COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE Background Sequence Listing [0001] This application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 4, 2023, is named 009583_00004_WO.xml and is 22,411 bytes in size. Field [0002] This disclosure is directed to compounds that treat inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. This disclosure is also directed to compositions comprising said compounds, methods of using said compounds or said compositions for treating IBD, as well as methods for synthesizing said compounds including intermediates used therein. State of the Art [0003] Inflammatory bowel disease (IBD) is a general term used to describe disorders that cause a chronic inflammatory condition of the gastrointestinal tract. The two most common forms of the IBD disease group are ulcerative colitis and Chron’s disease. Ulcerative colitis is mostly restricted to the colon while Chron’s disease can affect any part of the gastrointestinal (GI) tract. [0004] The chronic intestinal inflammation resulting from IBD leads to an array of symptoms, including abdominal pain, diarrhea, anemia, and weight loss. The clinical course of IBD is highly variable, both between individuals and during the life of a given individual with periods of inactivity interspersed with acute flares which, depending on the degree, require medication, hospitalization, and sometimes, bowel surgery. The pathogenesis of IBD is driven by an abnormal and prolonged T-cell and NK (natural killer) cell-mediated immune response directed towards the commensal gut microbiota that occurs in genetically susceptible individuals. Most of the documented IBD risk genes are related to diverse immune functions, including innate immune functions such as physical barrier integrity, control of microbiota diversity, and autophagy. [0005] Loss of physical barrier integrity is predicated on the loss of epithelial cells in the intestinal wall leading to inflammation / infection, and then involvement of an immune response that is characteristic of IBD. The mainstay of medical therapy for IBD currently relies on the suppression of the immune system. Four classes of drugs are employed to this end, aminosalicylates, corticosteroids, immunomodulators, and biologics. The rationale for the application of such drugs is that, if inflammation is controlled, homeostatic mechanisms for tissue healing and repair will operate and bring the system back to normalcy. Nevertheless, because this rationale does not take into consideration the root causes of disease, the underlying pathologies are likely to reoccur upon cessation of treatment and individuals may, therefore, require life-long therapies. [0006] Because most of the genetic associations established for IBD relate to genes responsible for the interaction between the gut epithelia, the immune system, the microbiota, and dietary elements, it is not surprising that chronic inflammation arises secondary to molecular changes associated with dysbiosis, infection, dietary imbalances, and host metabolism. These molecular changes are mostly due to the breakdown of the barrier function of the gut epithelia which then leads to inflammation. To date, the use of immune suppressive drugs to treat IBD simply does not provide a satisfactory long-term treatment option for patients with IBD nor does it address barrier breakdown as a root cause of IBD. [0007] Accordingly, there is an ongoing unmet need to treat IBD by addressing the loss of barrier function in the patient which precedes inflammation and immune system involvement. Summary [0008] This disclosure provides, in part, for compounds (drug conjugates or simply conjugates) of an IL22 thioredoxin fusion protein having one or more laquinimod groups bound thereto. The fusion protein comprises an IL22 portion and a thioredoxin portion linked together by a covalent bond or a first linker. The thioredoxin portion can include more than one thioredoxin protein linked together with or without a linker or coupled to either end of the IL22 portion. The full sequence of an exemplary fusion protein is provided herein (e.g., SEQ ID NOS: 2, 3, 7, 9, 11, 15 and 17). The IL22 portion of the protein-drug conjugate provides for targeted intracellular delivery into epithelial cells of the gastrointestinal tract including intestinal epithelial stem cells. [0009] One or more laquinimod groups or derivatives thereof are then bound to the thioredoxin portion of the fusion protein via an enzymatically cleavable linker. Binding is made to distinct amino acid sites available for attachment of the linker. In one embodiment, the free thiol functionality found only on the side chain of free cysteine residues (as opposed to cysteine residues that form a disulfide bond) is used for conjugation via the second linker. Specifically, the thioredoxin portion of the fusion protein contains three (3) non-paired cysteines (free thiol) in the fusion protein that are available for conjugation using thiol-reactive chemistry while the IL22 portion contains no non-paired cysteine residues. [0010] In view of the availability of free cysteine residues only on the thioredoxin portion of the fusion protein, selective attachment of the linker having a cleavable laquinimod or a derivative thereof bound thereto to the thioredoxin portion of the fusion protein can be accomplished. Such selectivity allows for intact retention of the IL22 portion of the fusion protein. [0011] Accordingly, in one embodiment, there is provided a drug conjugate comprising: a) a fusion protein comprising an IL22 portion and a thioredoxin portion linked together by a covalent bond or a first linker; b) one or more laquinimod groups attached to separate sulfur atoms of free cysteine side chains in the thioredoxin portion of the fusion protein each through a separate second linker, wherein said first and second linkers comprise from 1 to about 40 non-hydrogen atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus provided that the remaining valences of said atoms are satisfied with hydrogen or deuterium atoms. [0012] In one embodiment, the drug conjugate is represented by the formula A: [(LAQ)n - L ² -S - ]b-FP-Y A where n is from 1 to 4; Y is hydrogen or L ¹ -TR; b is from 1 to 3 when Y is hydrogen and from 1 to 6 when Y is L ¹ -TR; L ² is an enzymatically cleavable linker; L ¹ is a linker or a covalent bond; FP is a fusion protein of the formula TR-L ¹ -IL22 where TR is thioredoxin or a biologically active fragment thereof, and IL22 is interleukin-22 or a biologically active fragment thereof bound to L ¹ or to TR when either or both L ¹ moieties is/are a covalent; LAQ is laquinimod or derivative thereof; and S is the sulfur atom of a thiol group of free cysteine of the thioredoxin portion of the fusion protein; as well as pharmaceutically acceptable salts thereof. [0013] In one embodiment, the second linker, L ² , comprises a cleavable covalent functionality or group which, when disassembled in the presence of intracellular enzymes, releases laquinimod or a derivative thereof in the intracellular milieu of intestinal epithelial cells. In some embodiments, the second linker comprises a cleavable covalent functionality or group that comprises an amino acid or a polypeptide of from 2 to about 10 amino acids. In one embodiment, the cleavable linker is a 2 or 3 amino acid polypeptides that cleaves in the presence of intracellular endosomal cathepsins or endosomal glycosidases. In another embodiment, the second linker contains glucuronic acid that stabilizes the second linker and, when removed by intracellular enzymes, allows for disassembly of that cleavable covalent functionality or group and release of free laquinimod or a derivative thereof. [0014] In one embodiment, each of the second linkers is attached to the sulfur atom of a free cysteine residue found on the thioredoxin portion of the fusion protein to form a sulfide bond. The second linker contains a cleavable covalent functionality or group that allows for cleavage of the laquinimod or derivative thereof from the linker in the presence of intracellular enzymes thereby providing intracellular concentrations of both free laquinimod or its derivative thereof and the fusion protein. [0015] In another embodiment, when Y is hydrogen, from about 1 to about 3 second linkers each comprising from about 1 to about 4 laquinimod groups or a derivative thereof attached thereto are, on average, covalently bound in a cleavable manner to a free cysteine residue of the thioredoxin portion of the fusion protein, thereby providing up to 12 laquinimod compounds or derivatives of a laquinimod compound that are released by intracellular enzymes in the intestinal epithelial cells. When Y is L ¹ -TR, then the number of laquinimod compounds that are released by intracellular enzymes in the intestinal epithelial cells can be up to 24. [0016] In one embodiment, the conjugates described herein can be used in methods to inhibit de-epithelialization of the intestinal barrier. When so used, the protein-drug conjugates inhibit the onset or further progression of an IBD episode in a patient. [0017] Accordingly, in one embodiment, there is provided a method for inhibiting de-epithelialization of the intestinal barrier in a patient suffering from an ongoing inflammatory bowel disease episode which method comprises administering an effective amount of a conjugate (as described herein) or a pharmaceutical composition comprising said conjugate to the patient to inhibit de- epithelialization or further de-epithelialization of the intestinal barrier. [0018] In one embodiment, the conjugates described herein can be used in methods to initiate re-epithelialization of the intestinal barrier. When so used, the conjugates therapeutically treat damage to the epithelium of the intestinal barrier caused by an IBD episode in a patient. [0019] Accordingly, in one embodiment, there is provided a method for initiating re-epithelialization of the intestinal barrier in a patient suffering from an inflammatory bowel disease episode which method comprises administering an effective amount of a conjugate (as described herein) or a pharmaceutical composition comprising said conjugate to the patient to initiate re-epithelialization of the intestinal barrier. [0020] Without being limited to any theory, the IL22 portion of the fusion protein that forms a part of the conjugates described herein provides directional guidance and intracellular delivery into the intestinal epithelial cells including epithelial stem cells resulting in target specificity to the conjugate. This is because intracellular delivery of the conjugate is restricted to those cells that express the heterodimer receptor for IL22, constituted by the IL22R1 and IL10R2 pair. These receptor pairs are continuously expressed in intestinal epithelial cells such as intestinal epithelial stem cells but not, for example, in undamaged lung or liver tissue. Accordingly, the conjugates described herein will target intestinal epithelial cells in the absence of damage to the lung tissue or liver tissue. In an embodiment, patients suffering from diseases or conditions that cause damage to the lung or liver tissue are preferably evaluated for the use of the conjugates and methods described herein. Such lung diseases include, by way of example only, COPD (chronic obstructive pulmonary disease), lung cancer, pulmonary hypertension, pneumonia, tobacco smoking related diseases, and the like. Such liver diseases include, by way of example only, hepatitis (A, B, C, etc.), cirrhosis of the liver, NASH (non- alcoholic steatohepatitis), and the like. At the discretion of the clinician, these patients can likewise be treated for their IBD as described herein or excluded from such treatment. [0021] In one embodiment, the second linker connecting laquinimod or derivatives thereof to the fusion protein that comprises a cleavable covalent functionality or group that is selectively cleaved upon intracellular absorption of the conjugate into the intestinal epithelial cells including intestinal epithelial stem cells. When so cleaved, the disassembled conjugate provides for free laquinimod or a derivative thereof and free fusion protein. In this embodiment, the IL22 portion of the freed fusion protein stimulates the expansion of intestinal epithelial stem cells. Likewise, the freed laquinimod or a derivative thereof initiates stem cell differentiation and maturation into epithelial cells. Hence, the IL22 portion of the fusion protein and laquinimod or a derivative thereof act synergistically and in a coordinated fashion to induce stem cell proliferation coupled with differentiation and maturation of epithelial cells leading to repair of the intestinal barrier. [0022] Accordingly, in one embodiment, laquinimod or a derivative thereof is represented by formula I: Formula I where R is hydrogen or L ² -X; R ¹ and R ² are independently selected from hydrogen, chloro, bromo, iodo, hydroxyl, C ₁ -C ₄ alkyl and L ² -X; L ² is a monovalent or multivalent linker; and X is a reactive functional group capable of forming a covalent sulfide bond with a thiol (SH) group. [0023] In one preferred embodiment, the conjugate described herein is represented by formula I-A as follows: where b is 1-3, FP is a fusion protein (e.g., as defined herein), S and L ² are as defined above. In the above formula, only a single laquinimod compound or a derivative thereof is attached to the linker, and the linker is then referred to as monovalent. In such a case, only one laquinimod compound or derivative thereof is provided for each free cysteine residue on the protein-drug conjugate. [0024] In one embodiment, there is provided a laquinimod monovalent linker compound which is used to covalently attach to the fusion protein which compound is represented by formula I-B as follows: Formula I-B where q is from 1 to about 10. In this embodiment, the linker is represented by

