylalanine-glutamin (i.e. Phe-Gln or FQ). In these embodiments, the amino acid unit may be valine-glutamine (i.e. Val-Gln or VQ) or leucine-glutamine (i.e. Leu-Gln or LQ). [00286] In some embodiments, the connector unit CU may have the following structure: ## H NH 2 , which comprises the dipeptide valine-citrulline as the amino acid unit -W w -; and wherein * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). [00287] In some embodiments, the connector unit CU may have the following structure: ## * , which comprises the dipeptide valine-alanine as the amino acid unit -W w -; and wherein * denotes the attachment point to the Y; and ## denotes the attachment point to the cytotoxic moiety (-CM). [00288] The connector unit (-CU-) may have the following structure: # , is as defined herein; * denotes the attachment point to the Y; and # denotes the attachment point to the cytotoxic moiety (-CM). [00289] In some embodiments, the connector unit CU may have the following structure: # * wherein * denotes the attachment point to the Y; and # denotes the attachment point to the cytotoxic moiety (-CM). Cytotoxic Moiety (-CM) [00290] The present disclosure provides antibody drug conjugates (ADCs) comprising a cytotoxic moiety. The term “cytotoxic moiety”, “drug”, “drug moiety”, “payload” or “cytotoxic payload”, both of which can be used interchangeably, as used herein refers to a chemical or biochemical moiety that is conjugated to an anti-NaPi2b antibody (Ab), or antigen binding fragment thereof. In this regard, it is again referred to the antibody drug conjugate (ADC) of formula (I) described herein. The antibody (Ab) can be conjugated to several identical or different cytotoxic moieties using any methods described herein or known in the art. In some embodiments, the cytotoxic moiety may be a molecule which has a cytotoxic effect on mammalian cells, may lead to apoptosis, and/or may have a modulating effect on malignant cells. The cyototoxic moiety may be hydrophobic. [00291] In some preferred embodiments the cytotoxic moiety is an anti-cancer agent. Accordingly, the cyototoxic moiety may be selected from the group consisting of camptothecins, maytansinoids, calicheamycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. Camptothecin Moiety [00292] Preferably, the cytotoxic moiety CM is a camptothecin moiety. The term “camptothecin moiety” includes camptothecin itself and analogues of camptothecin. Camptothecin is a topoisomerase poison, which was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. Camptothecin was isolated from the bark and stem of Camptotheca acuminata (Camptotheca, Happy tree), a tree native to China used as a cancer treatment in Traditional Chinese Medicine. Camptothecin has the following structure: . The term „campthothecin moiety“ also comprises camptothecin analogoues. In this regard, the term “camptothecin moiety” denotes any moiety which comprises the structure of camptothecin: , and which may be optionally substituted. The optional substituents may include, as illustrative non- limiting examples, (C 1 -C 10 )alkyl, (C 3 -C 8 )carbocyclo, (C 3 -C 8 )heterocyclo, aryl, an amino group, a hydroxy group, a carbonyl group, an amide group, an ester group, a carbamate group, a carbonate group and/or a silyl group. The camptothecin moiety may have one or more functional group(s) which are capable to form a bond to the linker L. A person skilled in the will readily select a suitable camptothecin moiety having a desired biological activity. Camptothecin analogues have been approved and are used in cancer chemotherapy today, such as e.g. topotecan, irinotecan, or belotecan. [00293] The following camptothecin analogues are also envisioned by the term m t th in m i t : 4 H H H H F H H H Further camptothecin analogues, which may be used as camptothecin moiety, are described in WO 2019/236954 and EP 0495432. [00294] In some embodiments, the camptothecin moiety (CM) is selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan and gimatecan. Preferably, the camptothecin moiety is selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan and belotecan. SN38 has the following structure: ; and the structures of exatecan, camptothecin, topotecan, irinotecan and belotecan are as described herein. [00295] More preferably, in any one of the embodiments described herein, the camptothecin moiety CM is exatecan having the following structure: NH 2 O N F N O HO O . Still more preferably, the camptothecin moiety (CM) is exatecan having the following structure: O O . Preferably, in any one of these embodiments the exatecan is bound to the connector unit CU via the amino group (i.e., via the NH 2 group of exatecan). When the exatecan is bound to the connector unit CU via the amino group, one hydrogen atom of the amino group of exatecan is replaced by the connector unit CU. Accordingly, exatecan bound to the connector unit CU via the amino group can be depicted, e.g., as follows: or , wherein # indicates the attachment point to the connector unit CU. [00296] In some aspects/embodiments the present invention also relates to a conjugate having the formula (I): , or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-NaPi2b antibody as described herein; is a double bond; or V is absent when is a double bond; or V is H when is a bond; X R 3 C when is a double bond; or R 4 X is C when is a bond; Y is NH; R1 is a polyethylene glycol unit having the structure: K F o , wherein: indicates the position of the O; KF is as defined herein; preferably KF is H; and o is an integer as defined herein; preferably o is an integer ranging from 8 to 30; more preferably from 16 to 30; still more preferably from 20 to 28; still more preferably, o is 22, 23, 24, 25 or 26; still more preferably, o is 23, 24 or 25; even more preferably o is 24; R3 is H; R4 is H; CU is a connector unit having the following structure: * H 2 , wherein # indicates the attachment point to the Y and * indicates the attachment point to the camptothecin moiety (CM); CM is a camptothecin moiety; m is 1; and n is an integer as defined herein; preferably n is an integer ranging from 1 to 10; more preferably from 2 to 10; still more preferably from 4 to 10; still more preferably from 6 to 10, still more preferably from 7 to 10, even more preferably n is 8; or preferably n is an integer ranging from 1 to 10, more preferably from 2 to 8, still more preferably from 3 to 6, still more preferably n is 4 or 5, even more preferably n is 4. Preferably, is a double bond; V is absent; X is R 3 C ; and R3 is H. R 4 In some embodiments, may be a bond; V may be H; X may be R 3 C ; R3 may be H; and R4 may be H. Preferably, the camptothecin moiety CM is exatecan having the following structure: O O . More preferably, the camptothecin moiety is exatecan having the following structure: O O . Preferably, in any one of these embodiments the exatecan is bound to the connector unit CU via the amino group. [00297] In some aspects/embodiments the present invention also relates to an antibody drug conjugate (ADC) having the following formula (Ia): F O O O O N H H N N O N N H H Ab S P O N O N O H O O 23 OH N NH H 2 OH O O n (Ia) wherein: Ab is an anti-NaPi2b antibody as described herein; and n is an integer a defined herein; preferably n is an integer ranging from 1 to 10; more preferably from 2 to 10; still more preferably from 4 to 10; still more preferably from 6 to 10, still more preferably from 7 to 10, even more preferably n is 8; or preferably n is an integer ranging from 1 to 10, more preferably from 2 to 8, still more preferably from 3 to 6, still more preferably n is 4 or 5, even more preferably n is 4. Auristatins [00298] In some embodiments the cytotoxic moiety CM is an auristatin. Preferably, the auristatin is monomethyl auristatin F (MMAF) or monomethyl auristatin E (MMAE). More preferably, the auristatin is monomethyl auristatin E (MMAE). [00299] In some embodiments the cytotoxic moiety CM is monomethyl auristatin F (also known as MMAF). MMAF is represented by the following structural formula: Preferably, MMAF is bound to the connector unit CU via the N terminus indicated with an asterisk (“*”). Accordingly, when MMAF is bound to the connector unit CU via the N terminus, the hydrogen atom of the N terminus of MMAF is replaced by the connector unit CU. [00300] In some embodiments the auristatin drug moiety is monomethyl auristatin E (also known as MMAE). Preferably, MMAE is bound to the connector unit CU via the N terminus indicated with an asterisk (“*”). Accordingly, when MMAE is bound to the connector unit CU via the N terminus, the hydrogen atom of the N terminus of MMAE is replaced by the connector unit CU. [00301] These molecules noncompetitively inhibit binding of vincristine to tubulin (at a location known as the vinca/peptide region) but have been shown to bind to the RZX/MAY region. Compounds of Formula (II) [00302] In some aspects/embodiments the present invention also relates to a compound having the formula (II): , or a pharmaceutically acceptable salt or solvate thereof, wherein: or is a double bond; V is absent when is a triple bond; or V is H or (C 1 - is a double bond; X R 3 C a triple bond; or X is when is a double bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue CU is a connector unit; CM is a cytotoxic moiety; and m is an integer ranging from 1 to 10. [00303] Preferably R3 is H or (C 1 -C 8 )alkyl; more preferably R3 is H. Preferably R4 , when present, is H or (C -C )alkyl; more preferably R4 , when present, i 5 1 8 s H. Preferably R , when present is H or (C -C )alkyl; more preferabl 5 6 1 8 y R , when present, is H. Preferably R , when present is H or (C 1 -C 8 )alkyl; more preferably R6, when present, is H. Preferably R7 , when present is H or (C 1 - C 8 )alkyl; more when present, is H. [00304] Preferably, is a triple bond; V is absent; X is R 3 C ; and R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R3 is H or (C 1 - C )al 3 8 kyl; more preferably R [00305] More preferably, represents a triple bond; V is absent; X represents R 3 C , and R 3 represents H or (C 1 -C 8 )alkyl. Preferably, R 3 represents H or (C 1 -C 6 )alkyl, more preferably H or (C 1 -C 4 )alkyl, still more preferably H or alkyl. Even more preferably, R 3 is H. [00306] In some embodiments, may be a double bond; V is H or (C 1 -C 8 )alkyl, R 4 preferably V is H; X is R 3 C ; R 3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; more preferably R3 is H or (C 3 4 1-C 8 )alkyl, more preferably R is H; R is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably, R4 is H or (C -C )alkyl, 4 1 8 R is H. [00307] In some embodiments, may represent a double bond; V may be H or (C 1 - R 4 C 8 )alkyl; X may represent R 3 C ; and R 3 and R 4 may independently represent H or (C 1 -C 8 )alkyl. Preferably, R3 and R4 independently represent H or (C1-C6)alkyl, more preferably H or (C1-C4)alkyl, still more preferably H or (C1-C2)alkyl. Preferably, R3 and R4 are the same; even more preferably, R 3 , R 4 and V are the same. More preferably, R 3 and R 4 are both H. Preferably, V is H or (C 1 - C 6 )alkyl, more preferably H or (C 1 -C 4 )alkyl, still more preferably H or (C 1 -C 2 )alkyl. Even more preferably, V is H. In preferred embodiments, R 3 , R 4 and V are each H. [00308] In any one of the compounds of formula (II), any variable may be defined as described herein, in particular as with regard to the antibody drug (ADCs) of formula (I) and/or the thiol-containing molecule of formula (III). Accordingly, , V, X, Y, R1 , R3, R4 , R5, R6, R7 , CU, CM, m and n may be as defined herein. Preferably, Y is NH. Method of Preparing an Antibody Drug Conjugate (ADC) [00309] In some aspects/embodiments the present invention relates to a method of synthesis of the antibody drug conjugates (ADCs) of the present invention. [00310] In some aspects/embodiments the present invention also relates to a method of preparing an antibody conjugate (ADC) of formula (I), said method comprising: reacting a compound of formula (II) , or a pharmaceutically acceptable salt or solvate thereof, wherein: is a triple bond; or is a double V is absent when is or V is H or (C 1 - is a double bond; X is R 3 C when is a triple bond; or R 4 X is R 3 C when is a double bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; and m is an integer ranging from 1 to 10; with a thiol-containing molecule of formula (III) , wherein Ab is an anti-NaPi2b antibody as described herein; and n is an integer ranging from 1 to 20; resulting in an antibody drug conjugate (ADC) of formula (I) (I) or a pharmaceutically acceptable salt or solvate therein; wherein: Ab is an anti-NaPi2b as described herein; is a double bond when in a compound of formula (II) is a triple bond; or is a bond when in a compound of formula (II) is a double bond; V is absent when is a double bond; or V is H or (C 1 - when is a bond; X is R 3 C when is a double bond; or R 4 X is R 3 C when is a bond; Y is NH, S, O, or CH 2 ; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic or optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; m is an integer ranging from 1 to 10; and n is an integer ranging from 1 to 20. [00311] Preferably R3 is H or (C 3 4 1-C 8 )alkyl; more preferably R is H. Preferably R , when present, is H or (C -C )alkyl; more preferably R4 , when pr 5 1 8 esent, is H. Preferably R , when present is H or (C -C )alkyl; more preferably R5, when present, is H. Preferably R6 1 8 , when present is H or (C -C 8 )alkyl; more preferably R6, 7 1 when present, is H. Preferably R , when present is H or (C 1 - C 8 )alkyl; more when present, is H. [00312] Preferably, is a triple bond; V is absent; X is R 3 C ; and R3 is H or an optionally substituted aliphatic residue or an substituted aromatic residue; preferably R3 is H or (C 1 - C )alkyl; m 3 8 ore preferably R represents a double bond. [00313] More preferably, represents a triple bond; V is absent; X represents R 3 C , R 3 represents H or (C 1 -C 8 )alkyl; and represents a double bond. Preferably, R 3 represents H or (C 1 -C 6 )alkyl, more preferably H or (C 1 -C 4 )alkyl, still more preferably H or (C 1 -C 2 )alkyl. Even more preferably, R 3 is H. [00314] In some embodiments, may be a double bond; V is H or (C 1 -C 8 )alkyl, R 4 preferably V is H; X is R 3 C ; R 3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; and may represent a bond; more preferably R3 is H or (C 1 - C )alkyl, more preferably 3 4 8 R is H; R is H or an optionally substituted aliphatic residue or an optionally substituted aromatic R4 is H or (C 4 1-C 8 )alkyl, preferably R is H. [00315] In some embodiments, may represent a double bond; V may be H or (C 1 - R 4 alkyl; X may represent R 3 C ; R 3 and R 4 may independently represent H or (C 1 -C 8 )alkyl; and may represents a bond. Preferably, R 3 and R 4 independently represent H or C 1 -C 6 -alkyl, more preferably H or C 1 -C 4 -alkyl, still more preferably H or C 1 -C 2 -alkyl. Preferably, R 3 and R 4 are the same; even more preferably, R 3 , R 4 and V are the same. More preferably, R 3 and R 4 are both H. Preferably, V is H or C 1 -C 6 -alkyl, more preferably H or C 1 -C 4 -alkyl, still more preferably H or C 1 - C 2 -alkyl. Even more preferably, V is H. In embodiments, R 3 , R 4 and V are each H. [00316] With regard to the representations and used herein, it is noted that, as a person skilled in the art, each carbon atom is tetravalent. Accordingly, a * structure , wherein X and V are as defined herein and the asterisk indicates attachment to the phosphorus, includes the , * R 3 , R 4 and V are as defined herein. A structure , wherein X and V are as defined herein, the asterisk (*) indicates attachment to the phosphorus * to the receptor binding molecule (RBM), includes the structures and R 3 R4 * H # S V , wherein R 3 , R 4 and V are as defined herein, and H is hydrogen. A wavy bond indicates that the configuration of the double bond may be E or Z. It is also possible that the compound is present as a mixture of the E and Z isomers. [00317] When the anti-NaPi2b antibody (Ab) comprises one or more disulfide bridges, the method may further comprise reducing at least one disulfide bridge of the antibody in the presence of a reducing agent to form a thiol group (SH). The resulting compound of formula (III) may then be reacted with a compound of formula (II) to yield an antibody drug conjugate (ADC) of formula (I). The reducing agent may be selected from the group consisting of tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), sodium dithionite, sodium thiosulfate, and sodium sulfite. Accordingly, the reducing agent may be dithiothreitol (DTT). The reducing agent may be sodium dithionite. The reducing agent may be sodium sulfite. Preferably, the reducing agent is tris(2- carboxyethyl)phosphine (TCEP). [00318] Preferably, the reducing of at least one disulfide bridge comprises using about 1 to about 3 equivalents, preferably about 1 to about 2 equivalents, more preferably about 1 equivalent of the reducing agent per 1 disulfide bridge to be reduced. In this context, it is noted that in theory 1 eq. of the reducing agent, in particular of a reducing agent as described herein, is necessary to reduce 1 disulfide bridge to give 2 thiol groups (SH). [00319] Preferably, the thiol-containing molecule of formula (III) is reacted with about 1 to about 4 equivalents, preferably about 1 to about 3 equivalents, more preferably about 1 to about 2 equivalents, still more preferably about 1 to about 1.5 equivalents of the compound of formula (II) per thiol group (SH). [00320] Preferably, the reaction of a compound of formula (II) with a thiol-containing molecule of formula (III) is carried out in an aqueous medium. [00321] Preferably, the reaction of the compound of formula (II) with the thiol-containing molecule of formula (III) is performed under neutral pH or slightly basic conditions. Still more preferably the reaction is performed at a pH of from 6 to 10. Even more preferably, the reaction is performed at a pH of from 7 to 9. [00322] In any one of the methods, any variable may be defined as described herein, in particular as with regard to the conjugates (ADCs) of formula (I) and/or the compound of formula (II). Accordingly, , , V, X, Y, R1 , R3, R4 , R5, R6, R7 , CU, CM, m and n may be as defined herein. Preferably, Y is NH. [00323] Methods of preparing compounds of formula (II) are known in the art. As illustrative examples, compounds of formula (II), wherein the group Y is NH, may be prepared by using techniques and conditions, e.g. a Staudinger phosphonite reaction, as e.g. described in WO 2018/041985 A1, which is hereby incorporated by reference. Compounds of formula (II), wherein Y is S or O, may be prepared by using techniques and conditions as e.g. described in WO 2019/170710, which is hereby incorporated by reference. In an analogous manner to the compounds of formula (II), wherein Y is S or O, as described in WO 2019/170710, compounds of formula (II), wherein Y is CR6R7 , may be prepared, as illustrative examples, by substitution at the phosphorus atom using, e.g., a suitable organometallic compound, such as e.g. a Grignard compound or an organolithium compound. A person skilled in the art readily selects suitable methods and conditions to prepare compounds of formula (II). The Examples section of the present disclosure also comprises guidance on how to prepare or obtain compounds of formula (II) and/or antibody drug conjugates (ADCs) of formula (I). [00324] The present invention also relates to an antibody drug conjugate of formula (I) obtainable or being obtained by any method of preparing an antibody drug conjugate of formula (I) as described herein. [00325] In some aspects/embodiments the present invention relates to cancer. Cancer can be any cancer. Preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non-small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer and fallopian tube cancer. [00326] In some aspects/embodiments the present invention relates to a composition or kit comprising the anti-NaPi2b, antibody drug conjugate (ADC), hybridoma, nucleic acid, expression vector and/or host cell of the present invention. [00327] In some aspects/embodiments the present invention relates to methods of treatment (e.g., of a patient) and uses of the antibody, antibody drug conjugate (ADC), nucleic acid, expression vector, host cell, composition and/or kit of the present invention. [00328] In some aspects of the present invention, the antibody of the present invention is expressed as an Fc-silenced (LALA mutation) IgG1 in CHO cells, purified via Protein A chromatography. [00329] The present invention further relates to the following items: 1. An anti-NaPi2b antibody (e.g., an antibody against NPT2B_HUMAN Sodium-dependent phosphate transport protein 2B, e.g., having UniProt Accession Number: O95436 or SEQ ID NO: 1 and/or an antibody against NPT2B_RAT Sodium-dependent phosphate transport protein 2B, e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2), wherein said NaPi2b antibody is capable of the following: a) binding to said human Napi2b (e.g., SEQ ID NO: 1) and/or rat Napi2b (e.g., SEQ ID NO: 2), preferably said binding to said human and rat Napi2b having about the same K D , further preferably said antibody is selected from the group consisting of: AV-25, AV-15, AV-18, AV-21 and AV-29 antibody), further most preferably said about same K D having up to 50% difference (e.g., up to 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 7%, 5%, 4%, 3%, 2% or 1% difference); b) cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2), preferably said cross-reactivity is improved (e.g., by at least 10%) compared to corresponding cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2) of the parental antibody (e.g., comprising SEQ ID NOs 54 and 55, e.g., as shown in Figure 1), further preferably the cross-reactivity with rat Napi2b is measured with endogenous rat Napi2b, most preferably said endogenous Napi2b is located on the cell surface. c) cross-reactivity with cynomolgus monkey (e.g., Macaca fascicularis) Napi2b (e.g., having UniProtKB Accession Number: A0A2K5UHY1 or SEQ ID NO: 3; d) internalization, preferably by the means of the antigen-mediated antibody internalization; further preferably said internalization is improved (e.g., by at least 10%, e.g., 15%) compared to corresponding internalization of the parental antibody (e.g., comprising SEQ ID NOs 54 and 55, e.g., as shown in Figure 1); f) optionally, not having a dipeptide deamidation site in a heavy chain variable region’s (V H ) CDR2, preferably said absent dipeptide deamidation site is NG (Asn-Gly) in V H CDR2. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody not having a dipeptide deamidation site in a heavy chain variable region’s (V H ) CDR2, preferably said absent dipeptide deamidation site is NG (Asn-Gly) in V H CDR2, further preferably wherein the absence of said deamidation site decreases post-translational modification/s of corresponding V H CDR2 (e.g., improving homogeneity and/or simplifying the production process of said antibody). The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody having cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2), preferably said cross-reactivity is improved (e.g., by at least 10%, e.g., 15%) compared to the corresponding cross-reactivity with rat Napi2b (e.g., having UniProt Accession Number: Q9JJ09 or SEQ ID NO: 2) of the parental antibody (e.g., comprising SEQ ID NOs 54 and 55, e.g., as shown in Figure 1), further preferably wherein the cross-reactivity with rat Napi2b is measured with endogenous rat Napi2b, most preferably wherein said endogenous Napi2b is located on the cell surface. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is capable of internalization, preferably by the means of the antigen- mediated antibody internalization; further preferably said internalization is improved (e.g., by at least 10%, e.g., 15%) compared to corresponding internalization of the parental antibody (e.g., comprising SEQ ID NOs 54 and 55, e.g., as shown in Figure 1). The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is binding to said human Napi2b (e.g., SEQ ID NO: 1) and/or rat Napi2b (e.g., SEQ ID NO: 2) with an improved (e.g., by at least 10%, e.g., 15%) K D compared to corresponding K D of the parental antibody (e.g., comprising SEQ ID NOs 54 and 55, e.g., as shown in Figure 1). The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is capable of binding (e.g., specifically binding) to an extracellular domain of said NaPi2b (e.g., comprising amino acids 122-135 and/or amino acids 235-361 and/or 429- 485 and/or amino acids 547-552 of the human Napi2b having SEQ ID NO: 1). The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody has one or more of the following characteristics: a) having KD to an endogenously expressed human Napi2b in the range from about 0.01 to about 10 nmol/L, preferably in the range from about 1 to about 10 nmol/L, further preferably from about 1 to about 7 nmol/L, further preferably from about 1 to about 4 nmol/L (e.g., in OVCAR-3 cells (e.g., HTB-161#, ATCC) endogenously expressing Napi2b), further preferably said KD is measured by the means of a FACS assay, further most preferably having said KD in the range from about 2.661 to about 6.644 nmol/L; and/or b) optionally, having KD in the range from about 0.01 to about 10 nmol/L to an immobilized exogenous full-length Napi2b and/or one or more fragments thereof, preferably said one or more fragments comprising at least one extracellular domain (ECD) of said Napi2b (e.g., said ECD comprising amino acids 122-135 and/or amino acids 235-361 and/or 429-485 and/or amino acids 547-552 of the human Napi2b having SEQ ID NO: 1) and/or one or more fragments of said ECD (e.g., having length from about 15 to about 30 amino acids), wherein said full-length Napi2b and/or one or more fragments thereof are fused or not fused to one or more protein tags (e.g., 6 x His-tags, FLAG, HA, V5, Fc-fusion, MBP, SUMO, TEV, GFP, TST), preferably preferably said KD is measured by the means of an ELISA assay, preferably from about 0.05 to about 0.2 nmol/L, further preferably having said KD in the range from about 0.071 to about 0.147 nmol/L. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is an antibody comprising: a) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 4 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 5; preferably said anti-NaPi2b antibody is the AV-25 antibody comprising: a light chain comprising SEQ ID NO: 6 and a heavy chain comprising SEQ ID NO: 7; b) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 8 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 9; preferably said anti-NaPi2b antibody is the AV-15 antibody comprising: a light chain comprising SEQ ID NO: 10 and a heavy chain comprising SEQ ID NO: 11; c) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 12 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 13; preferably said anti-NaPi2b antibody is the AV-18 antibody comprising: a light chain comprising SEQ ID NO: 14 and a heavy chain comprising SEQ ID NO: 15; d) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 16 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 17; preferably said anti-NaPi2b antibody is the AV-21 antibody comprising: a light chain comprising comprising SEQ ID NO: 18 and a heavy chain comprising comprising SEQ ID NO: 19; e) a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 20 and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) identity to SEQ ID NO: 21; preferably said anti-NaPi2b antibody is the AV-29 antibody comprising: a light chain comprising comprising SEQ ID NO: 22 and and a heavy chain comprising comprising SEQ ID NO: 23. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is: a) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 24, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 25, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 26 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 27, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 28, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 29; b) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 30, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 31, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 32 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 33, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 34, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 35; c) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 36, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 37, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 38 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 39, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 40, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 41; d) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 42, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 43, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 44 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 45, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 46, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 47; e) an antibody comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 48, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 49, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 50 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 51, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 52, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 53. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody has one or more of the following characteristics: a) a monoclonal antibody; b) a chimeric antibody and/or humanized anbibody; c) specifically recognizes Napi2b overexpressed on cancer cells; d) human IgG antibody, preferably a human IgG1 antibody; e) comprising kappa (κ) light chain; f) comprising lambda (λ) light chain; g) comprising Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA mutations), wherein said LALA mutations are capable of reducing immunocell effector function/s; h) capable of being internalized by target cells (e.g., cancer cells) expressing Napi2b; preferably said internalized antibody is directed to lysosomes; i) a tumor-selective antibody, preferably said tumor is a liquid and/or solid tumor; j) a malignant-cell selective antibody; k) binding to said human and/or rat Napi2b in a glycosylation-dependent manner, wherein said antibody binds to a glycosylated form of said Napi2b protein; l) having K D to an endogenously expressed human Napi2b in the range from about 0.01 to about 10 nmol/L, preferably in the range from about 1 to about 10 nmol/L, further preferably from about 1 to about 7 nmol/L, further preferably from about 1 to about 4 nmol/L (e.g., in OVCAR-3 cells (e.g., HTB-161#, ATCC) endogenously expressing Napi2b), further preferably said K D is measured by the means of a FACS assay, further most preferably having said K D in the range from about 2.661 to about 6.644 nmol/L; m) optionally, having K D in the range from about 0.01 to about 10 nmol/L to an immobilized exogenous full-length Napi2b and/or one or more fragments thereof, preferably said one or more fragments comprising at least one extracellular domain (ECD) of said Napi2b (e.g., said ECD comprising amino acids 122-135 and/or amino acids 235-361 and/or 429-485 and/or amino acids 547-552 of the human Napi2b having SEQ ID NO: 1) and/or one or more fragments of said ECD (e.g., having length from about 15 to about 30 amino acids), wherein said full-length Napi2b and/or one or more fragments thereof are fused or not fused to one or more protein tags (e.g., 6 x His-tags, FLAG, HA, V5, Fc-fusion, MBP, SUMO, TEV, GFP, TST), preferably preferably said K D is measured by the means of an ELISA assay, preferably from about 0.05 to about 0.2 nmol/L, further preferably having said K D in the range from about 0.071 to about 0.147 nmol/L. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is a a monoclonal antibody. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is a chimeric antibody and/or humanized anbibody. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is capable of specifically recognizes Napi2b overexpressed on cancer cells. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is a human IgG antibody, preferably a human IgG1 antibody. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody comprising kappa (κ) light chain. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody comprising lambda (λ) light chain. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody comprising Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA mutations (e.g., in Fc region of said antibody)), wherein said LALA mutations are capable of reducing immunocell effector function/s (e.g., wherein said antibody comprising a mutated (e.g., according to any one of the preceding items) Fc region (or fragment crystallizable region), e.g., the tail region of said antibody that when unmutated interacts with cell surface Fc receptors (e.g., wherein said Fc region of an immunoglobulin molecule composed of the constant regions of the heavy chains, e.g., and when unmutated is capable of binding to antibody receptors (Fc receptor) on cells and the Clq component of complement)). The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody capable of being internalized by target cells (e.g., cancer cells) expressing Napi2b; preferably said internalized antibody is directed to lysosomes. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is a tumor-selective antibody, preferably said tumor is a liquid and/or solid tumor. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is a malignant-cell selective antibody. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody is capable of binding to said human and/or rat Napi2b in a glycosylation- dependent manner, wherein said antibody binds to a glycosylated form of said Napi2b protein. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody having KD to an endogenously expressed human Napi2b in the range from about 0.01 to about 10 nmol/L, preferably in the range from about 1 to about 10 nmol/L, further preferably from about 1 to about 7 nmol/L, further preferably from about 1 to about 4 nmol/L (e.g., in OVCAR-3 cells (e.g., HTB-161#, ATCC) endogenously expressing Napi2b), further preferably said K D is measured by the means of a FACS assay, further most preferably having said K D in the range from about 2.661 to about 6.644 nmol/L The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody having K D in the range from about 0.01 to about 10 nmol/L to an immobilized exogenous full-length Napi2b and/or one or more fragments thereof, preferably said one or more fragments comprising at least one extracellular domain (ECD) of said Napi2b (e.g., said ECD comprising amino acids 122-135 and/or amino acids 235-361 and/or 429-485 and/or amino acids 547-552 of the human Napi2b having SEQ ID NO: 1) and/or one or more fragments of said ECD (e.g., having length from about 15 to about 30 amino acids), wherein said full-length Napi2b and/or one or more fragments thereof are fused or not fused to one or more protein tags (e.g., 6 x His-tags, FLAG, HA, V5, Fc-fusion, MBP, SUMO, TEV, GFP, TST), preferably preferably said K D is measured by the means of an ELISA assay, preferably from about 0.05 to about 0.2 nmol/L, further preferably having said K D in the range from about 0.071 to about 0.147 nmol/L. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody, wherein said antibody is coupled to a labelling group. The anti-NaPi2b antibody according to any one of the preceding items, wherein said anti- NaPi2b antibody, wherein said antibody said antibody is obtainable by a hybridoma (e.g., said antibody is a recombinant antibody). The anti-NaPi2b antibody according to any one of the preceding items, obtained according to Example 1, 2 or 3 herein and/or having characteristics as described in Example 1, 2 or 3 herein (e.g., Figures 1-50, particularly, 3, 4, 5, 6, 7, 8, 9, 19 and/or 20). The anti-NaPi2b antibody according to any one of the preceding items, wherein the antibody comprises one or more (e.g., 2) CDRs, heavy chain variable regions, light chain variable regions, heavy chain, light chains and/or signal sequences according to any one of the preceding items, preferably selected from the group consisting of: SEQ ID NOs: 4-53. The anti-NaPi2b antibody according to any one of the preceding items, wherein the antibody comprises at least one (e.g., 2) heavy and light chain, preferably according to any one of the preceding items. The anti-NaPi2b antibody according to any one of the preceding items, comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acid substitution/s (or mutations), preferably located in one or more regions selected from the group consisting of: CDRs (e.g., CDR1, CDR2, CDR3, e.g., CDR-H1, CDR-H2, CDR-H3, CDR-H1, CDR-L1, CDR-L2 and/or CDR-L3, e.g., according to any one of the preceding items, e.g., sequence listing as disclosed herein), V H (variable region heavy chain), V L (variable region light chain), C H (constant region heavy chain) or C L (constant region light chain), F(ab) and/or Fc region (e.g., as defined in Figure 1 herein) The anti-NaPi2b antibody according to any one of the preceding items, comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) highly conservative, conservative or equivalent amino acid substitution/s (or mutations), e.g., “Conservative or equivalent substitution/s” meaning substitutions as listed as “Exemplary Substitutions” in Table I below, “Highly conservative” substitutions as used herein meaning substitutions as shown under the heading “Preferred Substitutions” in Table I below:
