Antibody-drug conjugate that binds to CDCP1 and its use

Abstract

The present disclosure provides antibody-drug conjugates (ADCs), their linkers, and compounds useful for the treatment of cancer.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 389,743, filed on July 15, 2022; No. 63 / 400,703, filed on August 24, 2022; No. 63 / 489,473, filed on March 10, 2023; and No. 63 / 489,474, filed on March 10, 2023, all of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure generally relates to antibody - drug conjugates and methods for treating cancer and other diseases, including CUB domain - containing protein 1 (CDCP1) - targeted therapies.

Background Art

[0003] Numerous chemotherapeutic agents have been developed, but often exhibit unacceptable toxicity and / or lack of specificity for cancer cells over non - cancerous tissues. To avoid the non - specific cytotoxic effects of chemotherapeutic agents, targeted antibody therapies have revolutionized cancer treatment using several monoclonal antibodies that show clinical promise. Since antibodies against tumor - specific antigens often lack therapeutic activity, they are conjugated with cytotoxic agents to combine the effectiveness of chemotherapy with antibody targeting. In principle, the selective delivery of cytotoxic agents to specific tumor tissues by antibody binding should reduce the systemic toxicity of conventional small - molecule chemotherapeutic agents.

[0004] For the antibody - drug conjugate (ADC) approach to succeed, it is necessary to bind well to the target antigen in order to deliver the cytotoxic payload to the target cells without significantly binding to non - target cells, so that the ADC can deliver the toxic payload to the target cells, thereby internalizing it, and then releasing the payload upon entry into the appropriate intracellular compartment.

[0005] CDCP1 is widely expressed in human epithelial tissues. CDCP1 functions in the tyrosine phosphorylation-dependent control of cellular events involved in tumor invasion and metastasis, and its phosphorylation is observed only in mitotically detached cells or exfoliated cells, which is consistent with its role in the negative control of cell adhesion. Phosphorylation of CDCP1 is seen in several pre-invasive cancers, as well as in many cancers including invasive tumors and tumor metastases.

[0006] Despite the growing understanding of tumor-specific proteins for targeting using ADC therapy, the need for specific CDCP1-targeting ADCs that can be used for therapeutic purposes in cancer treatment remains unmet in the art.

Summary of the Invention

[0007] In one aspect, the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or a binding fragment thereof, and the antibody or the binding fragment thereof specifically binds to CUB domain-containing protein-1 (CDCP1), L is a linker of the formula -R * -L1-L A -, R * is succinimide, L1 is -[CH2] 1-3 -C(O)NH-, L A is -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA -, p is an integer from 5 to 10, and X AA is an amino acid sequence having two amino acid moieties, D is

Chemical Formula

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Chem.

Chem.

Chem.

[0008] In one aspect, the present disclosure provides a pharmaceutical composition comprising an antibody-drug conjugate of formula (I) and a pharmaceutically acceptable carrier.

[0009] In one aspect, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of formula (I) or a pharmaceutical composition of the present disclosure. In some embodiments, less than about 50% of the antibody-drug conjugate is converted to metabolite at about 24 hours after administration of a therapeutically effective amount of the antibody-drug conjugate to the subject. In some embodiments, about 50% of the antibody-drug conjugate is converted to metabolite at about 96 hours after administration of a therapeutically effective amount of the antibody-drug conjugate to the subject. In some embodiments, the antibody-drug conjugate is of formula 300:

Chemical formula

Chemical formula

Chemical formula

[0010] In one aspect, the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), D comprises a drug moiety, n is an integer from 1 to 20, L has the formula: [Chemical formula] and has: In some embodiments, the antibody or binding fragment thereof comprises (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody or binding fragment thereof comprises (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and It includes a variable light chain region (VL) that includes and / or consists of a VL complementarity-determining region 3 (CDRL3) that includes the amino acid sequence of SEQ ID NO: 8. In some embodiments, the drug moiety is

Chem.

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[0011] In one aspect, the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is an integer from 1 to 20, L-D is of the formula:

Chem.

[0012] In an aspect, the present disclosure provides an antibody-drug conjugate having any one of Formulas 1030-1064 or 1100-1118, wherein Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1).

[0013] In an aspect, the present disclosure provides an antibody-drug conjugate of any one of embodiments (I)-(XVII).