where q is defined above and the squiggle represents the point of attachment of the linker to laquinimod. [0025] In one embodiment, there is provided drug conjugate that contains a monovalent linker which conjugated is represented by formula I-C as follows: where b, q, and FP are as defined herein. In this case, b is 1, so only a single laquinimod compound or derivative thereof is attached to the fusion protein. However, as noted previously, up to 3 linkers (b is 1 to 3) can be attached to the fusion protein via a sulfide bond using the free cysteine residues of the thioredoxin portion of the fusion protein without disrupting any of the disulfide bridges on the fusion protein. In this case, the reaction of the linker with the cysteine thiol group converts the maleimide into a succinimide and the linker is defined as: where q is defined above and the squiggle on the bond protruding from the succinimide group represents the site of attachment to the sulfide formed by reaction with the SH group of the cysteine amino acid found on the thioredoxin portion of the fusion protein with the maleimide group. Note that in this case, the two methylene groups on the succinimide are equivalent and, as such, the point of attachment could be to either methylene group. [0026] In one embodiment, the conjugate is represented by formula I-D: where b and FP are as defined herein. In this case, b can be 1, 2 or 3 and when b is 2 or 3, multiple linkers each containing a single laquinimod compound or derivative thereof will be attached to the fusion protein each via a sulfide bond using the free cysteine residues of the thioredoxin portion of the fusion protein without disrupting any of the disulfide bridges on the fusion protein. [0027] In one embodiment, there is provided a laquinimod (or laquinimod derivative) divalent linker compound which is used to covalently attach to the fusion protein which compound is represented by formula I-E as follows: where the maleimide linker group attached to the fusion protein FP is represented by: where q is from 1 to about 10. In this embodiment, multiple laquinimod compounds (and/or derivatives thereof) are attached to the L ² linker comprising the maleimide linker group and the L ² linker is then referred to as multivalent (in this example, divalent). In such a case, multiple laquinimod compounds or derivatives thereof are provided for each free cysteine residue on the protein-drug conjugate. ^[0028] In one embodiment, the protein-drug conjugate described herein includes a divalent linker, and the conjugate is represented by formula I-F as follows:

Formula I-F where n and FP are as defined above and the succinimide-linker attached to the FP is represented by where q is from 1 to about 10. It is noted that in the above formulae I-F and I-E, only a single conjugate is attached to the thioredoxin portion of the fusion protein. This is shown solely for illustrative purposes with the understanding that up to 3 such divalent linkers can be attached. When all three linkers are employed, the total number of laquinimod molecules that can be released into the intracellular milieu is 6. [0029] In one embodiment, there is provided a method for re-epithelialization of an intestinal wall in a mammal which method comprises administering to said mammal an effective amount of a conjugate of any one of formula A, I, I-A, I-C, I-D, or I-F as described above or a mixture thereof. [0030] In one embodiment, there is provided a method for treating inflammatory bowel disease in a patient which method comprises administering to said patient an effective amount of a conjugate of any one of formula A, I, I-A, I-C, I-D, or I-F as described above or a mixture thereof. [0031] In one embodiment, L ² is a monovalent linker having a single laquinimod or derivative thereof bound thereto at one end and bound to a sulfur atom of the thioredoxin portion of the fusion protein at the other end. In another embodiment, L ² is a multivalent linker capable of linking from 2 to about 10 laquinimod or derivatives bound thereto at one end and bound to a sulfur atom of the thioredoxin portion of the fusion protein at the other end. [0032] Suitable multivalent linkers are described herein and are well known in the art and include dendrimers, polyols, polycarboxylates, and the like. [0033] In one embodiment, the linker includes a cleavable element that enzymatically disassembles in the presence of glucuronidase. [0034] In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of any one of a conjugate of formula A, I, I-A, I-C, I-D, or I-F as described above or a mixture thereof. [0035] In one embodiment there is provided an intermediate of the formula II: Formula II where R ³ is hydrogen or L ³ -maleimide where L ³ -maleimide together with - ^{NHC(O)CH2CH2NH- are} combined into L ² . It should be understood that the maleimide group, when coupled to the thiol group, converts to a succinimide group, which is then part of the linker. [0036] Another embodiment describes a protein-drug conjugate comprising a thioredoxin polypeptide linked to an interleukin-22 (IL22) polypeptide via a peptide linker, wherein one or more laquinimod molecules or derivatives are conjugated to one or more cysteine residues present in the thioredoxin polypeptide, and wherein the thioredoxin polypeptide is linked to the amino terminus of the IL22 polypeptide. The protein-drug conjugate can be glycosylated or not glycosylated. [0037] The above protein-drug conjugate comprises one or more laquinimod molecules, wherein the laquinimod molecules are conjugated by a linker, and said linker each contains one or more laquinimod molecules, and wherein the linker comprises from 1 to about 40 non-hydrogen atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus provided that atom valency is satisfied with hydrogen or deuterium atoms. [0038] Contemplated protein-drug conjugates described above and herein comprise a cleavable linker that cleaves in the presence of an intracellular enzyme located in intestinal epithelial cells and intestinal epithelial stem cells, cleaving the laquinimod or a derivative thereof from the fusion protein thereby releasing the laquinimod into the intracellular milieu. [0039] A protein-drug conjugate as described herein comprises a thioredoxin polypeptide linked to the IL22 polypeptide. The linkage of the two polypeptides can be by a peptide linker or via chemical conjugation or can have no linker. The peptide linker in the protein-drug conjugate can comprise 1 to 100 amino acids and any whole number in between. An exemplary peptide linker is Gly-Ser-Ala-Met (SEQ ID NO: 4). For example, in some embodiments, the peptide linker can comprise 2-4 amino acids, 4-8, 8- 16, 8-15, 3-8, and 10 amino acids. [0040] The protein-drug conjugate can comprise a mammalian thioredoxin, or a primate thioredoxin (e.g., monkey, chimpanzee, or another primate thioredoxin), or a human thioredoxin. The protein-drug conjugate can comprise a mammalian IL22, a primate IL22, or a human IL22. The IL22 can be a mature protein lacking the signal peptide or comprising the signal peptide. [0041] In another embodiment, the IL22 portion of the protein-drug conjugate comprises a cysteine to serine mutation at positions 32 and 35 of a mature IL22 sequence. [0042] Another embodiment describes a protein-drug conjugate wherein from 0 to 2 of the free cysteine groups in the thioredoxin portion of the fusion protein lack a laquinimod molecule (or derivatives thereof) and are not conjugated to a cysteine in the IL22 polypeptide. [0043] Another embodiment contemplates a pharmaceutical composition comprising any of the above protein-drug conjugates and a pharmaceutically acceptable carrier or excipient. [0044] Also described are methods of treating a subject having an inflammatory bowel disease (IBD), the method comprising administering to the subject a protein-drug conjugate as described herein. The method comprising administering the drug in an amount sufficient to clinically ameliorate one or more of the following conditions: i) inhibiting de-epithelialization of intestinal epithelial barrier; ii) inhibiting microbial infection of the intestine; iii) preserving goblet cells in the intestine during infection; iv) enhancing epithelial cell integrity; v) enhancing epithelial cell proliferation; vi) enhancing epithelial cell differentiation; and vii) initiating re-epithelialization in compromised portions of the intestinal epithelial barrier. [0045] The protein-drug conjugate and methods of using it are to treat an inflammatory bowel disease, which can include ulcerative colitis and Crohn’s disease. The protein-drug conjugate be manufactured for use in treating an inflammatory bowel disease, for example as a medicament. Treatment can be for moderate and severe forms of inflammatory bowel disease. Brief Description of the Drawings [0046] Figure 1 demonstrates that both analyzed thioredoxin-IL22 fusion proteins (i.e., Thio-IL22 and Thio-C3235S-IL22) are expressed at high levels in the E. coli BL21(DE3) host. [0047] Figure 2 shows the results of the reporter bioassay for the samples analyzed using the human Thio-IL22 and human Thio-C3235S-IL22 constructs where Thio is an abbreviation for Thioredoxin. [0048] Figure 3 depicts the mechanisms underlying the design of the IL22 reporter cell line that is capable of independently measuring IL22 bioactivity and the activity of the drug payload once released inside the cell after IL22-receptor-mediated endocytosis of the protein-drug-conjugate (PDC). [0049] Figures 4A and 4B demonstrate the ability of the IL22 fusion PDC to activate both pathways as expected if IL22 is internalized and releases the laquinimod within the cell. Detailed Description [0050] This disclosure provides for compounds/conjugates that treat an inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. However, prior to discussing this disclosure in more detail, the following terms are first defined. Definitions [0051] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of or to the disclosure. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. [0052] A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named. [0053] The prefix “C ^u-v ” indicates that the following group has from u to v carbon atoms. For example, “C ^1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0054] The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations that may vary by ( + ) or ( - ) 10%, 5%, 1%, or any subrange or a subvalue there between. In one embodiment, the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%. [0055] “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. [0056] “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose that would result in materially altering the stated purpose of the compositions or methods. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. [0057] “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure. [0058] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C _1-20 alkyl), 1 to 12 carbon atoms (i.e., C _1-12 alkyl), 1 to 8 carbon atoms (i.e., C _1-8 alkyl), 1 to 6 carbon atoms (i.e., C _1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2). Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, may also be referred to as an “alkylene”. In addition, for the purposes herein, the substitution of an atom for a corresponding isotope of that atom is intended to be included within the scope of this invention. For example, whenever hydrogen (H) is recited, unless it is specifically stated otherwise, the hydrogen can be replaced with deuterium (D). [0059] Provided are also a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, stereoisomer, a mixture of stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. [0060] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, glucuronic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl) ₂ ), trialkyl amines (i.e., N(alkyl) ₃ ), substituted alkyl amines (i.e., NH ₂ (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) ₂ ), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl) ₂ ), tri(substituted alkenyl) amines (i.e., ^{N(substituted alkenyl)} ₃ ^{, mono-, di- or tri- cycloalkyl amines (i.e., NH} ₂ ^{(cycloalkyl),} HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0061] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers. Other examples of tautomeric structures are well-known in the art. [0062] The compounds, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, e.g., chiral high- pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0063] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. [0064] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. [0065] “Subject” refers to a mammal. The mammal can be a human or non- human mammalian organism. A “patient” refers to a human subject. [0066] “Treating” or “treatment” of a disease or disorder in a subject refers to 1) preventing the disease or disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or causing regression of the disease or disorder. The disease or disorder being treated is an “inflammatory bowel disease.” “Inflammatory bowel disease” and “inflammatory bowel disorder” and “IBD” as used interchangeably herein are used in the broadest sense and include all diseases and pathological conditions the pathogenesis of which involves recurrent inflammation of the intestine, including the small intestine and the colon. An inflammatory bowel disease includes ulcerative colitis and Crohn’s disease, as well as animal models used to mimic ulcerative colitis and Crohn’s disease. Ulcerative colitis can include moderate or severe ulcerative colitis and moderate and severe forms of Crohn’s disease. [0067] “Effective amount” refers to the amount of a protein-drug conjugate as described herein that is sufficient to treat IBD afflicting a subject or to prevent recurrence of IBD from arising in said subject or