preferably said one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) highly conservative, conservative or equivalent amino acid substitution/s (or mutations) are located in one or more regions selected from the group consisting of: CDRs (e.g., CDR1, CDR2, CDR3, e.g., CDR-H1, CDR-H2, CDR-H3, CDR-H1, CDR-L1, CDR-L2 and/or CDR-L3, e.g., according to any one of the preceding items, e.g., sequence listing as disclosed herein), V H (variable region heavy chain), V L (variable region light chain), C H (constant region heavy chain) or C L (constant region light chain), F(ab) and/or Fc region (e.g., as defined in Figure 1 herein). The antibody according to any one of the preceding items, wherein the %HMWS (high molecular weight species) of the antibody is less than 5% (e.g., as shown in Figure 20). A hybridoma, wherein said hybridoma produces the monoclonal antibody according to any one of the preceding items. A nucleic acid encoding the antibody according to any one of the preceding items. An expression vector comprising at least one of the nucleic acid molecules according to any one of the preceding items. An isolated host cell (e.g., an isolated recombinant host cell) comprising the vector and/or nucleic acid according to any one of the preceding items. An antibody drug conjugate (ADC) comprising the anti-NaPi2b antibody according to any one of the preceding items (e.g., obtained according to Example 1 herein and/or having characteristics as described in Example 1 and/or Example 2 and/or Example 3 herein). The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) cytotoxic moieties (e.g., cytotoxic payloads, e.g. Tubulin disrupting agents, e.g., Topoisomerase-I inhibitor/s, e.g., Auristatins or camptothecin, e.g., MMAE (Monomethyl auristatin E) or MMAF (monomethyl auristatin F), e.g., Exatecan (e.g., CAS Nr: 171335-80-1), preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties, preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) Exatecan cytotoxic moieties via one or more linkers, preferably via one or more phosphonamidate linkers. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said ADC comprising a humanized monoclonal NaPi2b-specific IgG1 antibody conjugated to a cytotoxic payload: a) wherein the cytotoxic pyload is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof; and/or b) wherein cytotoxic payload is a camptothecin moiety C selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan, and gimatecan; and/or c) wherein the cytotoxic pyload is conjugated via a cleavable linker (L), preferably wherein the linker L is cleavable by a protease, a glucuronidase, a sulfatase, a phosphatase, an esterase, or by disulfide reduction, more preferably wherein the linker is cleavable by a protease, preferably by a cathepsin such as cathepsin B; and/or d) wherein the linker L comprises a valine-citrulline-PAB moiety or a valine-alanine-PAB moiety; and/or e) wherein cytotoxic payload is Exatecan, conjugated via a chemical valine-citrulline-PAB or a valine-alanine-PAB release unit, wherein said release unit is cleavable by a protease. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-NaPi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties via an ethynylphosphonamidate-linker/s conjugation (e.g., to all eight interchain-cysteine residues), preferably each phosphonamidate linker carries at least one PEG24 moiety (e.g., to prevent aggregation of the ADC), further preferably said ADC carries up to said eight linker payload moieties and eight PEG24 moieties. An antibody drug conjugate (ADC), optionally according to any one of items 36 to 41, having the formula (I): , or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-NaPi2b antibody as defined in any one of the preceding items; is a double bond; or V is absent when is a double bond; or X R 3 C is a double bond; or X is when is a bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; m is an integer ranging from 1 to 10; and n is an integer ranging from 1 to 20. The antibody drug conjugate (ADC) according to item 42, wherein: R3 is H or (C 3 1-C 8 )alkyl; preferably R is H; R4 when present is H or (C1-C8)alkyl; preferably R4 , when present, is H; R5 when present is H or (C -C )alkyl; prefe 5 1 8 rably R , when present, is H; R6 when present is H or (C - 6 1C 8 )alkyl; preferably R , when present, is H; and R7 when present is H or (C 7 1-C 8 )alkyl; preferably R , when present, is H. The antibody drug conjugate (ADC) according to item 42 or 43, wherein is a double bond; V is absent; X is R 3 C ; and R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R3 is H or (C1-C8)alkyl; more preferably R3 is H. The antibody drug conjugate (ADC) according to item 42 or 43, wherein is a bond; V R 4 is H or (C 1 -C 8 )alkyl, preferably V is H; X is R 3 C ; R 3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; more preferably R3 is H or (C 1 -C 8 )alkyl, more preferably R3 is H; R4 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably, R4 is H or (C 4 1-C 8 )alkyl, preferably R is H. The antibody drug conjugate (ADC) according to any one of items 42 to 45, wherein Y is NH. The antibody drug conjugate (ADC) according to any one of items 42 to 46, wherein the connector unit CU is cleavable. The antibody drug conjugate (ADC) according to item 47, wherein the connector unit CU is cleavable by a protease, a glucuronidase, a sulfatase, a phosphatase, an esterase, or by disulfide reduction. The antibody drug conjugate (ADC) according to item 48, wherein the connector unit CU is cleavable by a protease, preferably by a cathepsin such as cathepsin B. The antibody drug conjugate (ADC) according to any one of items 42 to 49, wherein the connector unit (CU) comprises a valine-citrulline moiety. The antibody drug conjugate (ADC) according to item 50, wherein the connector unit CU is: O O O O * H N N N H H O # O N NH H 2 , wherein # indicates the attachment point to the Y and * indicates the attachment point to the cytotoxic moiety CM. The antibody drug conjugate (ADC) according to any one of items 42 to 49, wherein the connecgtor unit CU comprises a valine-alanine moiety. The antibody drug conjugate (ADC) according to item 52, wherein the connector unit CU is: ## * , wherein * indicates the attachment point to the Y and ## indicates the attachment point to the cytotoxic moiety. The antibody drug conjugate (ADC) according to any one of items 42 to 46, wherein the linker is non-cleavable. The antibody drug conjugate (ADC) according to any one of items 42 to 54, wherein R1 is a polyethylene glycol unit. The antibody drug conjugate (ADC) according to item 55, wherein the polyethylene glycol unit comprises 1 to 100 subunits having the structure: O ; The antibody drug conjugate (ADC) according to any one of items 42 to 56, wherein R1 is: K F o , wherein indicates the position of the O; KF is selected from the group consisting of -H, -PO 3 H, -(C 1 -C 10 )alkyl, -(C 1 -C 10 )alkyl- SO 3 H, -(C 2 -C 10 )alkyl-CO 2 H, -(C 2 -C 10 )alkyl-OH, -(C 2 -C 10 )alkyl-NH 2 , -(C 2 -C 10 )alkyl- NH(C 1 -C 3 )alkyl and -(C 2 -C 10 )alkyl-N((C 1 -C 3 )alkyl) 2 ; and o is an integer ranging from 1 to 100. The antibody drug conjugate (ADC) according to item 57, wherein K F is H. The antibody drug conjugate (ADC) according item 57 or 58, wherein o ranges from 8 to 30. The antibody drug conjugate (ADC) according to item 59, wherein o ranges from 20 to 28. The antibody drug conjugate (ADC) according to item 60, wherein o is 22, 23, 24, 25 or 26. The antibody drug conjugate (ADC) according to item 59, wherein o ranges from 8 to 16. The antibody drug conjugate (ADC) according to item 62, wherein o is 10, 11, 12, 13 or 14. The antibody drug conjugate (ADC) according to any one of items 42 to 63, wherein the cytotoxic moiety CM is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. The antibody drug conjugate (ADC) according to item 64, wherein the cytotoxic moiety CM is a camptothecin moiety. The antibody drug conjugate (ADC) according to item 65, wherein the camptothecin moiety is selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan, and gimatecan. The antibody drug conjugate (ADC) according to item 66, wherein the cytotoxic moiety CM is exatecan having the formula: O O . The antibody drug conjugate (ADC) according to item 67, wherein the cytotoxic moiety CM is exatecan having the formula: O O . The antibody drug conjugate (ADC) according to item 67 or 68, wherein the exatecan is bound to the connector unit CU via the amino group. The antibody drug conjugate (ADC) according to any one of items 42 to 69, wherein the number of cytotoxic moietes CM, in particular the number of camptothecin moieties, per receptor binding molecule is from 1 to 14, preferably from 2 to 14, more preferably from 4 to 14, still more preferably from 5 to 12, still more preferably from 6 to 12, still more preferably from 7 to 10, even more preferably 8. The antibody drug conjugate (ADC) according to any one of items 42 to 69, wherein the number of cytotoxic moieties CM, in particular the number of camptothecin moieties, per receptor binding molecule is from 1 to 14, preferably from 1 to 12, more preferably from 2 to 10, still more preferably from 2 to 8, still more preferably from 2 to 6, still more preferably from 3 to 5, even more preferably 4. The antibody drug conjugate (ADC) according to any one of items 42 to 69, wherein m is an integer ranging from 1 to 4, preferably 1 or 2, more preferably 1; and n is an integer ranging from 1 to 20, preferably from 1 to 10, more preferably from 2 to 10, still more preferably from 4 to 10, still more preferably from 6 to 10, still more preferably from 7 to 10, even more preferably 8. The antibody drug conjugate according to any one of items 42 to 69, wherein m is an integer ranging from 1 to 4, preferably 1 or 2, more preferably 1; and n is an integer ranging from 1 to 20, preferably from 1 to 10, more preferably from 2 to 8, still more preferably from 3 to 6, still more preferably 4 or 5, even more preferably 4. An antibody drug conjugate (ADC), optionally according to any one of items 42 to 73, having the formula (I): (I), or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-NaPi2b antibody as defined in any one of the preceding items; is a double bond; or V is absent when is a double bond; or V is H when is a bond; X R 3 C is a double bond; or X is when is a bond; Y is NH; R1 is a polyethylene glycol unit having the structure: K F o , wherein: indicates the position of the O; KF is H; and o is an integer ranging from 8 to 30; R3 is H; R4 is H; CU is a connector unit having the following structure: O O O O * H N N N H H O # O N NH H 2 , wherein # indicates the attachment point to the Y and * indicates the attachment point to the camptothecin moiety (CM); CM is a camptothecin moiety; m is 1; and n is an integer ranging from 1 to 10. The antibody drug conjugate (ADC) according to item 74, wherein is a double bond; V is absent; X is R 3 C ; and R3 is H. according to item 74, wherein is a bond; V is H; ; H. The antibody drug conjugate (ADC) according to any one of items 74 to 76, wherein the camptothecin moiety CM is exatecan having the formula: NH 2 O N F N O HO O . The antibody drug conjugate (ADC) according to item 77, wherein the exatecan is bound to the connector unit CU via the amino group. The antibody drug conjugate (ADC) according to any one of items 74 to 78, wherein o ranges from 20 to 28. The antibody drug conjugate (ADC) according to item 79, wherein o is 22, 23, 24, 25 or 26. The antibody drug conjugate (ADC) according to any one of items 74 to 80, wherein n ranges from 2 to 10, The antibody drug conjugate (ADC) according to item 81, wherein n is 8. The antibody drug conjugate (ADC) according to item 81, wherein n is 4. An antibody drug conjugate (ADC), optionally according to any one of items 74 to 82, having the following formula (Ia):
F O O O O N H H N N O N N H H Ab S P O N O N O H O O OH N NH OH 23 H O O 8 (Ia), wherein Ab is an anti-NaPi2b antibody as defined in any one of the preceding items. The antibody drug conjugate (ADC) according to item 64, wherein the cytotoxic moiety CM is an auristatin. The antibody drug conjugate (ADC) according to item 85, wherein the cytotoxic moiety is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). The antibody drug conjugate (ADC) according to item 86, wherein the cytotoxic moiety is monomethyl auristatin E (MMAE). The antibody drug conjugate (ADC) according to any one of the preceding items, wherein said ADC having a formula selected from the group consisting of: a) Formula I:
, wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); c) Formula III: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); d) Formula IV: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); f) Formula VI: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); g) Formula VII: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); , n range to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); i) Formula IX: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); 20 , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); m) Formula XIII: , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); , wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8); p) Formula XVI:
, wherein n is in the range from 0 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8). wherein is an anti-NaPi2b antibody as defined in any one of the preceding items. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein: a) said anti-NaPi2b monoclonal antibody is capable of specifically recognizing human Napi2b (e.g., SEQ ID NO: 1) and/or rat Napi2b (e.g., SEQ ID NO: 2) overexpressed on cancer cell/s; and b) upon binding of said ADC to said Napi2b overexpressed on cancer cells said ADC is capable of being internalized by the cells and trafficked into the lysosomal compartment, in which preferably a lysosomal protease (e.g., Cathepsin B) is capable of releasing said cytotoxic payload from the said ADC. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein the %HMWS (high molecular weight species) of the antibody is less than 5% (e.g., as shown in Figure 20). A compound having the formula (II): O X P CU Y CM m OR1 V (II), or a pharmaceutically acceptable salt or solvate thereof; wherein: is a triple bond; or is a double V is absent when is or V is H or (C 1 -C 8 )alkyl when is a double bond; X is R 3 C when is a triple bond; or a double bond; Y is NR5, S, O, or R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; is a connector unit; CM is a cytotoxic moiety; and m is an integer ranging from 1 to 10. The compound according to item 91, wherein: R3 is H or (C1-C8)alkyl; preferably R3 is H; R4 when present is H or (C -C )alk 4 1 8 yl; preferably R , when present, is H; R5 when present is H or (C -C )alkyl; p 5 1 8 referably R , when present, is H; R6 when present is H or (C -C )alkyl; pref 6 1 8 erably R , when present, is H; and R7 when present is H or (C -C )alkyl; prefe 7 1 8 rably R , when present, is H. The compound according to item 91 or 92, wherein is a triple bond; V is absent; X isR 3 C ; and R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R3 is H or (C 3 1-C 8 )alkyl, more preferably R is H. The compound according to item 91 or 92, wherein is a double bond; V is H or (C 1 - R 4 C )alkyl, pre R 3 C 3 8 ferably V is H; X is ; R is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R3 is H or (C 1 -C 8 )alkyl, more preferably R3 is H; R4 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; preferably R4 is H or (C 4 1-C 8 )alkyl, more preferably R is H. The compound according to any one of items 91 to 94, wherein Ab, V, X, Y, R1 , R3, R4 , R5, R6, R7 , CU, CM, m and n are as defined in any one of items 42 to 90; preferably, Y is NH. A method of producing an antibody drug conjugate (ADC), said method comprising: (a) conjugating the antibody according to any one of the preceding items to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) cytotoxic moieties (e.g., cytotoxic payloads, e.g. Tubulin disrupting agents, e.g., Topoisomerase-I inhibitor/s, e.g., Auristatins or camptothecin, e.g., MMAE (monomethyl auristatin E) or MMAF (monomethyl auristatin F), e.g., Exatecan), preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. The method of producing an antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-Napi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties, preferably via one or more linkers, further preferably via one or more phosphonamidate linkers. The method of producing an antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-Napi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8. most preferably to 8) Exatecan cytotoxic moieties via one or more linkers, preferably via one or more phosphonamidate linkers. The method of producing an antibody drug conjugate (ADC) according to any one of the preceding items, wherein said anti-Napi2b antibody is conjugated to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably from 1 to 10, further preferably from 2 to 10, most preferably from 4 to 10, further most preferably from 6 to 10, further most preferably from 7 to 10, further most preferably 4 or 8, most preferably to 8) camptothecin (e.g., Exatecan) cytotoxic moieties via an ethynylphosphonamidate-linker/s conjugation (e.g., to all eight interchain-cysteine residues), preferably each phosphonamidate linker carries at least one PEG moiety, with up to 24 PEG units (e.g., to prevent aggregation of the ADC), further preferably said ADC carries up to said eight linker payload moieties and eight PEG24 moieties. The method of producing an antibody drug conjugate (ADC) according to any one of the preceding items, wherein said ADC comprising a humanized monoclonal Napi2b-specific IgG1 antibody conjugated to a cytotoxic payload: a) wherein the cytotoxic pyload is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof; and/or b) wherein cytotoxic payload is a camptothecin moiety C selected from the group consisting of exatecan, DXD, SN38, camptothecin, topotecan, irinotecan, belotecan, lurtotecan, rubitecan, silatecan, cositecan, and gimatecan; and/or c) wherein the cytotoxic pyload is conjugated via a cleavable linker (L), preferably wherein the linker L is cleavable by a protease, a glucuronidase, a sulfatase, a phosphatase, an esterase, or by disulfide reduction, more preferably wherein the linker is cleavable by a protease, preferably by a cathepsin such as cathepsin B; and/or d) wherein the linker L comprises a valine-citrulline-PAB moiety or a valine-alanine-PAB moiety; and/or e) wherein cytotoxic payload is Exatecan, conjugated via a chemical valine-citrulline-PAB or a valine-alanine-PAB release unit, wherein said release unit is cleavable by a protease. A method of preparing an antibody drug conjugate (ADC), optionally according to any one of items 96 to 100, said method comprising: reacting a compound of formula (II) , or a pharmaceutically acceptable salt or solvate thereof; wherein: is a triple bond; or is a double V is absent when is or V is H or (C 1 - is a double bond; X is R 3 C when is a triple bond; or R 4 X is R 3 C when is a double bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; and m is an integer ranging from 1 to 10; with a thiol-containing molecule of formula (III) , wherein Ab is an anti-NaPi2b antibody as defined in any one of the preceding items; and n is an integer ranging from 1 to 20; resulting in an antibody drug conjugate (ADC) of formula (I) (I), or a pharmaceutically acceptable salt or solvate thereof; wherein: Ab is an anti-NaPi2b as defined in any one of the preceding items; is a double bond when in a compound of formula (II) is a triple bond; or is a bond when in a compound of formula (II) is a double bond; V is absent when is a double bond; or V is H or (C 1 - when is a bond; X R 3 C when is a double bond; or R 4 X is C when is a bond; Y is NR5, S, O, or CR6R7; R1 is an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R3 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R4 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R5 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R6 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; R7 is H; or an optionally substituted aliphatic residue or an optionally substituted aromatic residue; CU is a connector unit; CM is a cytotoxic moiety; m is an integer ranging from 1 to 10; and n is an integer ranging from 1 to 20. The method according to item 101, wherein: R3 is H or (C -C )alk 3 1 8 yl; preferably R is H; R4 when present is H or (C -C )alkyl; preferabl 4 1 8 y R , when present, is H; R5 when present is H or (C 5 1-C 8 )alkyl; preferably R , when present, is H; R6 when present is H or (C -C )alkyl; prefera 6 1 8 bly R , when present, is H; and R7 when present is H or (C 1 -C 8 )alkyl; preferably R7 , when present, is H. The method according to item 101 or 102, wherein is a triple bond; V is absent; X isR 3 C ; R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue, preferably R3 is H or (C 3 1-C 8 )alkyl, more preferably R is H, and is a double bond. The method according to item 101 or 102, wherein is a double bond; V is H or (C 1 - R 4 C 8 )alkyl, preferably V is H; X is R 3 C , R3 is H or an optionally substituted aliphatic residue or an optionally substituted aromatic residue, preferably R3 is H or (C 1 -C 8 )alkyl, more preferably R3 is H; R4 is H or (C 1 -C 8 )alkyl, preferably R4 is H; and is a bond. The method according to any one of items 101 to 104, wherein the reaction is performed under neutral pH or slightly basic conditions, preferably at a pH of from 6 to 10. The method according to any one of items 101 to 105, further comprising reducing at least one disulfide bridge of the antibody in the presence of a reducing agent to form a thiol group (SH). The method according to item 106, wherein the reducing agent is selected from the group consisting of tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), sodium dithionite, sodium thiosulfate, and sodium sulfite; preferably wherein the reducing agent is tris(2-carboxyethyl)phosphine (TCEP). The method according to item 106 or 107, wherein the reducing of at least one disulfide bridge comprises using about 1 to about 3 equivalents, preferably about 1 to about 2 equivalents, more preferably about 1 equivalent of the reducing agent per disulfide bridge to be reduced. The method according to any one of items 101 to 108, wherein the thiol-containing molecule of formula (III) is reacted with about 1 to about 4 equivalents, preferably about 1 to about 3 equivalents, more preferably about 1 to about 2 equivalents, still more preferably about 1.5 equivalents of the compound of formula (II) per thiol group (SH). The method according to any one of items 101 to 109, wherein the reacting a compound of formula (II) with a thiol-containing molecule of formula (III) is carried out in an aqueous medium. The method according to any one of items 101 to 110, wherein Ab, V, X, Y, R1 , R3, R4 , R5, R6, R7 , CU, CM, m and n are as defined in any one of items 42 to 90; preferably Y is NH 2 . n antibody drug conjugate (ADC) produced by the method according to any one of the preceding items. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein the %HMWS (high molecular weight species) of the antibody is less than 5%, preferably thus decreasing aggregation of said ADC and/or decreasing toxicity of said ADC against the normal (e.g., non-cancer) tissue. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein the drug to antibody ratio (DAR) is in the range between 0 and 20, preferably is in the range between 1 and 20, further preferably is in the range between 2 and 12, most preferably is in the range between 4 and 10, further most preferably is in the range between 4 and 8. The antibody drug conjugate (ADC) according to any one of the preceding items, wherein DAR of said ADC is 4 or 8, preferably 8. A composition or kit comprising said anti-Napi2b, antibody drug conjugate (ADC), hybridoma, nucleic acid, expression vector and/or host cell according to any one of the preceding items. The composition according to any one of the preceding items, wherein said composition is a pharmaceutical and/or diagnostic composition. The composition or kit according to any one of preceding items, wherein a drug (e.g., cytotoxic moieties (e.g., cytotoxic payloads, e.g. Tubulin disrupting agents, e.g., Topoisomerase-I inhibitor/s, e.g., Auristatins or camptothecin, e.g., MMAE (monomethyl auristatin E) or MMAF (monomethyl auristatin F), e.g., Exatecan) to antibody ratio (DAR) is in the range between 0 and 20, preferably is in the range between 1 and 20, further preferably is in the range between 2 and 12, most preferably is in the range between 4 and 10, further most preferably is in the range between 4 and 8. A composition or kit comprising said anti-NaPi2b antibody, antibody drug conjugate (ADC), hybridoma, nucleic acid, expression vector and/or host cell according to any one of the preceding items. A method for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non- small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer, fallopian tube cancer, lung adenocarcinoma (e.g., as in Example 2 and/or 3 herein), said method comprising: administering a therapeutically or prophylactically effective amount of the antibody, antibody drug conjugate (ADC), nucleic acid, expression vector, host cell, composition or kit according to any one of the preceding items. The antibody, antibody drug conjugate (ADC), nucleic acid, expression vector, host cell, composition or kit according to any one of the preceding items, for use as a medicament and/or in therapy. The antibody, antibody drug conjugate (ADC), nucleic acid, expression vector, host cell, composition or kit according to any one of the preceding items, for use in one or more of the following methods: (a) method for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non-small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer, fallopian tube cancer, lung adenocarcinoma (e.g., as in Example 2 and/or 3 herein); (b) method for monitoring development of cancer and/or for assessing the efficacy of cancer therapy; (c) method for screening a candidate compound for anti-cancer activity; (d) method for altering resistance of cancer cells to chemotherapy; (e) method for sensitizing cancer cells to chemotherapy; (f) method for inhibiting the growth of cancer cell expressing NaPi2b; (g) method for production or preparation of an antibody; (h) method for immunizing a non-human animal; (i) method for preparation of a hybridoma; (j) method according to any one of the preceding items; (k) method according to any one of (a)-(j), wherein said method is an in vivo, in vitro, or ex vivo method. Use of the antibody, antibody drug conjugate (ADC), nucleic acid, expression vector, host cell, composition or kit according to any one of the preceding items, for one or more of the following: (a) for treatment, amelioration, prophylaxis and/or diagnostics of cancer, preferably said cancer is a solid and/or metastatic cancer, further preferably said cancer is selected from the group consisting of: lung cancer, ovarian cancer, thyroid cancer, nonsquamous non-small cell lung carcinoma, nonmucinous ovarian carcinoma, papillary thyroid carcinoma, renal cancer, endometrial cancer, uterus cancer, ureter cancer, bladder cancer, fallopian tube cancer and lung adenocarcinoma (e.g., as in Example 2 and/or 3 herein); (b) for monitoring development of cancer and/or for assessing the efficacy of cancer therapy; (c) for screening a candidate compound for anti-cancer activity; (d) for altering resistance of cancer cells to chemotherapy; (f) for sensitizing cancer cells to chemotherapy; (g) for inhibiting the growth of cancer cell expressing NaPi2b; (h) for production or preparation of an antibody; (i) for immunizing a non-human animal; (j) for preparation of a hybridoma; (k) in a method according to any one of the preceding items; (l) use according to any one of (a)-(k), wherein said use is an in vivo, in vitro, or ex vivo use. The antibody drug conjugate (ADC), composition, kit, method and/or use according to any one of the preceding items, wherein a dose (e.g., therapeutic dose, e.g., effective therapeutic dose, and/or daily dose, e.g., single or multiple daily dose, and/or total dose) comprises or consists of the ADC according to any one of the preceding items in the amount of at least about 10 mg/kg body weigt of the treatment subject (e.g., animal or human patient), preferably in the amount from about 10 to about 20 mg/kg, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more mg/kg), or in the total amount of at least about 700- 2000mg of the ADC according to any one of the preceding items (e.g., as in Example 2 and/or 3 herein). The antibody drug conjugate (ADC), composition, kit, method and/or use according to any one of the preceding items, wherein a dose (e.g., therapeutic dose, e.g., effective therapeutic dose, and/or daily dose, e.g., single or multiple daily dose, and/or total dose) of the ADC according to any one of the preceding items is administered (e.g., orally or intravenously) one or more times (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10, e.g., every second or third day or once or twice a week) during a period of at least about 1 week (e.g., 1-4 weeks, e.g., 3 weeks, one or two months) with or without dose escalation (e.g., as in Example 2 and/or 3 herein). The antibody drug conjugate (ADC), composition, kit, method and/or use according to any one of the preceding items, wherein a treatment regiment comprises or consists of administration (e.g., orally or intravenously) of a dose (e.g., therapeutic dose, e.g., effective therapeutic dose, and/or daily dose, e.g., single or multiple daily dose, and/or total dose) of the ADC according to any one of the preceding items one or more times (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10, e.g., every second or third day or once or twice a week) during a period of at least about 1 week (e.g., 1-4 weeks, e.g., 3 weeks, one or two months) with or without dose escalation (e.g., as in Example 2 and/or 3 herein). 128. The antibody drug conjugate (ADC), composition, kit, method and/or use according to any one of the preceding items, further comprising one or more therapeutic agents (e.g., anti- cancer agent or medications). 