[0014] In an aspect, the present disclosure provides an antibody-drug conjugate having Formula (I), Ab-[L-D] n Formula (I) In Formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 1, L-D has the formula:

Chemical formula

[0015] In an aspect, the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 4, L-D has the formula:

Chemical formula

[0016] In an aspect, the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab includes an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 8, L-D has the formula:

Chemical formula

[0017] In an aspect, the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 1, L-D is of the formula:

Chemical formula

[0018] In one aspect, the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 4, L-D is of the formula:

Chemical formula

[0019] In one aspect, the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or a binding fragment thereof specifically binds to CUB domain-containing protein-1 (CDCP1), n is 8, L-D has the formula:

Chemical formula

[0020] In an aspect, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The foregoing summary and the following detailed description of embodiments of the present disclosure will be better understood when read in conjunction with the accompanying drawings and figures.

[0022]

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[0023] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

[0024] Definitions As used herein, the terms “administer,” “administration,” or “administering” refer to (1) providing, giving, dosing, and / or prescribing by or under the direction of a healthcare provider or an authorized agent thereof in accordance with the present disclosure, and / or (2) administering, ingesting, or causing to be consumed by a mammal in accordance with the present disclosure.

[0025] As used herein, the terms “co-administer,” “co-administering,” “administered in combination with,” “administer in combination with,” “simultaneously,” and “concurrently” encompass the administration of two or more active pharmaceutical ingredients to a subject such that both the active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.

[0026] The terms “active pharmaceutical ingredient” and “drug” antibodies, conjugates, and compounds are described herein. The terms “active pharmaceutical ingredient” and “drug” may also include the compounds described herein that bind to and thereby modulate the activity of a protein, including but not limited to CDCP1.

[0027] The term "isostere" refers to a group or molecule whose chemical and / or physical properties are similar to those of another group or molecule. "Bioisostere" is a type of isostere that refers to a group or molecule whose biological properties are similar to those of another group or molecule. For example, a carboxylic acid can be replaced by one of its bioisosteres, including but not limited to alkyl esters (COOR), acyl sulfonamides (CONR-SO2R), hydroxamic acids (CONR-OH), hydroxamates (CONR-OR), tetrazoles, hydroxyisoxazoles, isoxazol-3-ones, and sulfonamides (SO2NR), where each R independently represents hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0028] The term "in vivo" refers to events that occur within the body of a subject.

[0029] The term "in vitro" refers to events that occur outside the body of a subject. An in vitro assay may include a cell line assay in which live or dead cells are used, and may also include a cell-free assay in which intact cells are not used.

[0030] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a compound or combination of compounds described herein that is sufficient to effect the intended use, which includes, but is not limited to, treating a disease. A therapeutically effective amount can vary depending on the intended use (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight, age, and gender), the severity of the disease state, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. The terms also apply to amounts that would induce a particular response (e.g., a decrease in platelet adhesion and / or cell migration) in target cells. Specific dosages will vary depending on the particular compound selected, the dosage regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is carried.

[0031] As used herein, the term "therapeutic effect" includes a therapeutic benefit and / or a prophylactic benefit. Prophylactic effects include delaying or eliminating the occurrence of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, delaying, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0032] As used herein, the terms "treat", "treatment", and / or "treating" can refer to the management of a disease, disorder, condition, or symptom thereof for the purpose of curing, ameliorating, stabilizing, and / or controlling the disease, disorder, or condition, or symptom thereof. With respect to controlling a disease, disorder, or medical condition, more specifically, "control" can include the absence of progression of a condition as evaluated by response to a method described herein, such response being either complete (e.g., bringing a disease into remission) or partial (e.g., alleviation or improvement of any symptoms associated with the condition). As used herein, the terms "prevent", "preventing", and / or "prevention" can refer to reducing the risk of developing a disease, disorder, or medical condition.

[0033] As used herein, the terms "modulate" and "modulation" refer to a change in the biological activity of a biological molecule (e.g., protein, gene, peptide, antibody, etc.), such a change can be related to an increase in the biological activity of a biological molecule (e.g., increase in activity, agonism, activation, expression, upregulation, and / or increase in expression), or a decrease in biological activity (e.g., decrease in activity, antagonism, inhibition, inactivation, downregulation, and / or decrease in expression).

[0034] The terms "QD", "qd", or "q.d" mean once a day (quaque die), once a day (once a day), or once a day (once daily). The terms "BID", "bid", or "b.i.d." mean twice a day (bis in die), twice a day (twice a day), or twice a day (twice daily). The terms "TID", "tid", or "t.i.d." mean three times a day (ter in die), three times a day (three times a day), or three times a day (three times daily). The terms "QID", "qid", or "q.i.d." mean four times a day (quater in die), four times a day (four times a day), or four times a day (four times daily).