patient, and a decrease in the rate of developing IBD or a decrease in the severity of IBD. An effective amount of the compound (protein- drug conjugate) can ameliorate, in the subject administered the protein-drug conjugate, one or more of the following conditions: i) inhibiting de-epithelialization of intestinal epithelial barrier; ii) inhibiting microbial infection of the intestine; iii) preserving goblet cells in the intestine during infection; iv) enhancing epithelial cell integrity; v) enhancing epithelial cell proliferation; vi) enhancing epithelial cell differentiation; and vii) initiating re-epithelialization in compromised portions of the intestinal epithelial barrier. [0068] By the term “amelioration” is meant a clinically noticeable change in one or more of the features as compared to the patient’s pre-treatment condition. [0069] “Administration” refers to any art-recognized form of administration to a subject including oral (including oral gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, oral, colonic, topical), transmucosal (e.g., colonic, nasal, etc.), and the like. Oral administration contemplates that conjugates can be enteric coated to allow for release in the intestines and not elsewhere in the gastrointestinal tract. The route of administration is selected by the attending clinician and is based on factors such as the age, weight, and general health of the patient as well as the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally. Here, the compound for administration is a protein-drug conjugate as described herein comprising a thioredoxin molecule (or thioredoxin variant), an IL22 (or a functional IL22 variant), and laquinimod or a laquinimod derivative conjugated to the fusion protein. The protein- drug conjugate (PDC) can be glycosylated or not glycosylated (aglycosylated) or wherein glycosylation has been reduced from that normally expressed on a human thioredoxin protein or a human IL22 protein. If synthesized in bacteria, such as E. coli, the fusion protein will not be glycosylated. [0070] The term “linker” refers to a group that connects a first group to a second group. In the case of Formula I above, a linker is used to connect one or more laquinimod molecules (or a derivative thereof) to the thioredoxin portion of the fusion protein to form a protein-drug conjugate. In one embodiment, the linker comprises at least one and up to about 40 non-hydrogen atoms including carbon, nitrogen, oxygen, sulfur, and phosphorus. Where appropriate, these atoms include hydrogen (including all isotopes) or halo to satisfy the valence of the atoms. The linker is a cleavable linker and can be either monovalent or multivalent. [0071] The term “cleavable linker” means that the linker comprises a cleavable functionality – that is to say that the functionality or a covalent bond is readily cleaved into a first component and a second component by, for example, intracellular enzymes. [0072] The term "free cysteine" refers to a cysteine amino acid in a polypeptide where the thiol group (-SH) is retained and is not part of a disulfide group (-S-S-). [0073] The term "laquinimod derivative" refers to laquinimod compounds of the formula:

where R, R ¹ , and R ² are as defined above provided that R, R ¹ and R ² cannot all be hydrogen. [0074] The term "intestinal epithelial barrier" or "IEB" is well known as one of the largest interfaces between the environment and the internal milieu of the body. [0075] The term “thioredoxin polypeptide” refers to a thioredoxin protein or functional portion thereof possessing redox activity. Exemplary thioredoxin polypeptides include mammalian and primate thioredoxin polypeptides. A human thioredoxin is another exemplary polypeptide. The thioredoxin can be glycosylated or non-glycosylated. The C-terminus of thioredoxin can be attached to the N-terminus of the IL22. Less preferably, the N-terminus of the thioredoxin can be attached to the C-terminus of the IL22. In some embodiment more than one thioredoxin can be linked together, such as Trx-Trx-IL22 or Trx-Trx-Trx-IL22. Another variant includes placing the IL22 in the middle of a thioredoxin sequence, such as that exemplified for the APT sequence discussed in the examples. [0076] Each of the terms “interleukin-22 polypeptide”, “IL22 polypeptide”, “IL-22 polypeptide” refers to an IL22 protein or functional portion thereof that can bind to the IL22 receptor (i.e., the heterodimer composed of IL10R2 and IL22R1 subunits) thereby inducing the IL22 receptor signaling pathway. The IL22 polypeptide can be a full-length polypeptide or can be a mature protein lacking the amino-terminal signaling peptide. Exemplary IL22 polypeptides include mammalian and primate IL22 polypeptides, such as monkey IL 22 (XP_001117159) as discussed in Neto et al., “Interleukin-22 Forms Dimers that are Recognized by Two Interleukin-22R1 Receptor Chains,” Biophysical J. 94: 1754-1765, 2008. A human IL22 polypeptide is another exemplary polypeptide. The IL22 polypeptide can be glycosylated or non-glycosylated. The term “IL22 receptor” or “IL22R” refers to a heterodimer consisting of IL22R1 and IL10R2 or naturally occurring variants thereof. See, e.g., Ouyang et al., 2011 Ann. Rev. Immunol.29: 159-63. Naturally occurring variants of IL22R and IL22 can include alternatively spliced forms and allelic variants of the polypeptide. Muteins of IL22 are also contemplated for use in the protein- drug conjugates, including high-affinity IL22 muteins that have improved binding to their receptor. Exemplary IL22 muteins for human and mouse sequences are described in e.g., Saxton et al., “The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design,” Immunity 54: 660-672, 2021. [0077] The term “pharmaceutically acceptable carrier” refers to a compound that serves to assist in drug delivery. A drug carrier can improve the selectivity, effectiveness, and/or safety of administering the drug, e.g., the drug conjugated fusion protein. The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic. [0078] A “pharmaceutically acceptable excipient” is a pharmacologically inactive compound such as a diluent, a disintegrant, a lubricant, a glidant, or a binder comprised in a pharmaceutical product having the active. A pharmaceutically acceptable excipient is one that is useful in preparing a pharmaceutical composition comprising the active pharmaceutical ingredient, e.g., the drug conjugated thioredoxin-IL22 fusion protein. The pharmaceutically acceptable excipient is generally safe, non-toxic, and is acceptable for animal use, such as veterinary use or human use. Reference to “an excipient” includes both one and more than one such excipient. [0079] The term “X is a reactive functional group capable of forming a covalent sulfide bond with a thiol (SH) group” refers to those functional groups that will react with a thiol (SH) group of cysteine to form a covalent sulfide bond. The following table illustrates some of these reactive functional groups which are well known in the art as are others. General Synthetic Methods [0080] The protein-drug conjugates described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reagents or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0081] After synthesis, the protein-drug conjugates described herein can be lyophilized for stable storage. After lyophilization, the conjugate can be placed glass vials that preferably limit light entry into the vial. The lyophilized form can be later solubilized using for example DMSO (dimethyl sulfoxide) and then placed in saline for administration. Lyophilization can include freezing followed by sublimation and optionally desorption under sterile lyophilization environments (ISO5 environment). A conjugate salt form can include glycine. [0082] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. [0083] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as SigmaAldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1- 40 (John Wiley, and Sons, 2019), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 8th Edition, 2019), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). A. Synthesis of Laquinimod - Linker (L ² ) [0084] In the synthetic schemes illustrated below, the specific linker employed is for illustrative purposes only and other linkers, which are well-known in the art, can be employed in place thereof. SCHEME 1 [0085] In one embodiment, illustrated in Scheme 1, laquinimod is converted to its corresponding oxide salt, compound 1 as the first step in the Williamson reaction. The reaction proceeds by the addition of a stoichiometric amount of a base such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, and the like to laquinimod, compound 1, in a suitable polar aprotic solvent such as acetonitrile, methyl t-butyl ether, methyl ethyl ketone (MEK), and N,N- dimethylformamide (DMF). The salt employed is preferably, but not necessarily, a pharmaceutical acceptable salt. The reaction is maintained under conventional conditions defined by the known Williamson reaction to form the corresponding 4-oxide (not shown). Alternatively, if the linker contains a hydroxyl group that group can be converted to the corresponding mesylate by conventional mesylation reactions and then coupled to the hydroxyl group of laquinimod. [0086] The laquinimod oxide, compound 1, can be recovered and purified or is used as is and combined with at least a stoichiometric equivalent of dipeptide, compound 2, while maintaining the reaction at a suitable temperature, typically 0º to 100º C. The reaction is maintained until the reaction is substantially complete which typically occurs in about 30 minutes to 48 hours. The resulting product, compound 3, can be recovered by conventional procedures including concentration, precipitation, crystallization, chromatography, and the like or used as is in the next step of the overall reaction. Alternatively, if the benzyl chloride group of the linker is replaced with benzyl alcohol, the hydroxyl group can be converted to the corresponding benzyl mesylate by conventional mesylation reactions. The mesylate can they be coupled to the oxide (compound 1) of laquinimod to form an ether linkage. [0087] Next, Scheme 2 shows the formation of an N-maleimide, compound 5, from compound 3.

SCHEME 2 [0088] Specifically, the t-Boc group of compound 3 is removed under conventional conditions well known in the art to provide for compound 4. For example, the t-Boc group of compound 3 can be removed by contacting the compound with a solution of from about 10% to about 30% trifluoroacetic acid in dichloromethane (v/v). The solution is maintained with gentle stirring for about 1 to about 4 hours. Compound 4 is then recovered by conventional procedures including concentration, precipitation, crystallization, chromatography, and the like but is preferably used in the next step without isolation or purification. [0089] Next, in one embodiment, the free amine of compound 4 is contacted with at least a stoichiometric amount of maleic anhydride under conditions also well known in the art to form the maleimide, compound 5. Purification of compound 5 proceeds via well recognized procedures including chromatography, precipitation, crystallization, and the like. [0090] Alternatively, the maleimide synthesis utilizes at least a stoichiometric amount (e.g., a slight excess) of N-methoxycarbonylmaleimide. The reaction proceeds in a suitable solvent such as tetrahydrofuran / saturated sodium bicarbonate initially maintained at about 0ºC and slowly allowing the solution to warm to room temperature over a span of from about 1 to 5 hours. The desired product, compound 5, comprises laquinimod bound to a linker which, in turn, contains a reactive maleimide for coupling to free thiol groups on the fusion protein. [0091] In another embodiment, a glucuronic acid-based linker, compound 6, which comprises an enzymatically cleavable linker, laquinimod, and a reactive group capable of reacting with a thiol functionality to form a sulfide bond can be used and a representative such a linker is provided below: [0092] An important function of compound 6 is its ability to enzymatically disassemble in the intracellular milieu where free laquinimod is released from the remainder of the linker. Without being limited to any theory, disassembly is initiated in the presence of glucuronidase during endocytosis of the conjugate into the epithelial cells including epithelial stem cells. Once the glucuronyl group is removed (compound 6A), disassembly proceeds by the resonance structures of the phenol group of the compound in the acidic media of the endosomes resulting in the elimination of the oxy group. Such an elimination is disclosed by Greenwald, et al., J. Med. Chem., 42:3657-3667 (1999) which reference is incorporated herein by reference in its entirety. The schematics for the disassembly of this linker are set forth in Scheme 3 below to provide for compound 6B (laquinimod) and compound 6C.

SCHEME 3 [0093] Specifically, enzymatic removal of the glucuronic acid group is achieved by glucuronidase found in the endosomes of epithelial cells. Upon removal, the resulting compound, compound 6A, comprises a 4-hydroxybenzyloxy group which, due to the acidic medium found in the endosomes, releases the oxy portion of the benzyloxy group which results in the intracellular release of free laquinimod, compound 6B, and the remainder of the linker coupled, as depicted, to the maleimide group found in 6C. Note, however, that in practice the maleimide group will have been converted to a succinimide group when coupled to the fusion protein as depicted previously. [0094] As to the linker depicted in SCHEME 3 above, one route for the synthesis of compound 6 proceeds commercially available compound 11 (Boc Sciences, 45-16 Ramsey Road, Shirley, NY 11967, USA) which, in turn, starts with compound 10 as an intermediate reagent as shown in SCHEME 3A below.