129. The antibody drug conjugate (ADC), composition, kit, method and/or use according to any one of the preceding items, further comprising administration (before, simoultaneously or consequently) of one or more therapeutic agents (e.g., anti-cancer agent or medication). *** [00330] It It is noted that as used herein, the singular forms “a”, “an”, and “the”, include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a reagent” includes one or more of such different reagents and reference to “the method” includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein. [00331] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention. [00332] The term "and/or" wherever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term". [00333] The term "about" or "approximately" as used herein means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. [00334] The term “less than” or in turn “more than” does not include the concrete number. [00335] For example, less than 20 means less than the number indicated. Similarly, more than or greater than means more than or greater than the indicated number, e.g., more than 80 % means more than or greater than the indicated number of 80 %. [00336] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of" excludes any element, step, or ingredient not specified. [00337] The term “including” means “including but not limited to”. “Including” and “including but not limited to” are used interchangeably. [00338] It should be understood that this invention is not limited to the particular methodology, protocols, material, reagents, and substances, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. [00339] All publications cited throughout the text of this specification (including all patents, patent application, scientific publications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. [00340] The content of all documents and patent documents cited herein is incorporated by reference in their entirety. EXAMPLES OF THE INVENTION [00341] An even better understanding of the present invention and of its advantages will be evident from the following examples, offered for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way. [00342] Example 1: [00343] General Information [00344] Chemicals, solvents and antibodies [00345] Chemicals and solvents were purchased from Merck (Merck group, Germany), TCI (Tokyo chemical industry CO., LTD., Japan), Iris Biotech (Iris Biotech GmbH, Germany), MCE (MedChemExpress, USA) and Carl Roth (Carl Roth GmbH + Co. KG, Germany) and used without further purification. Dry solvents were purchased from Merck (Merck group, Germany). PEG24 was purchased from BiochemPEG (Pure Chemistry Scientific Inc., United States). [00346] Preparative HPLC [00347] Preperative HPLC was performed on a BÜCHI Pure C-850 Flash-Prep system (BÜCHI Labortechnik AG, Switzerland) using a VP 250/10 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) for smaller scales. The following gradients were used: Method C: (A = H2O + 0.1% TFA (trifluoroacetic acid), B = MeCN (acetonitrile) + 0.1% TFA, flow rate 6 ml/min, 30% B 0-5 min, 30-70% B 5-35 min, 99% B 35-45 min. For bigger scales, a VP 250/21 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) was used with the following gradients were used: Method D: (A = H2O + 0.1% TFA (trifluoroacetic acid), B = MeCN (acetonitrile) + 0.1% TFA, flow rate 14 ml/min, 30% B 0-5 min, 30-70% B 5-35 min, 99% B 35-45 min. [00348] LC-MS [00349] Small molecules, linker-payloads, antibodies and ADCs were analyzed using a Waters H-class instrument equipped with a quaternary solvent manager, a Waters sample manager-FTN, a Waters PDA detector and a Waters column manager with an Acquity UPLC protein BEH C4 column (300 Å, 1.7 µm, 2.1 mm x 50 mm) for antibodies and ADCs. Here, samples were eluted at a column temperature of 80°C. The following gradient was used: A: 0.1% formic acid in H 2 O; B: 0.1% formic acid in MeCN. 25% B 0-1 min, 0.4 mL/min, 25-95% B 1-3.5 min 0.2 mL/min, 95% B 3.5-4.5 min 0.2 mL/min, 95-25% B 4.5-5 min 0.4 mL/min, 25-95% B 5-5.5 min 0.4 mL/min, 95-25%B 5.5-7.5 min 0.4 mL/min. Mass analysis was conducted with a Waters XEVO G2- XS QTof analyzer. Proteins were ionized in positive ion mode applying a cone voltage of 40 kV. Raw data was analyzed with MaxEnt 1. Small molecules and linker-payloads were analyzed with an Acquity UPLC-BEH C18 column (300 Å, 1.7 µm,2.1 mm x 50 mm). Here, samples were eluted at a column temperature of 45°C with a flow rate of 0.4 mL/min. The following gradient was used: A: 0.1% formic acid in H 2 O; B: 0.1% formic acid in MeCN.2% B 0-1 min, 2-98% B 1-5 min, 98%B 5-5.5 min, 98-2% B 5.5-6 min, 2% B 6-7min. [00350] CDR mutagenisis and Antibody Expression [00351] For the CDR mutagenesis campaign of the parental abtibody, a phage display library of 22x108 sequences (66% functional) was prepared based on homology modeling of antibody Fv regions, selection of surface CDR residues possibly involved in antigen binding (VH: 18 positions , VK: 16 positions identified) and analysis of amino acid usage at each position in NGS data (approx.2x106 IgG sequences) (Figure 1). Panning of the CDR mutation phage library for selection of affinity improved antibodies was carried out on antigen/Napi2b-expressing cells in 4 rounds of sequential antigen restriction achieved by increasing cell dilution. From the panning, 384 clones from each round were chosen (in total 1536 clones), produced as soluble scFv antibodies in E. coli, and screened for binding to human-Napi2b-expressing HEK293 cells and parental HEK293 cells using flow cytometry analysis. Signal to noise (N/S) between MFI of positive and MFI of negative cell line greater than 12 was chosen as hit selection criterium. According to the described selection criterium, 375 clones were identified and DNA-sequenced. From these results, 255 unique antibody sequences were identified and the off-rate of these clones was further analysed using BLI technology. In detail, biotinylated Napi2b-antigen was immobilized onto Streptavidin sensors and scFv association and dissociation was measured. The off-rate kinetics were modelled and clones fulfilling the following criteria, a significant binding response and high modelling accuracy had to be achieved, were ranked.5 antibody clones/sequences were selected for further in-depth analysis: AV-15, AV-18, AV-21, AV-25 and AV-29 (Figure 1). [00352] Antibodies were then transiently expressed in Expi-CHO-S cells (Thermo Fisher) by co-transfecting cells with pcDNA3.4 expression plasmids (Thermo Fisher), coding for the heavy and light chain of the respective sequences in a 1:1 ratio, using the Expi-CHO transfection system (Thermo Fisher). Cells were harvested by centrifugation at 300 g for 5 minutes at 4°C. To clear micro particles from supernatant, supernatants were centrifuged at 4000–5000 g for 30 min at 4 °C. For further clarification supernatants were passed through a 0.22 µm filter. Antibodies were purified from cleared and filtered supernatants via Protein A chromatography and analyzed by HPLC-SEC, HPLC-HIC, LC-MS and SDS-PAGE. [00353] Preparative Size-Exclusion-Chromatography [00354] Protein purification by size-exclusion chromatography was conducted with an ÄKTA Pure FPLC system (GE Healthcare, United States) equipped with a F9-C-fraction collector. [00355] ADC concentration determination [00356] The ADC concentrations were determined in a 96-well plate with a Pierce™ Rapid Gold BCA Protein Assay Kit (Thermo Fisher Scientific, USA) and a Bradford reagent B6916 (Merck, Germany) with pre-diluted protein assay standards of bovine gamma globulin (Thermo Fisher Scientific, USA). Results of both Assays were arithmetically averaged. [00357] Sample preparation of ADCs and antibodies for MS [00358] For antibody and ADC deglycosylation, 0.5 μl PNGase-F solution (Pomega, Germany, Recombinant, cloned from Elizabethkingia miricola 10 u/μl) and 5 µL of a 100 mM solution of DTT in water were added to 50 µl of 0.2 mg/mL antibody or ADC in PBS and the solution was incubated at 37 °C for at least 2 hours. Glycosylated mAbs and ADCs were incubated at a concentration of 0.2 mg/ml with 10 mM DTT for 1 hour. Samples were subjected to LC/MS, injecting 2 µl for each sample. [00359] Analytical size-exclusion chromatography [00360] Analytical size-exclusion chromatography (A-SEC) of the ADCs was conducted on a Vanquish Flex UHPLC System with a DAD detector, Split Sampler FT (4°C), Column Compartment H (25°C) and binary pump F (Thermo Fisher Scientific, USA) using a MAbPac SEC-1300 Å, 4 x 300 mm column (Thermo Fisher Scientific, USA) with a flow rate of 0.15 mL/min. Separation of different ADC/mAb populations have been achieved during a 30 minute isocratic gradient using a phosphate buffer at pH 7 (20 mM Na2HPO4/NaH2PO4, 300 mM NaCl, 5% v/v isopropyl alcohol as a mobile phase. 8 µg ADC/mAb where loaded onto the column for A-SEC analysis. UV chromatograms were recorded at 220 and 280 nm. [00361] Analytical hydrophobic interaction chromatography [00362] The measurements were conducted on a Vanquish Flex UHPLC System (2.9) with a MabPac HIC Butyl 4.6 x 100 mm column (Thermo Fischer Scientific, USA). Separation of different ADCs/antibodies have been achieved with the following gradient: A: 1 M (NH4)2SO4, 500 mM NaCl, 100 mM NaH2PO4 pH 7.4 B: 20 mM NaH2PO4, 20% (v/v) Isopropyl alcohol, pH 7.4.0% B: 0-1 min, 0-95% B: 1-15 min, 95% B: 15-20 min, 95-0% B: 20-23 min, 0% B: 23-25 min, with a flow of 700 uL/min.15 µg sample where loaded onto the column for each analysis. UV chromatograms were recorded at 220 and 280 nm. [00363] Charge Variant analysis [00364] The measurements were conducted on a Vanquish Flex UHPLC System (2.9) with a ProPac Elite WCX 5 µm 4 x 150 mm column (Thermo Fisher Scientific). Separation of antibody charge variants was performed with the following gradient: A: 1 x CX-1 buffer pH 5.6 B: 1 x CX-1 buffer pH 10.2 (Thermo Fisher Scientific). 0-100% B: 0-60 min, with a flow of 1 ml/min. 24 µg sample were loaded onto the column for each analysis. UV chromatograms were recorded at 280 nm. Charge variant analysis has been performed as described above. Indicated are changes after incubation for 7 days at 40°C with respect to day 0 (decrease of main peak in % and increase of acidic and basic species in %) (Figure 2). [00365] SDS-PAGE [00366] Samples were prepared for SDS-PAGE by incubation in SDS sample buffer (BioRad) supplemented with 25 mM DTT (95°C, 5 minutes) and separated on a 4-20% Polyacrylamide gel (BioRad 4-20% Mini Protean TGX), followed by Coomassie staining (Thermo Fisher Scientific Imperial Protein Stain). [00367] ADC synthesis: General Method for the conjugation of P5-based linker- payload constructs to antibodies to achieve DAR8. [00368] 50 μl of the respective anti-NaPi2b antibody (parental, AV15, AV18, AV21, AV25, AV29) in a solution of 10.0 mg/ml in P5-conjugation buffer (50 mM Tris, 1 mM EDTA, 100 mM NaCl, pH 8.3 at RT) were mixed with 3.33 µl of a 10 mM TCEP solution in P5-conjugation buffer. Directly afterwards, 1.67 µl of a 40 mM solution of the P5-Exatecan construct dissolved in DMSO were added. The mixture was shaken at 350 rpm and 25°C for 16 hours. The reaction mixtures were purified by preparative size-exclusion chromatography with a 25 ml Superdex™ 200 Increase 10/300GL (Cytiva, Sweden) and a flow of 0.8 ml/min eluting with sterile PBS (Merck, Germany). The antibody containing fractions were pooled and concentrated by spin-filtration (Amicon® Ultra- 2mL MWCO: 30 kDa, Merck, Germany). [00369] Binding to human and rat NaPi2B evaluated by Flow Cytometry [00370] HEK293 cells stably overexpressing human and rat Napi2b were generated by stable integration of a human or rat full-length Napi2b-mCherry-(GGGS)3x-mCherry expression construct under control of a human EF1 promoter and a Puromycin-selection cassette under a CMV promoter into the parental HEK293 cell line. In brief, cells were transfected with the linearized plasmids using Lipfectamine 2000 (Thermo Fisher) and selected with Puromycin antibiotic. Cells were then single cell cloned in 96-well plates via serial dilution under continuous antibiotic selection. Clones were screened for target expression via flow cytometry and mCherry fluorescence via flow cytometry and fluorescence microscopy. Target- and mCherry-positive clones were expanded and used for further experiments. To determine equilibrium binding constants (K D ), HEK293 cells stably expressing human (A and C), cynomolgus (B) or rat (D) full- length NaPi2b-mCherry were incubated with antibodies in concentrations ranging from 0.002 to 200 nM and stained with an Alexa-dye-labeled anti-human IgG H+L secondary antibody (Thermo Fisher Scientific) and analyzed by flow cytometry. Binding of antibodies was investigated on mCherry-positive cells. Mean fluorescence intensity (MFI) ratios were normalized to the secondary antibody control. The assay was performed in duplicates and data points were analyzed by a non- linear regression using a one-site specific binding model to derive K D values using Prism 9 software. Graph shows means of n = 2 ± SEM (Figure 3). [00371] Binding to immobilized human NaPi2B evaluated by ELISA [00372] Binding of increasing concentrations of parental mAb and AV mAb clones to a purified recombinant immobilized human Napi2b antigen was tested in an ELISA setting. [00373] To determine binding of parental and AV mAb clones to Napi2b antigen, flat-bottom surface-treated 96-well-plates (Nunclon, Thermo Fisher Scientific) were coated with 1 µg/mL purified recombinant human Napi2b antigen consisting of Napi2b-extracellular-loop2 expressed as Fc-fusion-6-His-tagged protein in Expi-HEK293 cells. After blocking with 2 % bovine serum albumin (Carl Roth) in 1x PBS-Tween 20 (0.05%), increasing antibody concentrations (0.00015, 0.00046, 0.00137, 0.00412, 0.01235, 0.03704, 0.11111, 0.33333, 1.00000, 3.00000, 9.00000 µg/ml) were allowed to bind for 2 hr at room temperature. Bound antibodies were detected by incubation with HRP-conjugated goat anti-human kappa light chain secondary antibody (dilution 1:10000 in blocking solution) for 1 hr at RT. Ultra-TMB (Thermo Fisher, 34028) substrate was added and incubated at room temperature for 15 to 30 min, after which 100 µl/well of 1 M Sulfuric Acid was added. Absorbance at 450 nm was measured within 10 min of addition of acid using a microplate reader Infinite M1000 Pro (Tecan). Apparent dissociation constants (K D ) were derived by non-linear regression using a one-site specific binding model using Prism 9 software. K D in µg/ml, 0.02209 parental mAb, 0.01581 AV15, 0.01494 AV18, 0,01248 AV21, 0,01060 AV25, 0.01238 AV29. Graph shows means of n = 2 ± SEM (Figure 4). [00374] Internalization evaluated via flow cytometry [00375] For pHrodo-based investigation of internalization, a goat anti-human IgG Fcγ fragment-specific secondary antibody (Jackson ImmunoResearch) was labeled with pHrodo™ Deep Red Antibody Labeling Kit (Thermo Fisher Scientific) according to manufacturer’s instructions. Napi2b-positive OVCAR-3 cells were incubated with 5 µg/ml parental mAb and AV mAb clones in presence of equimolar amounts of pHrodo Deep Red-labeled secondary antibody for 1 h, 5 h and 24 h at 37°C. An increase in MFI indicates the presence of AV antibodies in late endosomal and lysosomal compartments. The MFI ratio was determined by deviding the MFI of pHrodo-incubated cells by the MFI of unstained cells (Figure 5). [00376] Melting curves evaluated by NanoDSF [00377] The thermal stability of proteins was determined using nano differential scanning fluorimetry (nanoDSF) that measures temperature-dependent changes in the intrinsic fluorescence of tryptophane and tyrosine residues (Tycho NT.6, NanoTemper Technologies). For this, 1 µM of protein in PBS was absorbed by a capillary that was subsequently placed into the reader. Afterwards, the intrinsic protein fluorescence was measured at 330 nM and 350 nM while incubating at increasing temperatures. Changes in fluorescence signal indicated transitions in the folding state of the proteins and the temperatures at which a transition occurred are named as inflection temperatures (T i ) or also melting temperatures (T m ) (Haffke, M. et al., Label-free Thermal Unfolding Assay of G Protein-Coupled Receptors for Compound Screening and Buffer Composition Optimization.2016) (Figure 6). [00378] In vitro Cytotoxicity evaluated via Resazurin assay [00379] To investigate direct cytotoxicity of ADCs, respective cells were seeded in a 96-well plate (flat bottom, 5000 cells/well, suspended in 100µl medium) and incubated for 7 days with increasing concentrations of the ADCs in medium (0-3 µg/ml) to generate a dose-response curve. Before viability analysis, the supernatant over the adherent cells was removed and replaced by fresh medium. Killing was analyzed afterwards, using resazurin (Sigma-Aldrich) as the cell viability dye at a final concentration of 55 µM. Fluorescence emission at 590 nM was measured on a Microplate reader Infinite M1000 Pro (Tecan). Cell viability was measured by dividing the fluorescence of ADC-treated cells by the fluorescence from control cells, treated in the same way with medium only. Graph shows means of n = 2 ± SEM (Figure 7). [00380] Bystander Killing [00381] To analyze bystander activity of ADCs on target-negative cells, 20.000 NaPi2B- positive cells (OVCAR-3) were incubated with increasing concentrations of ADCs (0-3 µg/ml). After 5 days, half of the cell culture supernatant volumes was transferred to 5.000 NaPi2B-negative cells (SW-620) and incubated for another 5 days. Killing was analyzed by a resazurin-based viability measurement as described above (Figure 8). [00382] In vitro inhibition of Topoisomerase-I, by the delivery of Exatecan via the ADC [00383] TOPOisomerase-I inhibition by delivery of Exatecan via the TUB-040 ADC induces DNA-damage markers. OVCAR-3 cells were treated with 5 µg/mL TUB-040 or 5 nM free Exatecan for 72 h. Cells were stained with Live/Dead stain and for the DNA-damage markers active caspase-3, cleaved PARP and phosphorylated H2A.X (Ser-139) and analyzed by flow cytometry. Graphs show means of n = 2 ± SEM (Figure 9). [00384] In vivo PK-Evaluation of one ADC [00385] In vivo PK-experiments have been performed with AV25 and AV25-P5(PEG24)-VC- PAB-Exatecan. Female Sprague Dawley rats have been treated with 10 mg/kg of the unconjugated AV25 antibody or the ADC. Blood sampling has been performed after different time points and the ADC amount was quantified in a total antibody and an intact ADC ELISA-assay. [00386] To evaluate the PK of the ADCs in vivo, the total antibody concentration was measured at different time points in serum of ADC-treated SD rats. Total humanized anti-NaPi2B antibody was analyzed in rat serum over the range 2000 – 15,6 ng/ml. Nunc 96-well plate with (100 µl/well) were coated with NaPi2B diluted in PBS (required concentration: 0,25 µg/ml) and sealed with PCR Foil. Plates were incubated in a fridge to maintain a temperature between 2-8°C overnight. The coated plates were washed 3x with 300 µl PBST.200 µl/well of blocking solution (2 % Albumin in PBST) was added, the plate was sealed and an incubated at room temperature for 1 hour. The coated plates were washed 3x with 300 µl PBST. 100 µl/well of prepared standards (2000 – 15,6 ng/ml of the respective ADCs, QCs and test samples were added, the plates were sealed and incubated at room temperature for 1 hour. The plates were washed 3x with 300 µl PBST. 100 µl/well Anti-Human IgG (γ-chain specific)-Peroxidase antibody (dilution 1:60000 in PBS) was added and incubated for 1h at rt. The plates were washed 3x with 300 µl PBST. 50 µl/well TMB was added, the plates were sealed and incubated at room temperature for 15 min.50 µl/well of 1 M Sulfuric Acid was added. Using a Tecan Plate Reader, the absorbance at a wavelength of 450 nm was measured. [00387] To evaluate the stability of the ADCs in vivo, the intact ADC concentration was measured at different time points in serum of ADC-treated SD rats. Intact ADC was analyzed in rat serum over the range 2000 – 15,6 ng/ml. Nunc 96-well plate with (100 µl/well) were coated with rabbit anti-Exatecan mAb diluted in PBS (required concentration: 1 µg/ml) and sealed with PCR Foil. Plates were incubated in a fridge to maintain a temperature between 2-8°C overnight. The coated plates were washed 3x with 300 µl PBST.200 µl/well of blocking solution (2 % Albumin in PBST) was added, the plate was sealed and an incubated at room temperature for 1 hour. The coated plates were washed 3x with 300 µl PBST.100 µl/well of prepared standards (2000 – 15,6 ng/ml of the respective ADCs, QCs and test samples were added, the plates were sealed and incubated at room temperature for 1 hour. The plates were washed 3x with 300 µl PBST. 100 µl/well Goat Anti-Human IgG (H+L) Preabsorbed (dilution 1:25000 in PBS was added and incubated for 1h at rt. The plates were washed 3x with 300 µl PBST.100 µl/well TMB was added, the plates were sealed and incubated at room temperature for 10 min.100 µl/well of 1 M Sulfuric Acid was added. Using a Tecan Plate Reader, the absorbance at a wavelength of 450 nm was measured (Figure 10). [00388] Linker-payload synthesis [00389] General method 2 for the synthesis of PEGylated P5 building blocks via the [00390] A 25-ml Schlenk flask was charged with 267 mg bis(diisopropylamino)chlorophosphine (1.00 mmol, 1.00 eq.) under an argon atmosphere, cooled to 0 °C and 2.20 mL ethynylmagnesium bromide solution (0.5 M in THF, 1.10 mmol, 1.10 eq.) was added drop wise. The yellowish solution was allowed to warm to room temperature and stirred for further 30 minutes. 