[0035] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed by inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including substituted amines of natural origin, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike salts, cocrystals typically do not involve hydrogen transfer between the cocrystal and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal former and the drug in the crystal structure.

[0036] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "physiologically compatible" carrier or carrier medium is intended to include any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Their use in the therapeutic compositions of the present disclosure is contemplated, except when any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient. Additional active pharmaceutical ingredients, such as other drugs, may also be incorporated into the described compositions and methods.

[0037] A "prodrug" refers to a derivative of the compounds described in this specification, and its pharmacological action results from the conversion to an active compound by chemical or metabolic processes in vivo. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino, hydroxyl, or carboxylic acid group via an amide or ester bond. Amino acid residues include, but are not limited to, the 20 amino acids of natural origin commonly designated by one-letter or three-letter symbols, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also included. For example, a free carboxyl group can be derivatized as an amide or an alkyl ester (e.g., methyl ester and acetoxymethyl ester). Prodrug esters as used herein are esters and carbonates formed by reacting one or more hydroxyls of the compounds of the methods of the present disclosure with an alkyl, alkoxy, or aryl-substituted acylating agent using procedures known to those skilled in the art to produce acetates, pivalates, methyl carbonates, benzoates, etc. As a further example, a free hydroxyl group can be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters, and sulfate esters of hydroxyl groups. A free amine can also be derivatized to an amide, sulfonamide, or phosphonamide. All of the described prodrug moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups. Furthermore, any compound that can be converted in vivo to provide a bioactive agent is a prodrug within the scope of the present disclosure.Various forms of prodrugs are well known in the art. Comprehensive descriptions of prodrugs and prodrug derivatives are provided in (a)The Practice of Medicinal Chemistry,Camille G.Wermuth et al.,(Academic Press,1996),(b)Design of Prodrugs,edited by H.Bundgaard,(Elsevier,1985),(c)A Textbook of Drug Design and Development,P.Krogsgaard-Larson and H.Bundgaard,eds.,(Harwood Academic Publishers,1991). Generally, prodrugs are designed to improve the absorption of drugs, to extend the duration of action of drugs (the release of the parent drug from the prodrug is slowed and the first-pass metabolism of the drug is reduced), to target the action of drugs (e.g., targeting of organs or tumors, targeting of lymphocytes), to change or improve the water solubility of drugs (e.g., for i.v. preparations and eye drops), to improve local drug delivery (e.g., drug delivery to the skin and eyes), to improve the chemical / enzyme stability of drugs, or to reduce off-target drug effects, and more generally, to improve the therapeutic effects of the compounds used in the present disclosure, and can be designed to improve the penetration of drugs through biological membranes.

[0038] Unless otherwise indicated, the chemical structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are 13 C or 14 replaced by C-enriched carbon are within the scope of the present disclosure.

[0039] "Alkyl" refers to a straight-chain or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., (C1- 10 )alkyl or C1- 10refers to "(alkyl)". Whenever it appears in this specification, a numerical range such as "1 to 10" refers to each integer within the specified range. For example, "1 to 10 carbon atoms" means that an alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 10 carbon atoms. The definition is also intended to cover the use of the term "alkyl" when the numerical range is not specifically specified. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl moiety can be attached to the rest of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl, etc. Unless otherwise specified in this specification, an alkyl group can independently be heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(where t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(Ra )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or PO(OR a )2, and is optionally substituted by one or more of the substituents, and each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0040] "Alkylaryl" refers to a -(alkyl)aryl radical, where aryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.

[0041] "Alkylheteraryl" refers to a -(alkyl)heteraryl radical, where heteraryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl, respectively.

[0042] "Alkylheterocycloalkyl" refers to a -(alkyl)heterocyclic radical, where alkyl and heterocycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl, respectively.

[0043] The "alkene" moiety refers to a group consisting of at least 2 carbon atoms and at least 1 carbon-carbon double bond, and the "alkyne" moiety refers to a group consisting of at least 2 carbon atoms and at least 1 carbon-carbon triple bond. The alkyl moiety can be branched, straight-chain, or cyclic, regardless of whether it is saturated or unsaturated.