SCHEME 3A [0095] This reaction uses the acid chloride of β-alanine N-Fmoc, a commercially available reagent (SigmaAldrich, St. Louis, MO, USA) under conventional amidation conditions to provide for compound 11. In one embodiment, compound 10 is derived from the corresponding nitro derivative (not shown) by treatment with hydrogen / palladium. [0096] Next, the hydroxy group of compound 11 is mesylated using mesyl anhydride, Ms2O, under conventional conditions. Preferably, mesylation of the benzyl alcohol group is achieved using mesylate anhydride to provide for compound 12 as shown in Scheme 3B below: SCHEME 3B [0097] The resulting product, compound 12 (referred to hereafter as compound 13), can be isolated and optionally purified by conventional methods such as isolation, precipitation, chromatography, crystallization, and the like or, alternatively, used in the next step of the reaction without isolation and/or purification. [0098] Next, an alkali or alkaline salt of compound 14 is then combined with compound 13 to attach laquinimod as shown in Scheme 3C below: SCHEME 3C [0099] Scheme 3C illustrates the attachment of laquinimod oxide, compound 14, to compound 13 thereby providing for compound 15. Compound 14 is formed as above in Scheme 1 using the Williamson reaction whereby the oxide is present as a salt such as sodium salt. Alternatively, the sodium salt of compound 14 is commercially available from Simson Pharma Ltd., India. [0100] As per Scheme 3C, approximately equimolar amounts of compounds 13 and 14 are combined into a suitable solvent such as acetone, methylethylketone (MEK). The reaction is conducted at a temperature of from about 15ºC to about 70ºC for approximately 12 to 72 hours. The product, compound 15, can be isolated and optionally purified by methods well known in the art including chromatography, crystallization, precipitation, and the like, or used as is in the next reaction. [0101] Compound 15 is first deprotected by the addition of a base that deacetylates the protected hydroxy groups, deesterifies the methyl carboxyl ester, and removes the Fmoc group as shown in Scheme 3D below:

SCHEME 3D [0102] This reaction proceeds by the addition of an excess of a base such as lithium hydroxide cyclohexylamine, ethanolamine, and the like to compound 15 in a suitable solvent such as an aqueous combination of a C1-C3 alkanol (methanol, ethanol, isopropanol), an aqueous combination of water and tetrahydrofuran (e.g., 10:2 MeOH/THF and LiOH in 2 volumes of water), and the like. The reaction is maintained at about 0ºC to about 10ºC for about 1 to 5 hours and then brought to room temperature. [0103] The resulting free amine, compound 16, can be isolated and optionally purified by conventional methods such as isolation, precipitation, chromatography, crystallization, and the like or, alternatively, used in the next step of the reaction without isolation and/or purification. [0104] In the final step of Scheme 3D, compound 6 is prepared by amidating the free amino group of compound 16 with at least a stoichiometric amount of the commercially available pentafluorophenyl ester 3-[oxyethyloxyethyloxyethyl-(ethyl-2- maleimide)]propanoic acid (obtained from BroadPharm, 6625 Top Gun Dr., #103, San Diego, CA, USA 92121) under conventional conditions well known in the art to provide for compound 6. The reaction proceeds in a suitable solvent such as N,N- dimethylformamide, DMSO, and the like. The reaction is maintained at about -20ºC to about 10ºC for about 0.3 to 3 hours. The product, compound 6, is preferably isolated and purified by direct injection into preparatory HPLC prior to use in coupling to the fusion protein. [0105] Still further, a cleavable ester-based peptide linker containing laquinimod can be prepared as shown in Scheme 4 below. SCHEME 4 [0106] Specifically, the free amino group of the valine-citrulline dipeptide, compound 17, is contacted with maleic anhydride to provide for compound 18 under conventional conditions well-known in the art. Next, at least a stoichiometric equivalent of laquinimod, compound 19, is contacted with compound 18 under conventional esterification conditions to provide for the desired product, compound 20. Each step preferably employs an inert solvent and is generally conducted at a temperature of from about 0°C to about 60°C with gentle stirring. The reactions are maintained under these conditions until the reaction is substantially complete. The reaction mixture is then quenched and the desired product can be isolated and optionally purified or can be used without isolation or purification. [0107] In addition to the above, other esters could be formed by using well known amino -carboxylic acids such as amino protected di-beta-alanine or the free carboxyl maleimide derivative thereof which are represented by: where Pg ¹ is a carboxyl protecting group. A multivalent linker having three laquinimods attached thereto can be achieved using either aspartic-aspartic acid dimer or glutamic- glutamic acid dimer. A multivalent linker having four laquinimods attached thereto can be achieved using aspartic-aspartic-aspartic acid trimer or glutamic-glutamic-glutamic acid trimers. Mixtures of aspartic and glutamic acid dimers and trimers can also be used. B. Inclusion of additional releasable Laquinimod compounds on the drug- conjugate [0108] In a further embodiment, the number of laquinimod compounds that can be releasably delivered via the drug-conjugates described herein can be doubled, tripled, quadrupled, etc. by including additional carboxyl groups in the linker (L ² ). One such example is shown below in Scheme 5:

SCHEME 5 [0109] Specifically, in Scheme 5, compound 30 can be prepared in a manner similar to the reaction schemes provided previously. For example, as noted above, the amino functionality on compound 11 is obtained by reduction of the nitro group on the precursor compound. In such a case, retention of the nitro group during coupling of the laquinimod followed by reduction of the nitro group to the amino group using hydrogen/palladium provides for compound 30. Introduction of known N-Fmoc aspartic acid anhydride results in ring opening of the anhydride by the free amino group of compound 30 which occurs under conventional conditions to provide for a further carboxyl group as well as the Fmoc protected amino group as illustrated in compound 31. [0110] The further carboxyl group can be reacted with compound 30 to provide for a second laquinimod compound bound to the cleavable linker, compound 32. The Fmoc group is removed as described above with LiOH which also removes the acetyl groups and the methyl ester found on the glucuronic acid portions of the compound and subsequent reaction with POOC(CH2CH2O)3CH2CH2-N-maleimide (P = PFP or pentafluorophenyl) as described above provides for compound 33 which is suitable for reaction with the free cysteine residues of the fusion protein. [0111] In this approach, up to 6 laquinimod groups can be releasably attached to the fusion protein. Likewise, by using a tri-carboxylic acid group of a tetra-carboxylic acid group in place of the aspartic anhydride, up to 9 or 12 laquinimod groups, respectively, can be releasably attached to the fusion protein. [0112] In one embodiment, other multimeric, non-peptidic linkers can be used to conjugate the drug (e.g., laquinimod) to the fusion protein. Examples of such include, by way of example only, both of which are commercially available. C. IL22 Thioredoxin Fusion Protein [0113] The preparation of fusion proteins comprising IL22 has been disclosed in the art. See, e.g., WO 2019/148,026 which is incorporated herein by reference in its entirety. In addition, Example 7 hereinbelow provides for the synthesis of IL22- thioredoxin fusion proteins. Of interest, the IL22 portion of the fusion protein comprises no free cysteine residues whereas the thioredoxin portion of the fusion protein comprises 3 free cysteine residues. This means that the linkers described herein will covalently couple only to the thioredoxin portion of the fusion protein thereby retaining IL22 functionality. D. Conjugation of the Laquinimod Linkers to the Fusion Protein [0114] Formation of the laquinimod - linker - fusion protein conjugate proceeds as described in Scheme 6 below. In this Scheme, the linker is any of the laquinimod- linkers described above but can also be any suitable linker as is well known in the art. Laquinimod SCHEME 6 [0115] In Scheme 6, a linker compound containing laquinimod, compound 21, is contacted with the fusion protein, compound 22. As above, the fusion protein, compound 22, comprises a thioredoxin portion and an IL22 portion connected by L ¹ as defined above. The thioredoxin portion of the fusion protein contains 3 free cysteine (Cys) _residues which, for illustrative purposes, are identified by their -SH groups. Each of ^these groups is capable of reacting with the maleimide group of compound 21 in a classic Michael addition fashion to form up to three sulfide bonds as shown in compound 23, wherein the maleimide group is converted to a succinimide group. The extent of sulfide bond formation is dependent on the stoichiometry employed, the reaction conditions (time and temperature) as well as the location of the thiol groups in three-dimensional space. [0116] The reaction is conducted under conventional conditions well known in the art and Example 6 hereinbelow further exemplifies one known method for conjugation. E. Biology [0117] Upon administration to the patient, the conjugate is directed by the IL22 portion of the fusion protein to epithelial cells that express the heterodimer receptor for IL22, constituted by the IL22R1 and IL10R2 pair. As the intestinal epithelial cells, including stem cells, are constantly expressing these receptors, the IL2 portion of the fusion protein provides directional guidance directing the conjugate to these epithelial cells. The conjugate is then absorbed into these cells by the endosomes (endocytosis). These endosomes contain one or more enzymes that initiate disassembly of the conjugate thereby providing for free laquinimod and the fusion protein. [0118] Without being limited to any theory, Scheme 7 below illustrates this pathway. For the sake of illustration, Scheme 7 employs a single linker to the fusion protein. It is understood that if additional linkers are employed, the disassembly mechanism would occur in the same manner.