3.00 mmol (3.0 eq.) of the desired PEG-alcohol, dissolved in 5.56 mL 1H tetrazole solution (0.45 M in MeCN, 2.50 mmol, 2.50 eq.) were added and the white suspension was stirred overnight at room temperature. The formation of the desired phosphonite was monitored by 31P-NMR.1.0 mmol (1.0 eq.) of the desired azide dissolved in 2 mL of DMF, THF or MeCN was added and the suspension further stirred for 24h at room temperature. The crude reaction mixture was purified using preparative HPLC. [00391] P5(PEG12)-OSu [00392] The title compound was synthesized in accordance to general Method 2 from 19.5 mg bis(diisopropylamino)chlorophosphine (73 µmol, 1.00 eq.), 146 µL ethynylmagnesium bromide solution (0.5 M in THF, 73 µmol, 1.00 eq.), 100 mg of dodecaethylene glycol (183 µmol, 2.50 eq), 400 µL 1H-tetrazole solution (0.45 M in MeCN, 183 µmol) and 19 mg 4-azidobenzoic-acid-N- hydroxysuccinimide ester (73 µmol, 1.00 eq.). The product was obtained as colourless oil after preparative HPLC (Method D) and lyophilization. (42.5 mg, 50 µmol, 68%). 1H NMR (300 MHz, Acetonitrile-d3) δ 8.06 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 4.40 – 4.14 (m, 2H), 3.79 – 3.69 (m, 2H), 3.66 – 3.47 (m, 40H), 3.21 (d, J = 13.1 Hz, 1H), 2.86 (s, 4H), 1.30 (m, 2H), 1.13 – 0.79 (m, 2H). 13C NMR (151 MHz, CDCl 3 ) δ 169.77, 169.46, 161.66, 161.47, 152.75, 146.09, 132.90, 132.24, 117.82, 113.97, 113.29, 89.25, 88.92, 77.27, 77.06, 76.85, 74.69, 72.57, 71.19, 70.62, 70.54, 70.51, 70.47, 70.44, 70.36, 70.27, 70.20, 69.74, 69.70, 68.14, 65.77, 65.73, 61.63, 61.60, 40.72, 30.34, 25.68. 31P NMR (122 MHz, Acetonitrile-d + 3) δ -10.87. HRMS C 37 H 60 N 2 O 19 P calc.: 851.3573 [M+H]+, 851.3571. [00393] P5(PEG12)- [00394] The title compound was synthesized in accordance to general Method 2 from 40 mg bis(diisopropylamino)chlorophosphine (150 µmol, 1.00 eq.), 360 µL ethynylmagnesium bromide solution (0.5 M in THF, 180 µmol, 1.2 eq.), 245 mg of PEG12 (450 µmol, 3.0 eq), 0.83 mL 1H- tetrazole solution (0.45 M in MeCN, 450 µmol, 2.5 eq.) and 39 mg 4-azidobenzoic-acid (150 µmol, 1.00 eq.). The product was obtained as colourless oil after preparative HPLC (Method D) and lyophilization. (25 mg, 34 µmol, 23%). HR-MS for C + + 3 3 H 57 NO 16 P [M+H] calcd.: 754.3410, found 754.3398 (UV-trace in Figure 11). [00395] P5(PEG24)-OSu [00396] The title compound was synthesized in accordance to general Method 2 from 41 mg bis(diisopropylamino)chlorophosphine (159 µmol, 1.00 eq.), 370 µL ethynylmagnesium bromide solution (0.5 M in THF, 185 µmol, 1.2 eq.), 450 mg of PEG24 (388 µmol, 2.50 eq), 1.02 mL 1H- tetrazole solution (0.45 M in MeCN, 466 µmol, 3.0 eq.) and 40 mg 4-azidobenzoic-acid-N- hydroxysuccinimide ester (155 µmol, 1.00 eq.). The product was obtained as colourless oil after preparative HPLC (Method D) and lyophilization. (79 mg, 57 µmol, 37%). MS for C 2+ 6 1 H 109 N 2 O 30 P [M+2H]2+ calcd.: 690.3396, found 690.81. (UV-trace in Figure 12). [00398] A screw-cap-vial was charged with 34.3 mg of Exatecan Mesylate (0.0645 mmol, 1.0 eq.) and suspended in 645 µL of dry DMSO. 241 µL of a solution of a 0.4 mol/L solution of Fmoc-VC-PAB-PNP in dry DMSO (0.0967 mmol, 1.5 eq.), 64,5 µL of a 1 mol/L solution of HOBt hydrate in dry DMSO (0.0645 mmol, 1.0 eq.) and 113 µL of DIPEA were added (0.645 mmol, 10.0 eq.). The yellow solution was stirred for 2 h at 50°C. Afterwards, 425 µL of a solution of 50% Diethanolamine in dry DMSO (w/w) was added and the reaction mixture was allowed to stir at room temperature for another 30 minutes. 1.5 ml MeCN and 2.5 mL H 2 O added and the yellow solution was directly purified by preparative HPLC, using Method D. After lyophilization, 47.3 mg (76.7%, 0.0495mmol) of a yellowish solid were obtained as TFA-salt. [00399] HR-MS for C43H50FN8O + 9 [M+H]+ calcd.: 841.3680, found 841.3696 (UV-trace in Figure 13). [00400] NH2-VA-PAB-Exatecan TFA salt
[00401] A screw-cap-vial was charged with 1.23 mg of Exatecan Mesylate (0.00232 mmol, 1.0 eq.) and suspended in 23 µL of dry DMSO.8.7 µL of a solution of a 0.4 mol/L solution of Fmoc- VA-PAB-PNP in dry DMSO (0.00348 mmol, 1.5 eq.), 2.3 µL of a 1 mol/L solution of HOBt hydrate in dry DMSO (0.00232 mmol, 1.0 eq.) and 4 µL of DIPEA were added (0.0232 mmol, 10.0 eq.). The yellow solution was stirred over night at room temperature. Afterwards, 15 µL of a solution of 50% Diethanolamine in dry DMSO (w/w) was added and the reaction mixture was allowed to stir at room temperature for another 30 minutes. 1.5 ml MeCN and 2.5 mL H 2 O added and the yellow solution was directly purified by preparative HPLC, using Method C. After lyophilization, 1.01 mg (50.0 %, 0.00116 mmol) of a yellowish solid were obtained as TFA-salt. [00402] HR-MS for C 40 H 44 FN 6 O + 8 [M+H]+ calcd.: 755.3200, found 755.3201. (UV-trace in Figure 14). [00404] A screw-cap-vial was charged with 23,4 µL of a 200 mM solution of NH2-VC-PAB- Exatecan TFA salt in dry DMSO (0.00468 mmol, 1.0 eq.), 46,8 µL of a 200 mM solution of 2-(2- Hydroxyethoxy)ethyl-N-(4-benzoic-acid-N-hydroxysuccinimidees ter)-P-ethynyl phosphonamidate (P5(PEG2)-COOSu, 0.00936 mmol, 2.0 eq.) and 4.08 µL DIPEA (0.0234 mmol, 5.0 eq.). The solution was shaken for 5 hours at 50°C, cooled to room temperature, 1.5 ml MeCN and 2.5 mL H2O were added and the solution was directly purified by preparative HPLC, using Method C. After lyophilization, 1.33 mg (25.0 %, 0.00117 mmol) of a yellowish solid were obtained. [00405] HR-MS for C 56 H 64 FN 9 O 14 P+ [M+H]+ calcd.: 1136.4289, found 1136.4306. (UV-trace in Figure 15). [00407] A screw-cap-vial was charged with 51 µL of a 200 mM solution of NH2-VC-PAB- Exatecan TFA salt in dry DMSO (0.0102 mmol, 1.0 eq.), 102 µL of a 200 mM solution of PEG12-N- (4-benzoic-acid)-P-ethynyl phosphonamidate (P5(PEG12)-COOH, 0.0204 mmol, 2.0 eq.) in dry DMSO, 102 µL of a 250 mM solution of Pybop (0.0255 mmol, 2.5 eq.) in dry DMSO and 8.89 µL DIPEA (0.051 mmol, 5.0 eq.). The solution was shaken for 2 hours at room temperature, 1.5 ml MeCN and 2.5 mL H 2 O were added and the solution was directly purified by preparative HPLC, using Method D. After lyophilization, 15.91 mg (99.0 %, 0.0101 mmol) of a yellowish solid were obtained. [00408] HR-MS for C 76 H 105 FN 9 O 24 P2+ [M+H]2+ calcd.: 788.8492, found 788.8485. (UV-trace in Figure 16). [00410] A screw-cap-vial was charged with 102 µL of a 200 mM solution of NH2-VC-PAB- Exatecan TFA salt in dry DMSO (0.0204 mmol, 1.0 eq.), 204 µL of a 200 mM solution of (P5(PEG24)-OSu, 0.0408 mmol, 2.0 eq.) in dry DMSO, and 17.78 µL DIPEA (0.102 mmol, 5.0 eq.). The solution was shaken over night at room temperature, 1.5 ml MeCN and 2.5 mL H 2 O were added and the solution was directly purified by preparative HPLC, using Method D. After lyophilization, 25,76 mg (60.0 %, 0.01224 mmol) of a yellowish solid were obtained. [00411] HR-MS for C 2+ 2+ 1 00 H 153 FN 9 O 36 P [M+H] calcd.: 1053.5081, found 1053.50833. (UV- trace in Figure 17). [00413] A screw-cap-vial was charged with 11.6 µL of a 100 mM solution of NH2-VA-PAB- Exatecan TFA salt in dry DMSO (0.00116 mmol, 1.0 eq.), 8.7 µL of a 200 mM solution of PEG12- N-(4-benzoic-acid)-P-ethynyl phosphonamidate (P5(PEG12)-COOH, 0.00174 mmol, 1.5 eq.) in dry DMSO, 11.6 µL of a 200 mM solution of Pybop (0.00232 mmol, 2.0 eq.) in dry DMSO and 2.02 µL DIPEA (0.0116 mmol, 10.0 eq.). The solution was shaken for 2 hours at room temperature, 1.5 ml MeCN and 2.5 mL H 2 O were added and the solution was directly purified by preparative HPLC, using Method C. After lyophilization, 0.56 mg (32,2 %, 0.000375 mmol) of a yellowish solid were obtained. [00414] HR-MS for C 73 H 99 FN 7 O 23 P2+ [M+H]2+ calcd.: 745.8252, found 745.8255. (UV-trace in Figure 18). [00415] P5(PEG12)-Exatecan
[00416] A screw-cap-vial was charged with 50 µL of a 100 mM suspension of Exatecan Mesylate in dry DMSO (0.005 mmol, 1.0 eq.), 20 µL of a 250 mM solution of PEG12-N-(4-benzoic- acid)-P-ethynyl phosphonamidate (P5(PEG12)-COOH, 0.005 mmol, 1.0 eq.) in dry DMSO, 20 µL of a 300mM solution of Pybop (0.006 mmol, 1.2 eq.) in dry DMSO and 4.33 µL DIPEA (0.025 mmol, 5.0 eq.). The solution was shaken for 2 hours at room temperature, 1.5 ml MeCN and 2.5 mL H2O were added and the solution was directly purified by preparative HPLC, using Method C. After lyophilization, 2.63 mg (45.0 %, 0.0023 mmol) of a yellowish solid were obtained. [00417] HR-MS for C 57 H 77 FN 4 O 19 P+ [M+H]+ calcd.: 1171.4899, found 1171.4852. (UV-trace in Figure 19). [00418] mAb and ADC characterization [00419] Analytical overview of the Synthesized mAbs and ADCs from P5(PEG24)-VC- PAB-Exatecan (Figure 20) [00420] %HMWS have been measured by analytical size-exclusion chromatography, as described above. % indicates the area of peaks with a lower retention time with respect to the monomeric species. Charge variant analysis has been performed as described above. Indicated are changes after incubation for 7 days at 40°C with respect to day 0. ADC Retention time has been measured by Hydrophobic interaction Chromatography, as described above. The Ti has been obtained from the melting curves, measured by nano DSF, as described above. The binding affinity has been measured by flow cytometry (FACS on OVCAR-3 cells, or via ELISA on the isolated protein as described above. The Cytotoxicity has been assessed via a Resazurin assay, as described above. Internalization is stated as % of MFI ratio for pH rodo after 5-6 hours with respect to timepoint 0, as described above. [00421] Analytical Raw Data for an exemplary monoclonal antibody (Figure 21). [00422] (A-D) Analytical characterization of one of the described mAbs. The antibody was expressed in Expi-CHO cells and purified via Protein A chromatography, as described above. The mAb has been analyzed via HLPC-SEC (A), LC-MS (B), HLPC-HIC (C) and reducing SDS-PAGE (D). [00423] LC/MS analysis of the antibody clones [00424] Parental (Figure 22) [00425] Calculated LC: 23473, found: 23472 ; Calculated HC: 48705, found: 48706. [00426] AV15 (Figure 23) [00427] Calculated LC: 23459, found: 23458; Calculated HC: 48705, found: 48706. [00428] AV18 (Figure 24) [00429] Calculated LC: 23473, found: 23472; Calculated HC: 48632, found: 48634. [00430] AV21 (Figure 25) [00431] Calculated LC: 23473, found: 23472; Calculated HC: 48564, found: 48566. [00432] AV25 (Figure 26) [00433] Calculated LC: 23443, found: 23442 ; Calculated HC: 48632, found: 48634. [00434] AV29 (Figure 27) [00435] Calculated LC: 23443, found: 23442; Calculated HC: 48634, found: 48636. [00436] Analytical Raw Data for an exemplary ADC (Figure 28) [00437] Figure 28. (A-D) Analytical characterization of AV25-P5(PEG24)-VC-PAB-Exatecan (DAR8), synthesized and purified as described above. A) Analytical size-exclusion chromatography, B) LC-MS of the ADC product C) analytical hydrophobic interaction chromatography after conjugation. The data indicates that the ADC is fully conjugated to DAR8 with only low amounts of aggregates being present after purification. [00438] LC/MS analysis of the ADCs [00439] Parental-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 29) [00440] Calculated LC: 25579, found: 25577 ; Calculated HC: 55023, found: 55021. [00441] AV15-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 30) [00442] Calculated LC: 25565, found: 25563 ; Calculated HC: 55023, found: 55022. [00443] AV18-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 31) [00444] Calculated LC: 25579, found: 25577 ; Calculated HC: 54950, found: 54947. [00445] AV21-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 32) [00446] Calculated LC: 25579, found: 25577; Calculated HC: 54882, found: 54881. [00447] AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 33) [00448] Calculated LC: 25549, found: 25547; Calculated HC: 54950, found: 54950. [00449] AV29-P5(PEG24)-VC-PAB-Exatecan DAR8 (Figure 34) [00450] Calculated LC: 25549 found: 25547; Calculated HC: 54952, found: 54950. [00451] Example 2: Ex vivo serum stability, in vivo efficacy in a cell line derived xenograft model (CDX) and in vivo efficacy in patient derived xenograft models (PDX) of an exemplary ADC of the present invention: [00452] Ex vivo serum stability: [00453] Serum samples of the respective species were spiked with AV25-P5(PEG24)-VC- PAB-Exatecan DAR 8 at a concentration of 0.2 mg/ml in at least 80% serum. Samples were sterile filtered with UFC30GV0S centrifugal filter units (Merck, Germany) and incubated at 37°C for 1, 2, 3, 5 and 7 days. Samples for day 0 were directly processed further. [00454] Recombinant NaPi2B-antigen was coupled to Thermo NHS Magnetic beads according to the manufacturer´s instructions. The bead storage solution was removed from 40 µl of the NaPi2B-coupled bead suspension. The beads were incubated with 100 μl of the serum-ADC mix, premixed with 200 µl PBS, for 2h at room temperature. Afterwards, the supernatant was removed and the resin washed 2 times with 1 mL PBS-T. Following by incubation for 15 minutes with 10 μl 100 mM Glycin buffer pH 2.5 at room temperature. This solution was rebuffered to PBS by using 75 µL Zeba™ Spin Desalting Columns with 7K MWCO (Thermo Fisher Scientific, USA). The samples were processed further for MS-measurements, as described above. The Drug-to- Antibody ratio (DAR) was calculated from the MS intensities of the light chain adducts conjugated to 0 or 1 and heavy chain adducts conjugated to 0-3 molecules of P5(PEG24)-VC-PAB-Exatecan. [00455] The results clearly show that the linker between the AV25 antibody and the Exatecan drug molecules is highly stable in sera of different species, without a significant amount of payload loss after several days of incubation of the ADC (No change in the Drug-to-Antibody Ratio (DAR) (Figure 35). [00456] In vivo efficacy of the ADC in a cell line derived xenograft model (CDX): [00457] All animal experiments were conducted in accordance with German animal welfare law and approved by local authorities. In brief, 1x107 OVCAR-3 cells (100µL +100µL Matrigel) were subcutaneously injected to CB17-Scid mice. Treatment was initiated when tumours reached a mean tumour volume of 0.1-0.15 cm3 15 days after implantation. 