[0044] "Alkenyl" refers to a straight-chain or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing at least 1 double bond, and having 2 to 10 carbon atoms (i.e., (C2- 10 )alkenyl or C2- 10 alkenyl). Whenever it appears in this specification, a numerical range such as "2 to 10" refers to each integer within the specified range. For example, "2 to 10 carbon atoms" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, etc., containing a maximum of 10 carbon atoms. The alkenyl moiety can be bonded to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and pent-1,4-dienyl. Unless otherwise specified in this specification, the alkenyl group is independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(Ra )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO(OR a )2, and is optionally substituted by one or more substituents, and each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0045] "Alkenyl-cycloalkyl" means an -(alkenyl)cycloalkyl radical in which the alkenyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl, respectively. <>

[0046] "Alkynyl" means a straight-chain or branched hydrocarbon chain radical group consisting of only carbon and hydrogen atoms, containing at least one triple bond, and having 2 to 10 carbon atoms (i.e., (C2- 10 )alkynyl or C2- 10refers to alkynyl. Whenever it appears in this specification, a numerical range such as "2 to 10" refers to each integer within the specified range. For example, "2 to 10 carbon atoms" means that an alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 10 carbon atoms. Alkynyl can be bonded to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified in this specification, an alkynyl group is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamide, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(where t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or is optionally substituted by one or more substituents that are PO(OR a )2, and each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0047] "Alkynyl-cycloalkyl" means an -(alkynyl)cycloalkyl radical, where alkynyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl, respectively.

[0048] "Acylsulfonamide" means the group -C(=O)NR a -S(=O)2R a where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0049] "Carboxaldehyde" means the -(C=O)H radical.

[0050] "Carbonyl" means the group -C(=O)-. The carbonyl group may be substituted by the following exemplary substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, acylsulfonamide, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R a )2, -C(O)R a -NR a -OR a -, -C(O)OR a, -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO(OR a )2 may be replaced, and each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0051] "Carboxyl" refers to the -(C=O)OH radical.

[0052] "Cyano" refers to the -CN radical.

[0053] "Cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen and which may be saturated or partially unsaturated. Examples of cycloalkyl groups include those having 3 to 10 ring atoms (i.e., (C3- 10 )cycloalkyl or C3- 10Groups having (cycloalkyl) are exemplified. Whenever it appears in this specification, a numerical range such as "3 to 10" refers to each integer within the specified range. For example, "3 to 10 carbon atoms" means that a cycloalkyl group can be composed of 3 carbon atoms etc., including up to 10 carbon atoms. Exemplary examples of cycloalkyl groups include the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, etc., but are not limited thereto. Unless otherwise specified in this specification, a cycloalkyl group is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamide, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a 、-SR a 、-S(O) t R a -(t is 1 or 2), -S(O) t R a -(t is 1 or 2), -OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-OC(O)N(R a )2、-C(O)N(R a )2、-N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a )S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t ORa (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2), or PO(OR a )2 and is optionally substituted by one or more substituents, each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0054] "Cycloalkyl-alkenyl" means a -(cycloalkyl)alkenyl radical in which the cycloalkyl and alkenyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0055] "Cycloalkyl-heterocycloalkyl" means a -(cycloalkyl)heterocycloalkyl radical in which the cycloalkyl and heterocycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0056] "Cycloalkyl-heteroaryl" means a -(cycloalkyl)heteroaryl radical in which the cycloalkyl and heteroaryl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0057] The term "alkoxy" refers to a group -O-alkyl containing 1 to 8 carbon atoms in a straight chain, branched, cyclic arrangement, and combinations thereof, bonded to the parent structure through oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons.

[0058] The term "substituted alkoxy" refers to an alkoxy in which the alkyl moiety is substituted (i.e., -O-(substituted alkyl)). Unless otherwise indicated herein, the alkyl portion of an alkoxy group is independently alkyl, heteroalkyl, alkenyl, acylsulfonamide, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a 、-SR a 、-S(O) t R a -(where t is 1 or 2), -OC(O)-R a 、-N(R a )2, -C(O)R a 、-C(O)OR a 、-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or optionally substituted by one or more substituents that are PO(OR a )2, and each R ais independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0059] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=O)- bonded through the carbonyl carbon, and the alkoxy group has the specified number of carbon atoms. Thus, a (C1-6) alkoxycarbonyl group is an alkoxy group having 1 to 6 carbon atoms bonded to the carbonyl linker through its oxygen. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group in which the alkoxy group is a lower alkoxy group.