SCHEME 7 [0119] In Scheme 7, the IL22 portion of the drug-fusion protein conjugate directs the conjugate to epithelial cells including epithelial stem cells that express the heterodimer receptor for IL22, constituted by the IL22R1 and IL10R2 pair. Ligand receptor binding initiates intracellular absorption through endocytes via endocytosis. The endocytes comprise glucuronidase enzymes that cleave the glucuronic acid moiety from the conjugate. The acidic environment of the endocytes facilitates molecular disassembly of laquinimod from the rest of the conjugate thereby allowing for target-specific intracellular delivery of both laquinimod and IL22 into the intestinal epithelial cells. [0120] When disassembled, the IL22 portion of the freed fusion protein stimulates the expansion of intestinal epithelial stem cells. Likewise, the freed laquinimod or a derivative thereof initiates stem cell differentiation and maturation into epithelial cells. Hence, the IL22 portion of the fusion protein and laquinimod or a derivative thereof act synergistically and in a coordinated fashion to induce stem cell proliferation coupled with differentiation and maturation of epithelial cells leading to repair of the intestinal barrier. ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ [0121] Without being limited to any theory, there are two aspects of the AhR- mediated (aryl hydrocarbon receptor) responses are important for maintaining intestinal homeostasis. First, AhR-mediated responses are involved in intestinal epithelial stem cell homeostasis and barrier integrity. Second, AhR-mediated responses are involved in an anti-inflammatory and pro-regenerative immune response in mainly the epithelial cells of the digestive tract. Under inflammatory conditions, the epithelial cells of the liver, lung, and skin will respond to IL22) and therefore to the AhR agonist associated with it. In epithelial cell homeostasis/barrier integrity, the absence of AhR in the LGR5 ⁺ epithelial stem cell compartment has been demonstrated to impair stem cell differentiation into functional IECs (intestinal epithelial cell layer). The intestinal epithelium is regenerated throughout an individual’s adult life, with vigorous proliferation occurring in crypt compartments. The process is assisted by a stem cell (SC) compartment known to reside near the crypt compartment bottom. LGR5 ⁺ has been determined to be an epithelial stem cell marker. [0122] The inability to produce functional IECs (intestinal epithelial cells) leads to an eventual loss of the barrier integrity and consequently, increased inflammation and finally, tumorigenesis. All of this pinpoints the essentiality of the AhR-mediated pathway in intestinal biology. In addition to its impact on epithelial stem cells, dietary AhR ligands directly activate AhR functions in IECs that control the expression of genes that reinforce cell-to-cell adhesion and anti-microbial activity, therefore reinforcing barrier integrity. [0123] Again, without being limited to any theory, in addition to the role of IL22 to orchestrate various functional aspects underlying intestinal barrier integrity, IL22 supports mucosal healing by driving epithelial cell proliferation and regeneration after damage. Both homeostatic maintenance and repair of the epithelial barrier rely on asymmetric division of intestinal stem cells to yield an intestinal stem cell (ISC) and transit-amplifying cell (TA). TA cells proliferate and migrate out of the crypt compartment and then differentiate into mature intestinal epithelial cells (IECs). IL22 works by enhancing TA cell proliferation while concomitantly inhibiting ISC expansion. The presence of IL22 also accelerates the apoptosis of the older intestinal epithelial cells, thereby promoting intestinal epithelial cell regeneration. [0124] The binding of IL22 to its heterodimer receptor IL22-IL22R binding also activates the pro-proliferative MAPK (mitogen- activated protein kinase) pathway and the pro-survival AKT pathway. IL22 also induces JAK-mediated phosphorylation of STAT1 and under some inflammatory conditions, such as in conjunction with type I interferon (IFN) signaling. [0125] As with any pro-mitogenic signaling pathway, a negative feedback loop is present to ensure that cells do not over-proliferate to avoid tissue hyperplasia and tumorigenesis. In the case of tyrosine kinase-associated cytokine receptors, the negative feedback loop is anchored by members of the SOCS (Suppressors Of Cytokine Signaling) family. The SOCS protein members are induced as immediate early genes following cytokine signaling. SOCS proteins contain Scr Homology 2 domains (SH2), which bind to tyrosine-phosphorylated residues in the cytokine receptor and to JAK kinases, inhibiting their kinase activity and inducing their proteasomal degradation as part of Cullin-related ligases (CRLs) E3 ubiquitin ligase complexes. SOCS acts in the CRLs/E3 ubiquitin ligase complexes as a substrate binding domain of the complex. Under high basal inflammatory conditions, pleiotropic pro-inflammatory cytokines such as interleukin-6 (IL6) are present, and signal by binding to the IL6 receptor to increase the expression of SOCS family proteins. The increased SOCS protein family expression results in cross inhibition of multiple unrelated cytokine receptors, causing the development of a phenomenon known as cytokine resistance. [0126] Cytokine resistance may explain the inconsistent effects that have been reported to date of IL22 therapy in mediating experimental colitis. Thus, to establish an efficient therapy that can help promote healing, reconstitute intestinal barrier function and dampen inflammation, one has to be able to provide all the specific elements necessary to reestablish homeostasis in a tissue-specific fashion. [0127] While not being limited to this mode of action, a combination of (i) AhR agonists that can induce the IL22-independent activities such as maintaining the epithelial stem cell niche, driving functional differentiation of Treg T cells, stymying the differentiation of TH17 cells (CD4 T cells that can produce IL17), and (ii) IL22 (responsible for epithelial cell proliferation, induction of anti-microbial proteins, tight junction proteins, and mucins) should be able to promote the therapeutic reestablishment of the gut normal structure and function. G. Pharmaceutical Compositions and Dosing [0128] The protein-drug conjugates (also referred to herein as conjugates) described herein are best administered to a patient as a pharmaceutical composition. Such compositions are not limited to any particular formulation or pharmaceutical carrier, as such may vary. In general, the conjugates described herein will be administered as liquid pharmaceutical compositions by any of a number of known routes of administration including Topical, for mucosal delivery, orally in for example an eneteric coated capsule, or colonically, as well as by intravenous, intramuscular, subcutaneous, and intraperitoneal administration. However, compositions suitable for intravenous delivery are preferred. [0129] The liquid pharmaceutical compositions described herein have a concentration of the conjugate ranging from about 0.2 milligrams per mL to about 50 milligrams per mL. In some embodiments, the liquid pharmaceutical compositions comprise from about 0.5 mg per mL to about 20 mg/mL. These compositions are preferably aqueous pharmaceutical compositions and, in one embodiment, are sterile aqueous pharmaceutical compositions formulated for intravenous delivery, such as in saline. [0130] The protein-drug conjugates and pharmaceutical compositions comprising said conjugates are administered to the patient in an effective amount to treat IBD including any one or more of the following conditions associated with IBD; • inhibiting de-epithelialization of intestinal epithelial barrier; • inhibiting microbial infection of the intestine; • preserving goblet cells in the intestine during infection; • enhancing epithelial cell integrity; • enhancing epithelial cell proliferation; • enhancing epithelial cell differentiation; and • initiating re-epithelialization in compromised portions of the intestinal epithelial barrier. [0131] The dosing of the protein-drug conjugate of this invention is dependent on the age, sex, weight, severity of the condition, overall health of the patient, and other factors well known to the attending clinician. In one embodiment, the patient is treated with an effective amount of drug conjugate which is predicated in part on the amount of laquinimod released into the intestinal epithelial cells. This, in turn, is dependent on the amount of laquinimod per drug conjugate. In general, the amount of drug conjugate administered ranges from about 50 micrograms to 1 gram per day and preferably from about 100 micrograms to 100 milligrams. H. Combinations [0132] The protein-drug conjugates described herein can be used in combination with TNF-blockers, steroids, and 5-aminosalicylic acid, as well as conventional therapy currently used to treat IBD. EXAMPLES [0133] This disclosure is further understood by reference to the following examples, which are intended to be purely exemplary of this disclosure. This disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of this disclosure only. Any methods that are functionally equivalent are within the scope of this disclosure. Various modifications of this disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and any accompanying figures. Such modifications fall within the scope of the appended claims. [0134] In the specification and the examples below, all temperatures are in degrees Celsius unless indicated otherwise. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their art-recognized meaning. Abbreviation Meaning ^ chemical shift (ppm) AcOH acetic acid Boc or t-Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl DCM Dichloromethane DIEA Diisopropylethylamine DMF N,N-dimethylformamide eq. equivalent(s) ESI electrospray ionization EtOAc ethyl acetate EtOH Ethanol FICZ 6-formylindolo[3,2-b]carbazole Fmoc fluorenylmethyloxycarbonyl g Grams GI gastrointestinal ¹ H NMR proton nuclear magnetic resonance spectroscopy H hour(s) HPLC high performance liquid chromatography IEB Intestinal epithelial barrier IFN Interferon IL Interleukin, including IL6 and IL22 IL10R2 Interleukin 10 Receptor 2 IPA isopropyl alcohol Laq Laquinimod L Liter LDA lithium diisopropylamide M Molar MEK methyl ethyl ketone MeOH Methanol µg or µL Microgram or microliter respectively mg Milligram mmol Millimole mL Milliliter m/z mass-to-charge ratio MsOH methanesulfonic acid Min minute(s) N normal Pd/C palladium on carbon t-Bu tert-butyl THF tetrahydrofuran TR Thioredoxin (also Trx) UV Ultraviolet v/v volume/volume ratio wt % weight percent Preparative Example A – Synthesis of (9H-fluoren-9-yl)methyl (3-chloro-3- oxopropyl)carbamate (Reagent A) ^ ^ ^ Reagent A [0136] Commercially available Fmoc-^-alanine (3.5 g, 11.2 mmol) was converted according to well-known literature procedures to give reagent A. Preparative Example B - Laquinimod Sodium Salt (Compound 14) ^ [0135] 5-chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phen yl-3- quinolinecarboxamide sodium salt (laquinimod sodium salt) is a commercially available reagent. See, e.g., Finetech Industry Limited (Wuhan, Hubei, China). Example 1 - Synthesis of Compound 13 [0136] Approximately equimolar amounts of compound 11 and reagent A were combined in a suitable inert solvent in the presence of a sufficient amount of DIEA (diisopropylethylamine) to scavenge the acid generated during the reaction. The reaction was maintained at about 20°C for about 0.5 hours, which is a sufficient period of time to effect amidation thereby providing for compound 12. [0137] Alternatively, methyl-(4-triacetyl-^-D-glucopyranuronate)-3-Fmoc, compound 12, is commercially available – see, supra. [0138] A solution of compound 12 (1.33 g, 1.8 mmol) in DCM (20 mL) was chilled over an ice bath, under argon. DIPEA (320 uL, 1.8 mmol) was added followed by Ms2O (313 mg, 1.8 mmol) in one portion. The reaction was stirred for 30 minutes and additional portions of DIPEA (320 µ L, 1.8 mmol) and Ms2O (313 mg, 1.8 mmol) were added. The reaction was stirred for 1 hr and quenched with saturated sodium bicarbonate solution and diluted with DCM. The layers were separated, and the DCM layer was washed with brine and dried over sodium sulfate. The solution was concentrated on a RotoVap at water bath temperature of 25ºC. The residue was purified by silica gel chromatography using a gradient of 50-100% ethyl acetate / hexanes. Example 2 - Synthesis of Compound 15 [0139] Approximately equimolar amounts of compound 13 and compound 14 were dissolved in MEK. The resulting solution was heated to about 55ºC and maintained at that temperature for 30 hours. The reaction was then terminated and the solvent was stripped to yield a solid which was not purified or further isolated but was used in example below. Example 3 – Synthesis of Compound 16 (formate salt) [0140] Compound 15 (147 mg, 0.135 mmol) was dissolved in MeOH (10 mL) and THF (2 mL) and chilled over an ice bath. A solution of LiOH (16 mg in 1 mL