5 animals per group were treated once at day 0 with either 1 mg/kg, 3 mg/kg or 5 mg/kg of AV25-P5(PEG24)-VC-PAB- Exatecan DAR 8, Isotype-P5(PEG24)-VC-PAB-Exatecan DAR 8, or vehicle, as intravenous injection after randomisation into treatment and control groups. Tumour volumes, body weights and general health conditions were recorded throughout the whole study. [00458] Complete tumor remission over all dose levels (1,3 and 5 mg/kg) at a single injection was observed for the targeted AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8. Whereas only minor effects were observed for the highest dose of 5 mg/kg for the non-targeted isotype control Isotype- P5(PEG24)-VC-PAB-Exatecan DAR 8 (left) (Figure 36). This clearly shows a marked effect of NaPi2B targeting with AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8. The comparison to literature- known NaPi2B-targeting ADCs such as lifastuzumab vedotin, in in vivo models, derived from the same OVCAR3 cell line, shows a clear advantage for AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 over all tested dose levels. AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 does not show any tumor relapse until the end of the observation period with a single dose as low as 1 mg/kg, which is very unusual compared to other NaPi2B targeting ADCs, dosed even higher and more often in the same OVCAR3 model. [00459] In vivo efficacy of the ADC in patient derived xenograft models (PDX): [00460] All animal experiments were conducted in accordance with German animal welfare law and approved by local authorities. In brief, a 3x3 mm sample of a patient derived tumor sample was subcutaneously implanted into flanks of female immunodeficient NMRI nu/nu mice. Treatment was initiated when tumours reached a mean tumour volume of 0.1-0.15 cm3. Animals per group were treated once at day 0 with 10 mg/kg of AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 or vehicle, as intravenous injection. Tumour volumes, body weights and general health conditions were recorded throughout the whole study. [00461] The data clearly demonstrates very high and long-lasting efficacy in patient derived tumor models in vivo compared to the vehicle control in different tumor types such as lung, endometrial and ovarian cancer (Figure 37). [00462] In vivo toxicity in cynomolgus monkeys: [00463] Toxicology studies were performed in cynomolgus monkeys. Two animals for each group were dosed intravenously with 10 and 20 mg/kg AV25-P5(PEG24)-VC-PAB-Exatecan on days 1 and 22, with terminal necropsy at day 43. Three different analytes, including total ADC, intact ADC and free Exatecan were analyzed in the animal plasma samples through ELISA and LC/MS-MS. Exposure and pharmacokinetic (PK) parameters were assessed for each analyte. No severe changes in body weight, clinical chemistry, hematology and histopathology were observed at those dose levels. The HNSTD (highest nonseverely toxic dose) was defined to be at least 20 mg/kg in this study. [00464] For PK analysis, both, total ADC and intact ADC were measured via ELISA. The first ELISA setup is for the quantification of the human antibody (total antibody/total mAb). [00465] The first ELISA setup is for the quantification of the human antibody (total antibody/total mAb). For that, recombinant purified NaPi2B antigen is immobilized on protein- binding plates. Samples and standard dilutions are added to the wells and AV25-P5(PEG24)-VC- PAB-Exatecan, independently from its DAR, will be captured. A specific human detection antibody, recognizing the kappa-LC is added to the wells to enable quantification of the captured total antibody. [00466] The second ELISA setup is designed to specifically measure the intact ADC (with the linker-payload attached). For that an anti-payload specific antibody is immobilized on binding plates. Only AV25-P5(PEG24)-VC-PAB-Exatecan with (at least one) conjugated payload molecules are detected. Samples and standard dilutions are added to the wells and only payload- conjugated AV25-P5(PEG24)-VC-PAB-Exatecan will be captured. A specific human detection antibody, recognizing the kappa-LC, is added to the wells to enable quantification of the captured total antibody. [00467] The amount of free Exatecan in plasma samples from cynomolgus monkey after treatments with AV25-P5(PEG24)-VC-PAB-Exatecan, was determined by liquid-chromatography mass spectrometry (LCMS). A quantification method was established on a Xevo G2-XS qTOF machine, using MRM (multiple reaction monitoring) acquisition mode and specific mass transitions for Exatecan. Deuterated Exatecan-d5 was used as internal standard during all measurements. To quantify the amount of free Exatecan in serum samples from different treatment groups and timepoints, a liquid-extraction procedure was performed, separating protein content from lipophilic small molecules. For the preparation of calibration curves and control samples, pre-dilutions of Exatecan and Exatecan-d5 were prepared in ACN:H 2 O 1:1, at concentrations of 100 nM and 10 nM, respectively. The assay has been performed in accordance with a quantification assay that was previously described for DxD by Nagai et al., 2018. [00468] The PK analysis shows a good exposure profile, without enhanced in vivo clearance in the cross reactive species (Figure38). [00469] The HNSTD (highest nonseverely toxic dose) was defined to be at least 20 mg/kg in this study. This dose is at least 6-times higher compared to doses that were explored in toxicology studies with other NaPi2B-targeting ADCs (Figure 38). [00470] This significant improvement in increasing tolerability of the ADC and the excellent PK-profile could be attributed to the improved properties of the antibody clones described herein, such as reduced aggregation tendency of the AV25 clone that has been described above. Antibody and ADC aggregation has been shown to be one of the major off-target toxicity drivers of ADCs. [00471] Example 3: Further characterization of the AV25 mAb and ADCs based thereon [00472] For all data shown, AV25-P5(PEG24)-VC-PAB-Exatecan and AV25 refers to the LALA-mutated version of the AV25 mab, if not explicitly labeled as AV25-wt. [00473] Synthesis of anti-Napi2b comparison antibody [00474] DNA coding for the light chain (SEQ ID NO: 56 MLPSQLIGFLLLWVPASRGDIQMTQSPSSLSASVGDRVTITCRSSETLVHSSGNTYLEWY QQKPG KAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSFNPLTFGQG TKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*; LC is shown in italic) and heavy chain (SEQ ID NO: 57 MDWTWRILFLVAAATGAHSEVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAP GKG LEWVATIGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHRGFDV GHFDF WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APEAA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMH EALHNHYTQKSLSLSPGK*; HC is shown in italic) of anti-NaPi2b comparison antibody was synthesized (Geneart, Thermo Fisher). Signal sequences for heavy chain (SEQ ID NO: 58, MDWTWRILFLVAAATGAHS) and light chain (SEQ ID NO: 59, MLPSQLIGFLLLWVPASRG) were added. Light chain and heavy chain sequences were cloned into pcDNA3.4-TOPO (Thermo Fisher) expression plasmid. Antibodies were then transiently expressed in Expi-CHO-S cells (Thermo Fisher) by co-transfecting cells with pcDNA3.4 expression plasmids (Thermo Fisher), coding for the heavy and light chain of the respective sequences in a 1:1 ratio, using the Expi-CHO transfection system (Thermo Fisher). Cells were harvested by centrifugation at 300 g for 5 minutes at 4°C. To clear micro particles from supernatant, supernatants were centrifuged at 4000–5000 g for 30 min at 4 °C. For further clarification supernatants were passed through a 0.22 µm filter. Antibodies were purified from cleared and filtered supernatants via Protein A chromatography. [00475] Synthesis of anti-Napi2b comparison ADC [00476] 50 μl of a solution of a 10 mg/mL anti-Napi2b comparison antibody (66.67 µM) in Dulbecco’s-PBS (Merck KGaA) were mixed with 1.33 μl of a TCEP solution (0.5 mM in buffered solution, Merck KGaA diluted to 10 mM with PBS, 4 eq. TCEP with respect to the antibody). After 30 Min incubation at RT, 1,66 μl of a 20 mM solution of Maleimidocaproyl valine citruilline p- aminobenzyl carbamate-MonomethylauristatinE (MC-VC-PAB-MMAE) in DMSO (10.0 eq. with respect to the antibody) were added. The mixture was shaken (350 RPM) at room temperature (25°C) for 1 hour. The reaction mixture was purified by preparative size-exclusion chromatography with a 25 ml Superdex™ 200 Increase 10/300GL (Cytiva, Sweden) and a flow of 0.8 ml/min eluting with sterile PBS (Merck, Germany). The antibody containing fractions were pooled and concentrated by spin-filtration (Amicon® Ultra- 2mL MWCO: 30 kDa, Merck, Germany) and analyzed by MS, as described above. MS analysis has been performed as described in example 1. [00477] Figure 39 shows a MS analysis of the anti-Napi2b comparison ADC, synthesized by the method described above. Signals are annotated with the measured mass in Dalton and the absolute intensities. Shown is an exemplary spectrum from the conjugation reaction. The Drug-to- Antibody ratio of the final conjugated have been estimated from the MS signals to 3.5 to 4.0. LC: light chain of anti-Napi2b comparison antibody, HC: heavy chain anti-Napi2b comparison antibody. [00478] Binding to human NaPi2a, NaPi2b and NaPi2c evaluated by Flow Cytometry [00479] To determine concentration-dependent binding, HEK293 cells transiently or stably expressing human Napi2a-, Napi2b- and Napi2c-mCherry were incubated with antibodies or ADCs in concentrations ranging from 0.002 to 200 nM, stained with an Alexa-dye-labeled anti-human IgG H+L secondary antibody (Thermo Fisher Scientific), and analyzed by flow cytometry. Mean fluorescence intensity (MFI) ratios were normalized to the non-specific binding control. The assay was performed in duplicates and data points were analyzed by a non-linear regression using a one-site specific binding model using Prism 9 software. Graph shows means of n = 2 ± SD. [00480] In this experiment, specificity of AV25 and AV25-P5(PEG24)-VC-PAB-Exatecan towards Napi2b was determined. Of note, AV25 only shows binding to HEK293 cells overexpressing Napi2b (SLC34A2), but not Napi2a (SLC34A1) or Napi2c (SLC34A3). Both are members of the SLC34 family sharing 45.5-50.9% sequence homology with Napi2b. [00481] The experiment clearly demonstrates highest selectivity of AV25 to target NaPi2b over the other NaPi2 proteins. This highlights an important feature for the antibody disclosed herein for selective tumor targeting. [00482] Figure 40 shows the binding, expressed as MFI ratio, of unmodified AV25 mAb and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 ADC to HEK293-cells transfected with Napi2a (left), Napi2b (middle) and Napi2c (right). AV25 mAb and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 ADC bind specifically to NaPi2b. Graphs show n = 2 ± SD (note, error bars are too small to be displayed). [00483] In vitro Cytotoxicity evaluated via Resazurin assay Synthesis of anti-Napi2b comparison ADC vs AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 [00484] To investigate direct cytotoxicity of ADCs, respective cells were seeded in a 96-well plate (flat bottom, 5000 cells/well, suspended in 100 µl medium) and incubated for 7 days with increasing concentrations of the ADCs in medium (0-12 µg/ml) to generate a dose-response curve. Before viability analysis, the supernatant over the adherent cells was removed and replaced by fresh medium. Killing was analyzed afterwards, using resazurin (Sigma-Aldrich) as the cell viability dye at a final concentration of 55 µM. Fluorescence emission at 590 nM was measured on a Microplate reader Infinite M200 Pro (Tecan). Cell viability was measured by dividing the fluorescence of ADC-treated cells by the fluorescence from control cells, treated in the same way with medium only. Graph shows means of n = 2 ± SEM. [00485] In this experiment, the cytotoxicity on Napi2bhigh-expressing cell lines of AV25- P5(PEG24)-VC-PAB-Exatecan DAR 8 compared to anti-Napi2b comparison ADC, targeting NaPi2b was investigated. On HCC-78 AV25-P5(PEG24)-VC-PAB-Exatecan showed a tremendous increase in selective potency of a 15.5-fold lower IC50-concetration compared to anti-Napi2b comparison ADC. No unspecific toxicity was observed on target-negative cells. [00486] Figure 41 shows the cytotoxicity dose-response of AV25-P5(PEG24)-VC-PAB- Exatecan DAR 8 compared to anti-NaPi2b comparison ADC on 3 different cell lines. Shown are mean and SD of two measurements, as well as a dose-response-fit. Fluorescence in % of medium control is equal to % of viable cells. [00487] In vitro inhibition of Topoisomerase-I by the delivery of Exatecan via the ADC [00488] Topoisomerase-I inhibition by delivery of exatecan via the AV25-P5(PEG24)-VC- PAB-Exatecan DAR8 ADC induces DNA damage as detected by the accumulation of cleaved PARP, active caspase 3 and phosphorylated histon 2AX (pH2AX). OVCAR-3 and HCC-78 cells (both Napi2bhigh) were treated with increasing concentrations (0.05 – 12 µg/ml) of AV25- P5(PEG24)-VC-PAB-Exatecan or an Isotype control (isotype-P5(PEG24)-VC-PAB-Exatecan for 72 h. Cells were stained with live/dead stain (Thermo Fisher Scientific) and after fixation and permeabilization using the Fixation/Permeabilization kit (BD Biosciences) for the DNA damage markers active caspase 3, cleaved PARP and pH2AX (Ser-139) (all BD Biosciences) and analyzed by flow cytometry. Graphs show means of n = 2 ± SEM. [00489] AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 induces a concentration-dependent accumulation of DNA damage as shown by the increase of cleaved PARP-, active caspase 3- and pH2AX-positive HCC-78 (A) and OVCAR-3 (B) cells, whereas the isotype control remains inactive. [00490] The experiment clearly shows that the ADCs are delivering the exatecan selectively into the targeted cell and induce cell killing by topoisomerase-I-inhibition. [00491] Figure 42 shows the dose-dependent induction of DNA-damage and apoptosis markes in response to treatment with increasing concentrations of AV25-P5(PEG24)-VC-PAB- Exatecan DAR8. A corresponding non-targeting isotype control conjugate was included as negative control. HCC-78 cells (A, NaPi2bhigh) and OVCAR-3 cells (B, NaPi2bhigh) were treated with increasing concentrations (0.05 – 12 µg/ml) of AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 or the Isotype ADC (Isotype-P5(PEG24)-VC-PAB-Exatecan DAR8) for 72h, Cells were stained for cleaved PARP (left), Caspase 3 (middle) and pH2AX (right) and analyzed via flow cytometry. Graphs show means of n = 2 ± SEM. [00492] Interaction with complement factor C1q [00493] To reduce or even prevent interaction of the IgG1 backbone AV25 antibody with complement factors or Fc receptors (FcRs) that might trigger unwanted immune activation and/or FcR-mediated cellular uptake, the Fc-part of the AV25 antibody and the derived ADC AV25- P5(PEG24)-VC-PAB-Exatecan DAR8 has been silenced using two point mutations L234A and L235A (LALA). [00494] In this experiment, interaction of the LALA-silenced AV25 [00495] (HC-LALA: SEQ ID NO: 60 [00496] MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHW VKQAPGQGLEWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYC ARGET ARATFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVF SCSVMHEALHNHYTQKSLSLSPGK*; HC is shown in italic) vs Fc-wildtype AV25 (HC-wt: SEQ ID NO: 61: MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHWVKQAP GQGL EWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYCARGETARAT FAYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALH NHYTQKSLSLSPGK*; HC is shown in italic) with complement factor C1q was analyzed. C1q interaction studies were performed using the HTRF Human C1q Binding Kit (Cisbio) according to the manufacturer’s instructions. In brief, AV25 HC-wt and HC-LALA, a standard and an anti-MHC-I positive control (Invivogen) known to interact with C1q are captured and aggregated by an anti-human IgG Fab-biotin complexed to streptavidin, which binds streptavidin-labelled d2 (fluorescence acceptor). If the antibodies bind to human C1q, an anti-C1q antibody labelled with Europium cryptate (fluorescence donor) can come in close proximity to the fluorescence acceptor and fluorescence resonance energy transfer (FRET) is triggered. Fluorescence emission at 665 nm is measured on a microplate reader Infinite M200 Pro (Tecan). Graphs show means of n = 2 ± SD. [00497] While AV25 HC-wt binds similarly well to C1q as the standard and the anti-MHC-I positive control, interaction with C1q is completely abolished for AV25 HC-LALA. The reduced interaction with C1q is expected to decrease undesired activation of the innate immune system. [00498] Figure 43 shows the binding of the Fc region of the AV25 HC-LALA antibody versus the AV25 HC-wt antibody to recombinant hexameric C1q complement protein was measured in a HTRF (Homogenous Time-Resolved Fluorescence) based human C1q binding assay (HTRF Human C1q Binding Kit, Cisbio) according to manufacturer’s instructions. In brief, serial dilutions 280 nM - 11.6 nM of all tested antibodies (AV25 HC-wt, AV25 HC-LALA, α-MHC-I positive, IgG1 kit standard) were measured. HTRF ratio was calculated by dividing the acceptor emission signal at 665 nm by the donor emission signal at 620 nm and multiplying by 10000. Graph shows HTRF ratio at 70 nM concentration with the background (diluent only) HTRF ratio subtracted. Graph shows means of n = 2 ± SD. [00499] Interaction with FcRs [00500] To reduce or even prevent interaction of the IgG1 backbone AV25 antibody with complement factors or Fc receptors (FcRs) that might trigger unwanted immune activation and/or FcR-mediated cellular uptake, the Fc-part of the AV25 antibody and the derived ADC AV25- P5(PEG24)-VC-PAB-Exatecan DAR8 has been silenced using two point mutations L234A and L235A (LALA). [00501] In this experiment, interaction of the LALA-silenced AV25 (HC-LALA: SEQ ID NO. 62: MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHWVKQAP GQGL EWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYCARGETARAT FAYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE AAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALH NHYTQKSLSLSPGK*; HC is shown in italic) and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 vs Fc-wildtype AV25 (HC-wt: SEQ ID NO: 63, MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHWVKQAP GQGL EWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYCARGETARAT FAYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALH NHYTQKSLSLSPGK*; HC is shown in italic) with Fc gamma receptors (FcγRs) was analyzed. FcγR interaction studies were performed using the Lumit™ FcγR Binding Immunoassays (FcγRn, FcγRI, FcγRIIa/CD32 R131/H131 polymorphism, FcγRIIIa/CD16 V158/F158 polymorphism; Promega) based on a competition principle and luciferase detection according to the manufacturer’s instructions. In brief, AV25 HC- wt, HC-LALA and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8, a standard and trastuzumab as positive control were incubated with a Tracer-LgBiT and a FcγR-SmBiT. In the absence of an antibody analyte or if no interaction of the tested antibody with FcγRs takes place, Tracer-LgBiT binds to the FcγR-SmBiT target, resulting in