[0060] The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-O-C(O)-, and the group is bonded to the parent structure through the carbonyl functional group. Unless otherwise indicated herein, the alkyl portion of the alkoxycarbonyl group is independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a 、-SR a 、-S(O) t R a -(where t is 1 or 2), -OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-OC(O)N(R a )2、-C(O)N(R a )2、-N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(R a )2、N(R a )C(NR a )N(Ra ) 2, -N(R a ) S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a ) 2 (t is 1 or 2), or PO(OR a ) 2 and is optionally substituted by one or more substituents, each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0061] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)-, and the groups are attached to the parent structure through a carbonyl functional group. When the R radical is heteroaryl or heterocycloalkyl, the heteroatoms in the ring or chain contribute to the total number of atoms in the chain or ring. Unless otherwise specified herein, the alkyl, aryl, or heteroaryl moiety of an acyl group is independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(t is 1 or 2), -OC(O)-R a , -N(R a ) 2, -C(O)R a , -C(O)OR a , -OC(O)N(R<� a ) 2, -C(O)N(R a ) 2, -N(Ra )C(O)OR a ,-N(R a )C(O)R a ,-N(R a )C(O)N(R a )2,N(R a )C(NR a )N(R a )2,-N(R a )S(O) t R a (where t is 1 or 2),-S(O) t R a (where t is 1 or 2),-S(O) t OR a (where t is 1 or 2),-S(O) t N(R a )2(where t is 1 or 2),or PO(OR a )2 and is optionally substituted by one or more substituents,each R a is,independently,hydrogen,alkyl,fluoroalkyl,carbocyclic,carbocyclic alkyl,aryl,aralkyl,heterocycloalkyl,heterocycloalkyl alkyl,heteroaryl,or heteroaryl alkyl.

[0062] "acyloxy" refers to the R(C=O)O - radical,where R is alkyl,aryl,heteroaryl,heteroalkyl,or heterocycloalkyl,as described herein.When the R radical is heteroaryl or heterocycloalkyl,the heteroatoms contribute to the total number of atoms in the chain or ring.Unless otherwise stated herein,the R of the acyloxy group is,independently,alkyl,heteroalkyl,alkenyl,alkynyl,cycloalkyl,heterocycloalkyl,hydroxamate,aryl,arylalkyl,heteroaryl,heteroarylalkyl,hydroxy,halo,cyano,trifluoromethyl,trifluoromethoxy,nitro,trimethylsilyl,-OR a ,-SR a ,-S(O) t R a -(where t is 1 or 2),-OC(O)-R a ,-N(R a) 2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO(OR a )2 and is optionally substituted by one or more substituents, each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0063] Unless otherwise specified herein, "amino" or "amine" refers to the -N(R a )2 radical group, each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl. When the -N(R a )2 group has two R a substituents other than hydrogen, they can combine with the nitrogen atom to form a 4, 5, 6, or 7-membered ring. For example, -N(R a)2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise indicated herein, an amino group is independently alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(where t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or is optionally substituted by one or more substituents that are PO(OR a )2, and each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0064] The term "substituted amino" also refers to the group -NHR d and NR d R d N-oxides. N-oxides can be prepared by treating the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0065] "Amide" or "amido" refers to a chemical moiety having the formula -C(O)NR a R b or -NR a C(O)R b wherein R a and R b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloaliphatic (bonded through a ring carbon), and each of these moieties may itself be optionally substituted. For -C(O)NR a R b the R a and R b of the amide may optionally together with the nitrogen to which they are attached form a 4-, 5-, 6-, or 7-membered ring. Unless otherwise indicated herein, amide groups are independently optionally substituted by one or more of the substituents described herein for alkyl, amino, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide can be an amino acid or peptide molecule bonded to a compound disclosed herein, thereby forming a prodrug. Procedures and specific groups for making such amides are known to those of skill in the art and can be readily found in well-known references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, the entire contents of which are incorporated herein by reference.