water) was added in 200 µ L increments over 1 hr. The ice bath was removed and the reaction was stirred an additional 3 hr. The reaction solution was concentrated on a RotoVap with a 25ºC water bath to remove THF and MeOH. The residue was treated with methyl t-butyl ether (10 mL) and water (2 mL) and vortexed for 1 minute. The water layer was directly purified by preparative HPLC (XBridge C1810 µm OBD, 19x250 mm column at 245 nm, flow rate at 30 mL/min, 0.1% formic acid in water/ACN, 10% ACN to 100% ACN in water, 10 min ramp). The fraction at 4.59 min containing the desired mass was lyophilized to give the product as the formate salt MS (ESI+) m/z: 725.15 (M ⁺ ) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ ^ [0141] Compound 16, as described above, was combined in DMF with an approximately equimolar amount of 3-[oxyethyloxyethyloxyethyl-(ethyl-2- maleimide)]propanoic acid pentafluorophenyl ester, reagent C (PFP is pentafluorophenyl), which is commercially available. The amidation reaction proceeded via conventional techniques under completion. Afterward, the reaction mixture (DMF) was directly purified by preparative HPLC (XBridge C ₁₈ 10 µm OBD, 19 x 250 mm column at 245 nm, flow rate at 30 mL/min, 0.1% formic acid in water/ACN, 10% ACN to 100% ACN in water, 10 min ramp). The fraction containing the desired mass was collected and lyophilized to give the product MS (ESI+) m/z: 1008.47 , 1030.34 [M+Na ⁺ ] ⁺ . Example 5 – Method of Making an IL22 and Thioredoxin (IL22/Trx fusion protein [0142] To prepare a thioredoxin-IL22 conjugate, the following materials and methods were used. pET-27b plasmid vector and BL21(DE3) competent cells were purchased from Sigma-Millipore. Terrific Broth, antibiotics, restriction enzymes, and isopropyl ^-D-thiogalactopyranoside (IPTG) were obtained from ThermoFisher. All gene synthesis constructs were performed by GeneArt (Thermo Scientific). Cloning and expression were done following standard molecular biology protocols (Sambrook et al.). In brief, a His-tagged human Thioredoxin-IL22 fusion protein (having a GSAM peptide linker present between the thioredoxin and IL22) coding sequence was cloned into pET- 27b and transformed into E. coli cells, BL21 (DE3). The fusion protein also has a 6His tag at the amino terminus of the thioredoxin polypeptide. Alternative tags can be used instead of a His tag, such as a glutathione-S-transferase (GST) affinity tag, a HaloTag® protein, a Nano-Glo® HiBiT, a NanoLuc® luciferase, and the like. [0143] The BL21 (DE3) E. coli cells were grown in terrific broth media/kanamycin and induced by IPTG. Cultures were harvested by centrifugation after 20 hours at 20ºC. Cell pellets were lysed in 20 mM phosphate buffer at pH 8, 5% sorbitol, 5% glycerol, 100 mM KCl, 1% n-dodecyl-^-D-maltoside, an EDTA-free protease inhibitor cocktail, 300 µg/ml lysozyme, and 1 IU/ml of universal DNA nuclease. Lysates were incubated in the lysis buffer for 30 minutes under mild agitation and then sonicated for 10 cycles in ice (e.g., one cycle is 15 seconds ON, 1 minute OFF, 60% amplitude). Insoluble material was pelleted by centrifugation at 21,000 x g at 4ºC for 30 minutes. Supernatants were applied to HP Histrap nickel-Sepharose columns (Cytiva Life Sciences) and chromatographed according to the manufacturer’s instructions. Eluted peaks were analyzed for the presence of IL22 by ELISA. Biological activity was assessed using the IL22 reporter cell line. [0144] The thioredoxin-IL22 fusion protein was further purified by size-exclusion chromatography using a Superdex 75 PG column (Sigma) and re-analyzed as indicated above. The purified thioredoxin-IL22 fusion protein was stored at -80ºC in a storage buffer (i.e., 20 mM phosphate pH 7.5, 100 mM KCl, and 300 mM L-Arginine). [0145] The exemplified His-tagged Thioredoxin-IL22 fusion protein was created using the following sequences. The human thioredoxin protein (“Trx”) used in the example has the following sequence: MHHHHHHVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEKYSNVI FLEVDVDDCQDVASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV (SEQ ID NO: 1) [0146] The double underlined cysteines (“C”) in the Trx indicate the cysteines that are not paired. The single underlined cysteines represent cysteine-pairing as disulfides. The Trx is attached to the IL22 protein at the amino terminus of the IL22 protein at the carboxy terminus of Trx. The Trx methionine (M) is included at the amino terminus of the 6-histidine tag (SEQ ID NO: 5). A different tag can be used instead of the 6-His tag (SEQ ID NO: 5); therefore the Trx protein used in the fusion protein should not be limited to one comprising a 6-His tag (SEQ ID NO: 5). [0147] The human IL22 protein used lacks the 33 amino acid signal protein (i.e., MAALQKSVSS FLMGTLATSC LLLLALLVQG GAA, SEQ ID NO: 6) present on the immature IL22 at the amino terminus. One IL22 sequence used is: APISSHCRLDKSNFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLM KQVLNFTLEEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDT VKKLGESGEIKAIGELDLLFMSLRNACI (SEQ ID NO:2). [0148] The cysteines are bolded and underlined in the IL22 protein; the cysteines that are double underlined represent the cysteines that form a disulfide bond, while the cysteines with a single underline do not form disulfide bonds. [0149] The Trx (thioredoxin) protein is linked via a peptide linker to the IL22 protein using a 4-amino acid linker, i.e., GSAM (Glycine – Serine – Alanine – Methionine) (SEQ ID NO: 4). The peptide linker is depicted with brackets and underline. No peptide linker is required to link the two proteins. Alternative peptide linkers can be used and can range from one amino acid to 100 amino acids in length. Thus, the embodiments should not be limited to four amino acids or no peptide linker but can include any peptide linker having a sequence of 1 to 100 amino acids and any whole integer in-between. Alternatively, a chemical linker can be used instead of a peptide linker. For example, tyrosine can be used via click chemistry by reacting with PTAD (4- phenyl-3H- 1,2,4- triazole-3,5(4H)-dione). Alternatively, lysines (K) can also be used via the ε- amino group; however, lysines are undesirable given their abundance and associated lack of reproducibility. [0150] The exemplified full fusion protein as discussed in this example depicted below for Human Thioredoxin(C32SC35S)-IL22, having a cysteine to serine mutation at positions 32 and 35 as depicted with the asterisked cysteines: MHHHHHHVKQIESKTAFQEALDAAGDKLVVVDFSATWC ^* GPC ^* KMIKPFFHSLSEKYSNV IFLEVDVDDCQDVASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV[GSAM] PISSHCRLDKSNFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMK QVLNFTLEEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTV KK LGESGEIKAIGELDLLFMSLRNACI (SEQ ID NO: 3) [0151] The underlined cysteines depicted in the fusion protein of SEQ ID NO: 6 are those that form disulfide bonds. The peptide linker is encompassed by a box. Thus, the order of the sequences is the N-terminus-His-Tag – Trx – Peptide Linker – IL22-C- terminus. Interestingly, if the thioredoxin is expressed on the carboxy end of IL22, the biological activity in the form of inducing STAT3 activation falls by a full log fold. Therefore, while the protein order of IL22 and thioredoxin can be switched and still possess activity, it has been observed to have reduced activity. [0152] The nucleic acid encoding the His-Tagged thioredoxin-IL22 fusion protein was inserted into the pET27b (Novagen-Millipore-Sigma) vector. The nomenclature of “m” and “h” indicates “murine” and “human” respectively. The nucleic acid sequences for each variant is as follows: mThio-mIL22 (protein) MHHHHHHVKLIESKEAFQEALAAAGDKLVVVDFSATWCGPCKMIKPFFHSLCDKYSNVVF LEV DVDDCQDVAADCEVKCMPTFQFYKKGQKVGEFSGANKEKLEASITEYALPVNTRCKLEVS NFQ QPYIVNRTFMLAKEASLADNNTDVRLIGEKLFRGVSAKDQCYLMKQVLNFTLEDVLLPQS DRF QPYMQEVVPFLTKLSNQLSSCHISGDDQNIQKNVRRLKETVKKLGESGEIKAIGELDLLF M SLRNACV (SEQ ID NO: 7) mThio-mIL22 (nucleic acid) ATGCACCATCATCATCACCATGTGAAACTGATCGAAAGCAAAGAAGCATTTCAAGAAGCA CT GGCAGCAGCCGGTGATAAACTGGTTGTTGTTGATTTTAGCGCAACCTGGTGTGGTCCGTG TA AAATGATTAAACCGTTTTTCCATAGCCTGTGCGACAAATATAGCAATGTTGTTTTTCTGG AA GTGGATGTGGATGATTGTCAGGATGTTGCAGCAGATTGTGAAGTTAAATGTATGCCGACC TT CCAGTTCTATAAAAAGGGTCAGAAAGTGGGTGAATTTAGCGGTGCCAATAAAGAAAAACT GG AAGCAAGCATTACCGAATATGCACTGCCGGTTAATACCCGTTGTAAATTAGAAGTGAGCA AT TTCCAGCAGCCGTATATTGTTAATCGTACCTTTATGCTGGCAAAAGAAGCAAGCCTGGCA GA TAATAACACCGATGTTCGTCTGATTGGCGAAAAACTGTTTCGTGGTGTTAGCGCAAAAGA TC AGTGTTATCTGATGAAACAGGTGCTGAATTTTACCCTGGAAGATGTTCTGCTGCCGCAGA GC GATCGTTTTCAGCCTTATATGCAAGAAGTTGTTCCGTTTCTGACCAAACTGAGCAATCAG CT GAGCAGCTGTCATATTAGCGGTGATGATCAGAACATTCAGAAAAATGTTCGTCGCCTGAA AG AAACCGTTAAAAAGCTGGGTGAAAGCGGTGAAATTAAAGCAATTGGTGAACTGGATCTGC TGTTTATGAGCCTGCGTAATGCATGTGTTTAA (SEQ ID NO: 8) mThioC32S35S-mIL22 (protein) MVKLIESKEAFQEALAAAGDKLVVVDFSATWSGPSKMIKPFFHSLCDKYSNVVFLEVDVD DCQ DVAADCEVKCMPTFQFYKKGQKVGEFSGANKEKLEASITEYALPVNTRCKLEVSNFQQPY IVN RTFMLAKEASLADNNTDVRLIGEKLFRGVSAKDQCYLMKQVLNFTLEDVLLPQSDRFQPY MQE VVPFLTKLSNQLSSCHISGDDQNIQKNVRRLKETVKKLGESGEIKAIGELDLLFMSLRNA C VHHHHHH (SEQ ID NO: 9) mThioC32S35S-mIL22 (nucleic acid) ATGGTGAAACTGATCGAAAGCAAAGAAGCATTTCAAGAAGCACTGGCAGCAGCCGGTGA TAAACTGGTTGTTGTTGATTTTAGCGCAACCTGGTCAGGTCCGAGCAAAATGATTAAAC CGTTTTTCCATAGCCTGTGCGACAAATATAGCAATGTTGTTTTTCTGGAAGTGGATGTGG AT GATTGTCAGGATGTTGCAGCAGATTGTGAAGTTAAATGTATGCCGACCTTCCAGTTCTAT AAAAAGGGTCAGAAAGTGGGTGAATTTAGCGGTGCCAATAAAGAAAAACTGGAAGCAAG CATTACCGAATATGCACTGCCGGTTAATACCCGTTGTAAATTAGAAGTGAGCAATTTCC AGCAGCCGTATATTGTTAATCGTACCTTTATGCTGGCAAAAGAAGCAAGCCTGGCAGAT AATAACACCGATGTTCGTCTGATTGGCGAAAAACTGTTTCGTGGTGTTAGCGCAAAAGA TCAGTGTTATCTGATGAAACAGGTGCTGAATTTTACCCTGGAAGATGTTCTGCTGCCGC AGAGCGATCGTTTTCAGCCTTATATGCAAGAAGTTGTTCCGTTTCTGACCAAACTGAGC AATCAGCTGAGCAGCTGTCATATTAGCGGTGATGATCAGAACATTCAGAAAAATGTTCG TCGCCTGAAAGAAACCGTTAAAAAGCTGGGTGAAAGCGGTGAAATTAAAGCAATTGGTG AACTGGATCTGCTGTTTATGAGCCTGCGTAATGCATGTGTTCATCATCACCATCATCAT TAA (SEQ ID NO: 10) HThio-HIL22-APT (protein) MHHHHHHVKQIESKTAFQEALDAAGDKLVVVDFSATWCSGGGGSGGGGAPISSHCRLDKS NFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTLEEVLF PQS DRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEIKAIGELD LLF MSLRNACISGGGGSGGGGPCKMIKPFFHSLSEKYSNVIFLEVDVDDCQDVASECEVKCMP TFQ FFKKGQKV GEFSGANKEKLEATINELV (SEQ ID NO: 11) The HThio-HIL22-APT variant has the human thioredoxin VKQIESKTAFQEALDAAGDKLVVVDFSATWC (SEQ ID NO: 12) sequence then followed by IL22 and then followed by the remainder of the thioredoxin: PCKMIKPFFHSLSEKYSNVIFLEVDVDDCQDVASECEVKCMPTFQFFKKGQKVG EFSGANKEKLEATINELV (SEQ ID NO: 13). HThio-HIL22-APT (nucleic acid) ATGCATCATCACCATCATCATGTGAAGCAGATTGAAAGCAAAACCGCATTTCAAGAGGCA CTG GATGCAGCCGGTGATAAACTGGTTGTTGTTGATTTTAGCGCAACCTGGTGTAGCGGTGGT GGT GGTTCAGGTGGCGGTGGTGCACCGATTAGCAGCCATTGTCGTCTGGATAAAAGCAATTTT CAG CAGCCGTATATTACCAACCGTACCTTTATGCTGGCAAAAGAAGCAAGCCTGGCAGATAAT AAC ACCGATGTTCGTCTGATTGGCGAAAAACTGTTTCATGGTGTTAGCATGAGCGAACGTTGT TAT CTGATGAAACAGGTGCTGAATTTTACCCTGGAAGAAGTTCTGTTTCCGCAGAGCGATCGT TTT CAGCCTTATATGCAAGAAGTTGTTCCGTTTCTGGCACGTCTGAGCAATCGTCTGAGTACC TGT CATATTGAAGGTGATGATCTGCATATTCAGCGCAATGTTCAGAAACTGAAAGACACCGTT AAA AAGCTGGGTGAAAGCGGTGAAATTAAAGCAATTGGTGAACTGGATCTGCTGTTTATGAGC CTG CGTAATGCATGTATTTCAGGTGGTGGCGGTAGCGGAGGCGGTGGTCCGTGTAAAATGATT AAA CCGTTTTTCCATAGCCTGAGCGAGAAATATAGCAACGTGATTTTTCTGGAAGTGGATGTT GAT GATTGTCAGGATGTTGCAAGCGAATGTGAAGTTAAATGTATGCCGACGTTTCAGTTCTTT AAA AAGGGTCAGAAAGTGGGCGAATTTAGCGGTGCAAATAAAGAAAAACTGGAAGCCACCATT A ACGAGCTGGTTTAA (SEQ ID NO: 14) HThio-HIL22 (protein) MHHHHHHTTFNIQDGPDFQDRVVNSETPVVVDFHAQWCGPCKILGPRLEKMVAKQHGKVV MA KVDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGIKDEDQLEAFLKKLIGGSAMAPIS SH CRLDKSNFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFT LE EVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEI KAIGELDLLFMSLRNACI* (SEQ ID NO:15) Hthio-HIL22 (nucleic