maximum luminescence signal. In the case of successful interaction with FcγRs, the tested antibody/ADC will compete with Tracer-LgBiT for binding to the FcγR target, resulting in a concentration-dependent decrease in the luminescent signal. Luminescence is measured on a microplate reader Infinite M200 Pro (Tecan). Graphs show n = 1. [00502] While AV25 HC-wt binds similarly well to all FcγR as the IgG1 positive control, interaction with FcγR is either highly reduced or in most cases completely abolished for AV25 HC- LALA and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8. Interestingly, the positive control trastuzumab even shows reduced interaction with all FcγR compared to the positive control. In the FcγRn interaction experiment, the murine AV25 served as another negative control. [00503] The experiment clearly showed reduction of undesired interaction with FcγRI (CD64), CD16 and CD32, mediated by the incorporation of the LALA mutation into the AV25 antibody. The reduced interaction with those receptors is expected to decrease undesired uptake of the AV25 related ADC conjugates into non-targeted cells and thereby reduce undesired toxicities. Interaction with FcRn was only mildly reduced. [00504] Figure 44 shows dose-dependent binding of the Fc region of the AV25-HC-LALA antibody and the AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 ADC versus the AV25-HC-wt antibody to recombinant human FcRn and FcγR was measured using Lumit™ FcγR Binding Immunoassays (FcγRn, FcγRI, FcγRIIa/CD32 R131/H131 polymorphism, FcγRIIIa/CD16 V158/F158 polymorphism; Promega) according to the manufacturer’s instructions. Serial dilutions of AV25 HC-wt, AV25 HC-LALA and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8, a standard and trastuzumab as positive control were incubated with the Tracer-LgBiT and a FcγR-SmBiT. In the absence of an antibody analyte or if no interaction of the tested antibody with FcγRs takes place, Tracer-LgBiT binds to the FcγR-SmBiT target, resulting in maximum luminescence signal. In the case of successful interaction with FcγRs, the tested antibody/ADC will compete with Tracer-LgBiT for binding to the FcγR target, resulting in a concentration-dependent decrease in the luminescent signal. Luminescence was measured on a microplate reader Infinite M200 Pro (Tecan). Graphs show n = 1. [00505] ADCC [00506] To reduce or even prevent interaction of the IgG1 backbone AV25 antibody with complement factors or Fc ^ receptors (Fc ^Rs) that might trigger unwanted immune activation and/or FcR-mediated cellular uptake, the Fc-part of the AV25 antibody and the derived ADC AV25- P5(PEG24)-VC-PAB-Exatecan DAR8 has been silenced using two point mutations L234A and L235A (LALA). [00507] In this experiment, the antibody-dependent cellular cytotoxicity (ADCC) of the Fc- wildtype AV25 mAb (HC-wt: SEQ ID NO: 64, MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHWVKQAP GQGL EWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYCARGETARAT FAYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALH NHYTQKSLSLSPGK*; HC is shown in italic) and LALA-silenced AV25 mAb (HC-LALA: SEQ ID NO: 65, MDWTWRILFLVAAATGAHSEVQLVQSGAEVVKPGASVKMSCKASGYTFTGYIIHWVKQAP GQGL EWIGAIYPGSGATSYKQKFRGRATLTADTSTSTVYMELSSLRSEDSAVYYCARGETARAT FAYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE AAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALH NHYTQKSLSLSPGK*; HC is shown in italic) and AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 vs the isotypes and an anti-MHC-I positive control (Invivogen) was analyzed, which is mediated after interaction with FcγRIIIa (CD16). For the Calcein release-based antibody-dependent cellular cytotoxicity (ADCC) assay, peripheral blood mononuclear cells (PBMCs) were isolated from healthy donor buffy coats (purchased from DONAS GmbH) using LeucoSep tubes (Greiner Bio-One) and Histopaque®-1077 (density 1.077 g/ml, Merck) density gradient according to standard protocols. Afterwards, natural killer (NK) cells were MACS (magnetic cell separation)-sorted using human NK cell isolation kit (Miltenyi Biotec) by negative selection according to the manufacturer’s instructions yielding untouched human primary NK cells. Napi2b-positive target cells OVCAR-3 and HCC-78 (both Napi2bhigh) were stained with 16 µM Calcein AM (Thermo Fisher Scientific).40.000 NK cells and 10.000 Calcein-stained target cells were incubated at a 4:1 ratio in the presence of 15 µg/ml antibodies or ADCs. Cells permeabilized with 2.5% Triton X 100 (Merck) served as a positive control for maximum Calcein release. After 4 h, supernatants were transferred to a flat black non-binding 96-well plate (Greiner Bio-One) and fluorescence was measured at 485/535 nM via the Infinite M200 Pro reader (Tecan). The percent specific killing was calculated by dividing the Calcein released by antibody-mediated killing minus background Calcein release (NKs + targets) from Calcein released by Triton X-permeabilized cells (maximum killing) minus background Calcein release (targets only). Graphs show means of n = 2 ± SEM. [00508] The anti-MHC-I positive control and AV25 HC-wt triggered high ADCC activity in human NK cells, whereas all LALA-silenced antibodies and ADCs (AV25 HC-LALA, AV25- P5(PEG24)-VC-PAB-Exatecan DAR8 and isotype controls) did not induce ADCC or only in very low amounts. Reduced ADCC is expected to decrease undesired toxicities of AV25 related antibodies. [00509] Figure 45 shows a calcein release-based antibody-dependent cellular cytotoxicity (ADCC) assay. Co-cultures of healthy donor (HD)-derived NK cells and calcein-stained target- positive tumor cells (OVCAR-3 and HCC-78), in a 4:1 ratio, were incubated with 15 µg/ml of indicated antibodies or ADCs (anti-MHC-I antibody served as positive control). The percentage of specific killing was calculated by deviding the calcein released by antibody-mediated cell killing from calcein released by Triton X-permeabilized cells (maximum killing). Graphs show means of n = 2 ± SEM. [00510] AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 dose response and exposure PDX study (Lu7700) [00511] All animal experiments were conducted in accordance with German animal welfare law and approved by local authorities. In brief, a 3x3 mm sample of a patient derived tumor sample (Lu7700 non-small cell lung cancer (NSCLC) model, EPO Experimentelle Pharmakologie & Onkologie Berlin-Buch GmbH) was subcutaneously implanted into flanks of female immunodeficient NMRI nu/nu mice. Treatment was initiated when tumours reached a mean tumour volume of 0.1-0.15 cm3. Animals per group were treated once at day 0 with 5, 3 or 1 mg/kg of AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8, 5 mg/kg isotype-P5(PEG24)-VC-PAB-Exatecan DAR 8 or vehicle, as intravenous injection. Tumour volumes, body weights and general health conditions were recorded throughout the whole study. [00512] The data demonstrate highest and long-lasting efficacy for all tested ADC dose levels in the NSCLC PDX models in vivo compared to the vehicle control. The effect is highly specific for the targeted anti-TPBG-antibody, exemplified by the non-targeted isotype control ADC group at the highest dose. [00513] Figure 46 shows the results of an in vivo efficacy analysis of the AV25-P5(PEG24)- VC-PAB-Exatecan (DAR 8), which is a representative ADC of the present invention, in a patient- derived NSCLC xenograft model (PDX, Lu7700). Shown on the left is tumor volume over time after treatment once at day 0 with different dose levels of the AV25-P5(PEG24)-VC-PAB-Exatecan (DAR 8) (1, 3 and 5 mg ADC/kg bodyweight), an isotype control carrying the same amount of linker-payload (5 mg/kg) versus untreated (vehicle). Shown on the right are bodyweights of the animals treated with different dose levels of the AV25-P5(PEG24)-VC-PAB-Exatecan (DAR 8), an isotype control carrying the same amount of linker-payload versus untreated (vehicle). All results are shown as Mean and SEM of 4 animals per group. [00514] AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 dose response and exposure PDX study (Ov6668) [00515] All animal experiments were conducted in accordance with German animal welfare law and approved by local authorities. In brief, a 3x3 mm sample of a patient derived tumor sample (Ov6668 ovarian cancer model, EPO Experimentelle Pharmakologie & Onkologie Berlin-Buch GmbH) was subcutaneously implanted into flanks of female immunodeficient NMRI nu/nu mice. Treatment was initiated when tumours reached a mean tumour volume of 0.1-0.15 cm3. Animals per group were treated once at day 0 with 5, 3 or 1 mg/kg of AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 or vehicle, as intravenous injection. Tumour volumes, body weights and general health conditions were recorded throughout the whole study. [00516] The data demonstrate highest and long-lasting efficacy for all tested ADC dose levels in the PDX models in vivo compared to the vehicle control. Dose-proportionality for exposure has been demonstrated in the PK data. The PK analysis has been performed as described in example 1. [00517] Complete tumor remission with dose levels of 5 and 3 mg/kg in a ovarian cancer PDX at a single injection was observed for the targeted AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8. The 1mg/kg dosing in the ovarian cancer model also showed strong tumor regression which was followed by partial tumor re-growth after day 40. The PK analysis shows dose proportional exposure profiles and high stability of the AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 ADC at the tested dose levels 5, 3 and 1 mg/kg. [00518] The data demonstrate high and long-lasting efficacy for all tested ADC dose levels of AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 in the PDX model in vivo compared to the vehicle. No reduction in bodyweight suggests highest tolerability. The PK analysis shows dose proportional exposure profiles and high stability of the AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 ADC at the tested dose levels 5, 3 and 1 mg/kg. [00519] Figure 47 shows in A the results of an in vivo efficacy analysis of the AV25- P5(PEG24)-VC-PAB-Exatecan DAR 8, which is a representative ADC of the present invention, in a patient-derived ovarian cancer xenograft model (PDX, Ov6668). Shown on the left is tumor volume over time after treatment once at day 0 with different dose levels of the AV25-P5(PEG24)-VC-PAB- Exatecan (DAR 8) (1, 3 and 5 mg ADC/kg bodyweight) versus untreated (vehicle). Shown on the right are bodyweights of the animals treated with different dose levels of the AV25-P5(PEG24)-VC- PAB-Exatecan (DAR 8), versus untreated (vehicle). All results are shown as Mean and SEM of 9 animals per group. Figure B shows the in vivo PK evaluation for total and intact ADC for the three dose levels of the dose-response efficacy study as Mean and SD from three measurements per time point from mice treated once at day 0 with different dose levels of the AV25-P5(PEG24)-VC- PAB-Exatecan (1, 3 and 5 mg ADC/kg bodyweight). The PK analysis has been performed as described in example 1. [00520] AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 PDX studies (10mg/kg) [00521] The figure shows results of an in vivo efficacy analysis of a single 10 mg/kg dose of either AV25-P5(PEG24)-VC-PAB-Exatecan (DAR 8), which is a representative ADC of the present invention, or isotype-AV25-P5(PEG24)-VC-PAB-Exatecan (DAR 8) in three patient-derived ovarian cancer xenograft models with various NaPi2b expression levels and BRCA mutational states (PDX). The PDX experiments have been performed as described in example 2. [00522] The data clearly demonstrates very high and long-lasting efficacy in patient derived ovarian cancer tumor models in vivo compared to the vehicle control, even in very difficult to treat BRCA-mutated PDX models and models that exhibit low Napi2b target expression. [00523] Figure 48 shows the results of an in vivo efficacy analysis of the AV25-P5(PEG24)- VC-PAB-Exatecan (DAR 8), which is a representative ADC of the present invention, in patient- derived ovarian cancer xenograft models. Shown on top is tumor volume over time after treatment once at day 0 with 10 mg ADC/kg bodyweight of the AV25-P5(PEG24)-VC-PAB-Exatecan (DAR 8) or Isotype- P5(PEG24)-VC-PAB-Exatecan (DAR 8) versus untreated (vehicle). Shown on the bottom is a BRCA-mutated model with low NaPi2B expression (bottom left) and high NaPi2B expression (bottom right). All results are shown as Mean and SEM of 3 animals per group. [00524] Binding to NaPi2b-expressing cell lines OVCAR-3 and HCC-78 evaluated by Flow Cytometry – Upifitamab vs AV25 [00525] Upifitamab is antibody with the same sequence of the parental mAb of the present disclosure. Upifitamab has been purchased from MedChemExpressed to perform the following experiments. [00526] To determine concentration-dependent binding, NaPi2b-positive OVCAR-3 and HCC-78 were incubated with antibodies in concentrations ranging from 0.00075 to 30 µg/ml, stained with an Alexa-dye-labeled anti-human IgG H+L secondary antibody (Thermo Fisher Scientific), and analyzed by flow cytometry. Mean fluorescence intensity (MFI) ratios were normalized to the non-specific binding control. The assay was performed in duplicates and data points were analyzed by a non-linear regression using a one-site specific binding model using Prism 9 software. Graph shows means of n = 2 ± SD. [00527] In this experiment, the binding between AV25 and upifitamab on NaPi2b-positive cell lines was compared and K D values were determined. Of note, AV25 (K D on OVCAR-3 = 0.44 µg/ml, K D on HCC-78 0.42 µg/ml) shows improved binding and lower K D values compared to upifitamab (K D on OVCAR-31.11 µg/ml, K D on HCC-781.27 µg/ml). [00528] The experiment clearly demonstrates the superiority in binding of AV25 over Upifitamab. [00529] Figure 49 shows dose-dependent binding, expressed as MFI ratio, of increasing concentraions of Upifitamab or AV25 normalized to the non-specific binding control on two different NaPi2b-positive cell-lines (OVCAR-3, left, HCC78, right). Shown are mean and SD of two measurements, as well as a dose-response-fit. [00530] In vitro Cytotoxicity evaluated via Resazurin assay –Upifitamab-P5(PEG24)- VC-PAB-Exatecan vs AV25-P5(PEG24)-VC-PAB-Exatecan DAR8 [00531] Upifitamab is antibody with the same sequence of the parental mAb of the present disclosure. Upifitamab has been purchased from MedChemExpressed to perform the following experiments. Upifitamab has been furthermore conjugated to P5(PEG24)-VC-PAB-Exatecan and purified as DAR8 conjugate as described above in example 1. [00532] To investigate direct cytotoxicity of ADCs, respective cells were seeded in a 96-well plate (flat bottom, 5000 cells/well, suspended in 100 µl medium) and incubated for 7 days with increasing concentrations of the ADCs in medium (0-12 µg/ml) to generate a dose-response curve. Before viability analysis, the supernatant over the adherent cells was removed and replaced by fresh medium. Killing was analyzed afterwards, using resazurin (Sigma-Aldrich) as the cell viability dye at a final concentration of 55 µM. Fluorescence emission at 590 nM was measured on a Microplate reader Infinite M200 Pro (Tecan). Cell viability was measured by dividing the fluorescence of ADC-treated cells by the fluorescence from control cells, treated in the same way with medium only. Graph shows means of n = 2 ± SEM. [00533] In this experiment, the cytotoxicity on Napi2bhigh-expressing cell lines (OVCAR-3 and HCC-78) of AV25-P5(PEG24)-VC-PAB-Exatecan DAR 8 compared head-to-.head to Upifitamab- P5(PEG24)-VC-PAB-Exatecan DAR 8 was investigated. On both cell lines AV25-P5(PEG24)-VC- PAB-Exatecan showed an increase in selective potency of a 3.5 to 3.8-fold lower IC50- concetration compared to Upifitamab-P5(PEG24)-VC-PAB-Exatecan. No unspecific toxicity of the non-targeted isotype control was observed. [00534] The experiment clearly demonstrates the superiority in killing of AV25-P5(PEG24)- VC-PAB-Exatecan over upifitamab-P5(PEG24)-VC-PAB-Exatecan suggesting an increase in response in the cancer patient to a targeted treatment based on a targeting AV25 antibody, compared to the parental mAb or Upifitamab. [00535] Figure 50 shows the cytotoxicity dose-response of AV25-P5(PEG24)-VC-PAB- Exatecan DAR 8 compared to Upifitamab-P5(PEG24)-VC-PAB-Exatecan DAR 8 and an isotype control Isotype-P5(PEG24)-VC-PAB-Exatecan DAR 8 on two different cell lines. Shown are mean and SD of two measurements, as well as a dose-response-fit. Fluorescence in % of medium control is equal to % of viable cells. *** [00536] One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. Further, it will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The compositions, methods, procedures, treatments, molecules and specific compounds described herein are presently representative of certain embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention are defined by the scope of the claims. The listing or discussion of a previously published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. [00537] The invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by exemplary embodiments and optional features, modification and variation of the inventions embodied herein may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention. [00538] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. All documents, including patent applications and scientific publications, referred to herein are incorporated herein by reference for all purposes. [00539] Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.