acid) ATGCATCATCATCATCACCATACCACCTTTAACATTCAGGATGGTCCGGATTTTCAGGAT CG TGTTGTTAATAGCGAAACACCGGTTGTTGTTGATTTTCATGCACAGTGGTGTGGTCCGTG TA AAATTCTGGGTCCGCGTCTGGAAAAGATGGTTGCAAAACAGCATGGTAAAGTTGTTATGG CC AAAGTGGATATCGATGATCATACCGATCTGGCCATTGAATATGAAGTTAGCGCAGTTCCG AC CGTTCTGGCAATGAAAAATGGTGATGTTGTGGATAAATTCGTGGGCATCAAAGATGAAGA TC AGCTGGAAGCATTTCTGAAAAAGCTGATTGGTGGTAGCGCAATGGCACCGATTAGCAGCC AT TGTCGTCTGGATAAAAGCAATTTTCAGCAGCCGTATATTACCAACCGTACCTTTATGCTG GC AAAAGAAGCAAGCCTGGCAGATAATAACACCGATGTTCGTCTGATTGGCGAAAAACTGTT TC ATGGTGTTAGCATGAGCGAACGTTGTTATCTGATGAAACAGGTGCTGAATTTTACCCTGG AA GAAGTTCTGTTTCCGCAGAGCGATCGTTTTCAGCCTTATATGCAAGAAGTTGTTCCGTTT CT GGCACGTCTGAGCAATCGTCTGAGTACCTGTCATATTGAAGGTGATGATCTGCATATTCA GC GCAATGTTCAGAAACTGAAAGACACCGTTAAAAAGCTGGGTGAAAGCGGTGAAATTAAAG CA ATTGGTGAACTGGATCTGCTGTTTATGAGCCTGCGTAATGCATGTATCTAATAA (SEQ ID NO: 16) HThioC3235S-HIL22 (protein) MHHHHHHTTFNIQDGPDFQDRVVNSETPVVVDFHAQWSGPSKILGPRLEKMVAKQHGKVV MAK VDIDDHTDLAIEYEVSAVPTVLAMKNGDVVDKFVGIKDEDQLEAFLKKLIGGSAMAPISS HCR LDKSNFQQPYITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTLE EVL FPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEIKAI G ELDLLFMSLRNACI* (SEQ ID NO: 17) HThioC3235S-HIL22 (nucleic acid) ATGCATCATCATCATCACCACACCACCTTTAACATTCAGGATGGTCCGGATTTTCAGGAT CGT GTTGTTAATAGCGAAACACCGGTTGTTGTTGATTTTCATGCACAGTGGTCAGGTCCGAGC AAA ATTCTGGGTCCGCGTCTGGAAAAGATGGTTGCAAAACAGCATGGTAAAGTTGTTATGGCC AAA GTGGATATCGATGATCATACCGATCTGGCCATTGAATATGAAGTTAGCGCAGTTCCGACC GTT CTGGCAATGAAAAATGGTGATGTTGTGGATAAATTCGTGGGCATCAAAGATGAAGATCAG CTG GAAGCATTTCTGAAAAAGCTGATTGGTGGTAGCGCAATGGCACCGATTAGCAGCCATTGT CGT CTGGATAAAAGCAATTTTCAGCAGCCGTATATTACCAACCGTACCTTTATGCTGGCAAAA GAA GCAAGCCTGGCAGATAATAACACCGATGTTCGTCTGATTGGCGAAAAACTGTTTCATGGT GTT AGCATGAGCGAACGTTGTTATCTGATGAAACAGGTGCTGAATTTTACCCTGGAAGAAGTT CTG TTTCCGCAGAGCGATCGTTTTCAGCCTTATATGCAAGAAGTTGTTCCGTTTCTGGCACGT CTG AGCAATCGTCTGAGTACCTGTCATATTGAAGGTGATGATCTGCATATTCAGCGCAATGTT CAG AAACTGAAAGACACCGTTAAAAAGCTGGGTGAAAGCGGTGAAATTAAAGCAATTGGTGAA CTG GATCTGCTGTTTATGAGCCTGCGTAATGCATGTATCTAA (SEQ ID NO: 18) [0153] A full listing of each identified SEQ ID Nos. is as follows: SEQ ID NO. 1 Mature human IL22 SEQ ID NO.2 Gly-Ser-Ala-Met SEQ ID NO. 3 human thioredoxin C32C35-IL22 fusion protein SEQ ID NO. 4 Gly-Ser-Ala-Met SEQ ID NO. 5 6His tag SEQ ID NO. 6 IL22 signal peptide, for human IL22 which is cleaved upon maturation SEQ ID NO. 7 mThio-mIL22 (protein) SEQ ID NO. 8 mThio-mIL22 (nucleic acid) SEQ ID NO. 9 mThioC32S35S-mIL22 (protein) SEQ ID NO. 10 mThioC32S35S-mIL22 (nucleic acid) SEQ ID NO. 11 HThio-HIL22-APT (protein) SEQ ID NO. 12 Amino side of the Trx where the IL22 protein is upstream of this sequence for the human thio-HIL22-APT SEQ ID NO. 13 Carboxy side of the Trx where the IL22 protein is upstream of this sequence for the human thio-HIL22-APT SEQ ID NO. 14 HThio-HIL22-APT (nucleic acid) SEQ ID NO. 15 HThio-HIL22 (protein) SEQ ID NO. 16 Hthio-HIL22 (nucleic acid) SEQ ID NO. 17 HThioC3235S-HIL22 (protein) SEQ ID NO. 18 HThioC3235S-HIL22 (nucleic acid) [0154] The vector was expressed in E. coli BL21(DE3) after nucleic acid optimization for expression in E. coli. The genes were synthesized by the GeneArt service from ThermoFisher. GeneArt has a proprietary nucleic acid optimization tool that optimizes the sequence based on codon usage by any given expression platform. Example 6 – Conjugation of Laquinimod to the Trx-IL22 Fusion Protein [0155] Glucoronide-maleimide-laquinimod is a drug payload conjugatable moiety and is represented by compound 6: Compound 6 consists of a thiol-reactive maleimide group, a glucuronidase cleavable glucuronide linker, and a releasable drug payload (laquinimod). [0156] A. In the first example, lyophilized compound 6 was dissolved in DMSO (dimethyl sulfoxide) and adjusted to a 10 mM stock solution. The purified thioredoxin- IL22 fusion protein from Example 7 above was dissolved in 20 mM phosphate buffer, 100 mM KCl, maintained at pH 7.5, and an amount of the stock solution sufficient to provide for a 10-fold molar excess of compound 6 over the number of free cysteine residues in the fusion protein was added. The solution was stirred for 2 hours at room temperature followed by overnight incubation at 4ºC under mild agitation. [0157] B. Separately, a 2 mg/ml fusion thioredoxin-IL22 fusion protein from Example 7 (50 µM) was reacted in a 3-fold molar excess of the glucuronide-maleimide- laquinimod conjugate for 1 hour at room temperature with mild agitation. The reaction was quenched with an excess of L-cysteine and the mixture was desalted using a 26/10 HiPrep™ desalting column (Sigma Aldrich) according to manufacturer instructions. The desalted protein was put into a storage buffer (i.e., 20 mM phosphate pH 7.5, 100 mM KCl, and 300 mM L-Arginine). [0158] Next, the conjugated fusion proteins were exposed to a 10-fold molar excess (over disulfide Cysteine content) of TCEP to reduce disulfides and incubated at room temperature (RT) for 1 hour (under mild agitation) followed by the addition of a 2- fold molar excess (over TCEP; TCEP is the reducing agent, tris(2- carboxyethyl)phosphine) of dibromo-PEG-Maleimide-amino (the rebridging agent). The mixture was incubated for 2 hours at RT under mild agitation, desalted using a HiTrap desalting column (Cytiva) as described above, and stored at -80ºC until used. [0159] The degree of conjugation was measured by comparing the number of free thiols in the protein sample before and after conjugation using a commercial Thiol measuring kit Measure-IT™, Thermo Scientific) according to the manufacturer’s instructions. The drug-to-protein ratio was calculated to be approximately 2.97 drugs per protein molecule by optical density. The calculation assumed that lack of Thiol reactivity equates to the presence of a drug, so by measuring thiols before and after conjugation the number of drugs, i.e., mols of drugs/mol of protein can be estimated. It has been observed that the HThio-HIL22-APT protein variant (SEQ ID NO: 11) can conjugate more laquinimod molecules than the other constructs. The APT variant can deliver 5 molecules of laquinimod into a cell as opposed to the other variants, which can only deliver three. Example 7 – Drug Conjugate Trx-IL22 Fusion Protein Characterization [0160] The fusion protein was quantified by ELISA. The fusion protein’s biological activity was determined using an IL22-dependent reporter bioassay using HEK Blue IL22 cell line from InvivoGen according to the manufacturer’s instructions. The fusion protein was calibrated with commercially available recombinant IL22 (R&D Systems, Cat. No.782-IL-010/CF). [0161] The biological activity bioassay uses the epithelial cell line, HEK 293, which has been engineered to constitutively express a mouse IL22 receptor heterodimer. The HEK 293 cells are recombinantly engineered to have an IL22-responsive transcription factor mouse STAT3 and harbor an integrated copy of a plasmid containing a STAT3 sensitive promoter that drives the expression of a secreted alkaline phosphatase reporter protein. The cells are the InvivoGen IL22 reporter cell line. [0162] Results in Figure 1 demonstrate that both analyzed thioredoxin-IL22 fusion proteins (i.e., Thio-IL22 and Thio-C3235S-IL22) are expressed at high levels in the E. coli BL21(DE3) host. The Thio-C3235S-IL22 (murine is SEQ ID NO: 9 and human is SEQ ID NO: 17) is a variant wherein the cysteines at positions 32 and 35 have been changed to serine. The IL22 sequence and thioredoxin sequences are otherwise the same as that in the Thio-IL22 construct. Expression for the constructs is as described above using the listed sequences. The expression method is the same for both. [0163] ELISA used the mouse and Human IL22 Duo-Set ELISA package from R&D Systems according to their instructions. Samples were diluted in 10-fold (log) serial dilutions. [0164] Figure 2 shows the results of the reporter bioassay for the samples analyzed using the human Thio-IL22 and human Thio-C3235S-IL22 constructs. The analogous mouse constructs provided similar results (data not shown). C32 and C35 are the active cysteines in the thioredoxin catalytic domains. When mutated to serine, thioredoxin no longer possesses redox activity. However, the C32S / C35S thioredoxin double mutation maintains a chaperone-like activity, just no Redox activity. In the instance of the IL22/thioredoxin fusion protein, it was observed that mutating thioredoxin to avoid redox activity improves the biological activity of the IL22/thioredoxin fusion protein. The biological performance of a fusion partner does not necessarily improve by removing the redox activity of thioredoxin in all thioredoxin fusion proteins, but it does occur for IL22. [0165] “recHIL22” is a recombinant human IL22 protein obtained from R&D (same as above). [0166] The total Trx-IL22 fusion protein content of the samples was measured using a Thermo Fisher Bradford assay. The Thermo Fisher Bradford reagent and protein stock solutions were adjusted to 1 mg/ml according to manufacturer instructions. Protein samples were added to IL22 reporter cells (InvivoGen IL22 reporter cell line); the cells were cultured according to manufacturer instructions. Protein samples were assayed at the indicated concentrations in Figure 3. Supernatants from the cultured IL22 reported cells were collected after 24 hours of culture. Secreted alkaline phosphatase activity was measured using the colorimetric substrate provided with the InvivoGen IL22 cell line according to InvivoGen instructions (i.e., a secreted embryonic alkaline phosphatase (SEAP) substrate. [0167] Figure 3 depicts the mechanisms underlying the design of the IL22 reporter cell line that is capable of independently measuring IL22 bioactivity and the activity of the drug payload once released inside the cell after IL22-receptor-mediated endocytosis of the protein-drug-conjugate (PDC). Both the Thio-IL22 and ThioC3235S- IL22 share similar bioactivity to the recombinant human IL22. The data for the human Thio-IL22 and ThioC3235S-IL22 constructs are depicted. Tests done with the murine analogs to the human constructs produced similar results (data not shown). [0168] The glucuronide linker is cleaved by an endosomal glucuronidase in the targeted cell. The cleaved glucuronide linker releases the laquinimod payload. The red star depicted in Figure 3 represents laquinimod. The IL22-AHR reporter cell line uses the IL22 reporter HEK cell line described above as a starting point. The HEK cell line is then transfected with an AHR- GFP gene (Sino Biologicals, Cat. No. HG10456-ACG) and a plasmid carrying a drug response element (DRE) promoter (pGL4.43[luc2P XRE Hygro] from Promega Corp.),^which binds active, drug-loaded AHR and drives the expression of a firefly luciferase gene in the Promega plasmid. [0180] Figures 4A and 4B demonstrate the ability of the IL22 fusion PDC to activate both pathways as expected if IL22 is internalized and releases the laquinimod within the cell. The constructs used and depicted in Figures 4A and 4B were all using human sequences. The mouse analogs to the human constructs produced similar results (data not shown). [0169] The very high-affinity AHR agonist, the tryptophan metabolite FICZ, is used as a positive control along with the non-metabolizable AHR agonist, the pesticide TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). In Figure 4A, the reporter assay measures STAT3 activity at varying concentrations of IL22 PDC µg/ml. The PDS was diluted in complete media (DMEM, 5% FCS, 2 mM L-glutamine) and then administered to the cells. The IL22PDC was added directly to cell cultures at diverse concentrations as diluted in the complete media. The cells were cultured to about 50,000 cells/well of a 96- well plate. Once the IL22 PDC is administered to the cells, the cells are cultured with the PDC present 37ºC and 7 % CO ₂ for 21-24 hours and assayed. The results in Figure 4A reflect the measurements of thioredoxin-IL22 fusion without the drug (ThioIL22 – no laquinimod), with the drug (ThioIL22-Liq, “Liq” = laquinimod), Thioredoxin-IL22 fusion called ThioC3235SIL22 without the laquinimod payload, and with the drug (ThioC3235SIL22-Liq), human recombinant IL22 (recIL22 – the recombinant IL22 was obtained from R&D Systems), the tryptophan metabolite (FICZ) and the pesticide TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin or dioxin). The TCDD is used as a positive control. The IL22 (recIL22 – this is a human recombinant IL22) is the negative control. FICZ and TCDD were administered to the cells at concentrations of 10 nM as diluted in complete DMEM media as described above. FICZ and TCDD were from Sigma Chemical Co. [0170] In Figure 4B, the IL22-Liq carrying fusion proteins (i.e., ThioIL22-Liq and ThioC3235SIL22-Liq) were measured at 30 nM (i.e., 90 nM equivalent of laquinimod). Given there are three available cysteines (Cys or C) for conjugation, a 30 µM protein solution would contain 90 µM of cysteines conjugated, each with one drug relative to IL22-Liq forms at 3 nM (i.e., a 9 nM equivalent of laquinimod). The 30 nM activity is reflected at 1 IL22 PDC µg/mL, while the 3 nM is reflected at 0.1 IL22 PDC µg/mL in Figure 4B. [0171] The activity of the 30 nM versus 3 nM was measured using the AHR luciferase activity assay using the recombinant HEK 293 cells engineered to have an IL22-responsive transcription factor mouse STAT3 as described above. The HEK cells were cultured to about 50,000 cells/well of a 96-well plate. Cells are administered the various PDC reagents and controls and then the cells are cultured at 37ºC and 7 % CO ₂ for 21-24 hours and assayed. For the luciferase assay, Promega’s ONE-Glo™ homogeneous luciferase cell assay was used according to the manufacturer’s instructions). The amount of FICS AhR agonist and TCDD AhR agonist used in Figure 4B was again 10 nM as diluted in complete media. “Laq” means laquinimod. This experiment assumes a drug-to-protein ratio of 3 as explained above. [0172] One benefit of the conjugated drug fusion protein is that administering drugs, like laquinimod, in this form can be less toxic because the amount administered is restricted to the cells that have the receptors. The delivery of laquinimod is relevant both in stoichiometric quantity and timing to the cell wherein it is localized within the cell and not a systemic administration of the drug. Example 8 – Laquinimod Cleavage by β-Glucuronidase [0173] In this example, the following were provided: a) 0.25 mL of a 30 mM solution of compound 16 as the formate salt in distilled water was prepared; b) 0.10 mL of a β-Glucuronidase solution (400-800 units/mL) c) 0.50 mL of a buffer comprising 75 mM potassium phosphate buffer, 1% (w/v) bovine serum albumin, and a pH adjusted to 6.8 at 37°C; and d) 0.65 mL of distilled water. [0174] Each of a, c, and d were combined into a first solution and mixed by inversion. The enzyme solution was added to the first solution to form a second solution which was then incubated at 37°C. [0175] The purpose of this experiment was to determine if the enzyme was capable of liberating free laquinimod from the conjugate. Accordingly, samples were taken at different time points starting at T = 0 and T = 30 minutes. The molecular weight of compound 16 is 724.2147 whereas the molecular weight of laquinimod is 356.0928. [0176] LC evidenced a new peak corresponding to laquinimod at T =30. Likewise, mass spectroscopy also evidenced the release of laquinimod at T = 30. This supports that enzymatic cleavage of laquinimod is achieved as described herein. Embodiments Also described herein are one or more of the following embodiments. Embodiment 12. A conjugate comprising: a) a fusion protein comprising an IL22 portion and a thioredoxin portion linked together by a covalent bond or a first linker; and b) from 1 to about 3 second linkers each attached to one or more laquinimod groups, or derivatives thereof, and to a sulfur group of a cysteine side chain in said fusion protein, wherein said first linker, if present, and said second linker comprise from 1 to about 40 non-hydrogen atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus provided that the remaining valences of said non-hydrogen atoms are satisfied with hydrogen or deuterium atoms. Embodiment 13. The conjugate of Embodiment 1, wherein the 1 to about 3 second linkers are each a cleavable linker that cleaves in the presence of an intracellular enzyme found in intestinal epithelial cells or intestinal epithelial stem cells. Embodiment 14. The conjugate of Embodiment 1, wherein said 1 to about 3 second linkers are each attached to laquinimod or derivative thereof through a covalently bound to a free cysteine residue of the thioredoxin portion of the fusion protein. Embodiment 15. The conjugate of Embodiment 1, wherein each of the 1 to about 3 second linkers connecting laquinimod or a laquinimod derivative to the fusion protein is a cleavable linker that is selectively cleaved upon intracellular absorption of the conjugate into the intestinal epithelial cells. Embodiment 16. A conjugate of formula A: [(LAQ) _n - L ² -S - ] _b -FP-Y A where n is from 1 to 4; Y is hydrogen or L ¹ -TR; b is from 1 to 3 when Y is hydrogen and from 1 to 6 when Y is L ¹ -TR; is an enzymatically cleavable linker; FP is a fusion protein having a formula TR-L ¹ -IL22, where TR is a thioredoxin or a biologically active fragment thereof, L ¹ is a linker or a covalent bond, and IL22 is an interleukin-22 or a biologically active fragment thereof bound t _{o L} ¹ _{or to TR when L} ¹ _{is a covalent bond;} LAQ is laquinimod or derivative thereof; and S is a sulfur atom of a thiol group of a free cysteine of the thioredoxin portion of the fusion protein; or a pharmaceutically acceptable salt thereof.

Embodiment 17. The conjugate of Embodiment 5, wherein said conjugate is represented by formula I-A: I-A wherein L ² is a monovalent linker. Embodiment 18. The conjugate of Embodiment 5, wherein said conjugate is represented by formula I-B wherein q is from 1 to 10. Embodiment 19. The conjugate of Embodiment 5 which is represented by formula I-C

. Embodiment 20. The conjugate of Embodiment 5, wherein said conjugatesented by formula I-D wherein b is 1, 2, or 3. Embodiment 21. The conjugate of Embodiment 5, wherein said conjugatesented by formula I-E

wherein the maleimide linker group is represented by and wherein q is from 1 to 10. Embodiment 22. The conjugate of Embodiment 5, wherein said conjugateesented by formula I-F

Formula I-F wherein the succinimide-linker attached to the FP is represented by and wherein q is from 1 to 10. Embodiment 23. A conjugate, which is a protein-drug conjugate comprising a thioredoxin polypeptide linked to an interleukin-22 (IL22) polypeptide directly, via a chemical linker, or via a peptide linker, wherein one or more laquinimod molecules are conjugated to one or more cysteine residues present in the thioredoxin polypeptide. Embodiment 24. The conjugate of Embodiment 12, wherein the thioredoxin polypeptide is linked to an amino terminus of the IL22 polypeptide. Embodiment 25. The conjugate of Embodiment 12, wherein the thioredoxin polypeptide comprises 2 or 3 thioredoxin polypeptides linked together optionally with a peptide linker. Embodiment 26. The conjugate of Embodiment 12, wherein the conjugate is not glycosylated. Embodiment 27. The conjugate of Embodiment 12, wherein the one or more laquinimod molecules are conjugated by a linker and said linker each contains one or more laquinimod molecules, and wherein the linker comprises from 1 to about 40 non-hydrogen atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus provided that atom valency is satisfied with hydrogen or deuterium atoms. Embodiment 28. The conjugate of Embodiment 12, wherein the chemical or peptide linker is a cleavable linker that cleaves in the presence of an intracellular enzyme located in intestinal epithelial cells and intestinal epithelial stem cells. Embodiment 29. The conjugate of Embodiment 12, wherein the thioredoxin polypeptide is linked to the IL22 polypeptide by a peptide linker or via chemical conjugation. Embodiment 30. The conjugate of Embodiment 13, wherein the peptide linker comprises 1 to 100 amino acids. Embodiment 31. The conjugate of Embodiment 15, where the peptide linker comprises 10 amino acids or fewer. Embodiment 32. The conjugate of Embodiment 16, wherein the peptide linker is Gly-Ser-Ala-Met (SEQ ID NO: 4). Embodiment 33. The conjugate of any one of Embodiments 12-22, wherein the thioredoxin polypeptide is a human thioredoxin. Embodiment 34. The conjugate of any one of Embodiments 12-22, wherein the IL22 polypeptide is a human IL22. Embodiment 35. The conjugate of any one of Embodiments 12-23, wherein the thioredoxin polypeptide comprises SEQ ID NO: 1. Embodiment 36. The conjugate of any of Embodiments 12-24, wherein the IL22 is SEQ ID NO: 2 or SEQ ID NO: 2 wherein Cys32 and Cys35 are mutated to serine. Embodiment 37. The conjugate of Embodiment 24, wherein the thioredoxin polypeptide is SEQ ID NO: 1, the IL22 polypeptide is SEQ ID NO: 2, and the peptide linker is Gly-Ser-Ala-Met (SEQ ID NO: 4). Embodiment 38. The conjugate of any one of Embodiments 12-26, wherein the one or more laquinimod molecules or derivatives thereof are not conjugated to a cysteine in the IL22 polypeptide. Embodiment 39. A pharmaceutical composition comprising a conjugate of any one of Embodiments 1-27 and a pharmaceutically acceptable carrier or excipient. Embodiment 40. A method of treating a subject having an inflammatory bowel disease (IBD), the method comprising administering to the subject a conjugate of any one of Embodiments 1-27 or a pharmaceutical composition of Embodiment 28. Embodiment 41. A method for inhibiting de-epithelialization of an intestinal barrier in a patient at risk of an inflammatory bowel disease episode or inhibiting the further de-epithelialization of the intestinal barrier during an ongoing inflammatory bowel disease episode which method comprises administering an effective amount of a conjugate as described herein and/or of any one of Embodiments 1-27 or a pharmaceutical composition of Embodiment 28 to the patient to inhibit de- epithelialization or further de-epithelialization of the intestinal barrier. Embodiment 42. A method for initiating re-epithelialization of an intestinal barrier in a patient suffering from an inflammatory bowel disease episode which method comprises administering an effective amount of a conjugate as described herein and/or of any one of Embodiments 1-27 or a pharmaceutical composition of Embodiment 28 to the patient to initiate re-epithelialization of the intestinal barrier. Embodiment 43. The method of any one of Embodiments 29-31, wherein the conjugate is administered to said subject in an amount sufficient to clinically ameliorate one or more of the following conditions: i) inhibiting de-epithelialization of intestinal epithelial barrier; ii) inhibiting microbial infection of the intestine; iii) preserving goblet cells in the intestine during infection; iv) enhancing epithelial cell integrity; v) enhancing epithelial cell proliferation; vi) enhancing epithelial cell differentiation; and vii) initiating re-epithelialization in compromised portions of the intestinal epithelial barrier. Embodiment 44. The method of any one of Embodiments 29-32, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis. Embodiment 45. The conjugate of any one of Embodiments 1-27 for use in treating an inflammatory bowel disease. Embodiment 46. Use of a conjugate of any one of Embodiments 1-27 in the manufacture of a medicament for treating an inflammatory bowel disease.