[0066] "Aromatic", "aryl", or "Ar" refers to an aromatic radical having at least one ring with a conjugated pi electron system that is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl), having 6 to 10 ring atoms (e.g., C6-C 10 aromatic or C6-C 10 aryl). A divalent radical formed from a substituted benzene derivative and having a free valence on a ring atom is called a substituted phenylene radical. A divalent radical derived from a monovalent polycyclic hydrocarbon radical whose name ends in "-yl" by removing one hydrogen atom from a carbon atom having a free valence is named by adding "-idene" to the name of the corresponding monovalent radical. For example, a naphthyl group having two attachment points is called naphthylidene. Whenever it appears in this specification, a numerical range such as "6 to 10" refers to each integer within the specified range. For example, "6 to 10 ring atoms" means that an aryl group can be composed of 6 ring atoms, 7 ring atoms, etc., including a maximum of 10 carbon atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Unless otherwise specified in this specification, an aryl moiety is independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a 、-SR a 、-S(O) t R a -(where t is 1 or 2), -OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-OC(O)N(R a )2、-C(O)N(R a )2、-N(R a )C(O)OR a 、-N(R a )C(O)R a 、-N(R a )C(O)N(Ra ) 2, N(R a ) C(NR a ) N(R a ) 2, -N(R a ) S(O) t R a (t is 1 or 2), -S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a ) 2 (t is 1 or 2), or PO(OR a ) 2 and is optionally substituted by one or more substituents which are, each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0067] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical which is as defined herein for aryl and alkyl and is optionally substituted by one or more of the substituents described herein as suitable substituents for aryl and alkyl, respectively.

[0068] "Ester" refers to the chemical radical of the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloaliphatic (bonded through a ring carbon). Procedures and specific groups for making esters are known to those skilled in the art and can be readily found in well-known literature such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, the entirety of which is incorporated herein by reference. Unless otherwise stated herein, ester groups are independently alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(where t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(Ra )2 (where t is 1 or 2), or optionally substituted by one or more substituents that are PO(OR a )2, and each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0069] "Fluoroalkyl" refers to an alkyl radical as defined above, and is substituted by one or more fluoro radicals as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl radical can be optionally substituted as defined above for alkyl groups.

[0070] "Halo", "halide", or alternatively "halogen" is intended to mean fluoro, chloro, bromo, or iodo. The terms "haloalkyl", "haloalkenyl", "haloalkynyl", and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted by one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include fluoroalkyl groups and fluoroalkoxy groups respectively, where halo is fluorine.

[0071] "Heteroalkyl", "heteroalkenyl", and "heteroalkynyl" refer to optionally substituted alkyl, alkenyl, and alkynyl radicals and have one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be specified; for example, C1-C4 heteroalkyl refers to the total chain length, which in this example is four atoms in length. Heteroalkyl groups are independently substituted with one or more substituents selected from alkyl, heteroalkyl, alkenyl, alkynyl, acyl sulfonamide, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R a )2, -C(O)R a -C(O)OR a -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a -N(R a )C(O)R a -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or PO(OR a )2 and may be substituted with one or more substituents, each R ais independently hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0072] "Heteroalkyl aryl" means a -(heteroalkyl)aryl radical, where heteroalkyl and aryl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0073] "Heteroalkyl heteroaryl" means a -(heteroalkyl)heteroaryl radical, where heteroalkyl and heteroaryl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0074] "Heteroalkyl heterocycloalkyl" means a -(heteroalkyl)heterocycloalkyl radical, where heteroalkyl and heterocycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0075] "Heteroalkyl cycloalkyl" means a -(heteroalkyl)cycloalkyl radical, where heteroalkyl and cycloalkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0076] "Heteroaryl" or "heteroaromatic" or "HetAr" means an aromatic radical of 5 to 18 members, which may contain one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur and may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system (e.g., C5-C 13refers to (heteroaryl). Whenever it appears in this specification, a numerical range such as "5 to 18" refers to each integer within the specified range. For example, "5 to 18 ring atoms" means that a heteroaryl group can be composed of 5 ring atoms, 6 ring atoms, etc., containing up to 18 carbon atoms. A divalent radical derived from a monovalent heteroaryl radical whose name ends with "-yl" by removing one hydrogen atom from an atom with a free valence is named by adding "-idene" to the name of the corresponding monovalent radical. For example, a pyridyl group with two bonding points is pyridinylidene. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. A polycyclic heteroaryl group may or may not be fused. The heteroatoms in a heteroaryl radical are optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. Heteroaryl can be bonded to the rest of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, isoxazol - 3 - one, 5,8 - methano - 5,6,7,8 - tetrahydroquinazolinyl, naphthyridinyl, 1,6 - naphthyridinonyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a - octahydrobenzo[h]quinazolinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4 - d]pyrimidinyl, pyridinyl, pyrido[3,2 - d]pyrimidinyl, pyrido[3,4 - d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 - tetrahydroquinazolinyl, 5,6,7,8 - tetrahydrobenzo[4,5]thieno[2,3 - d]pyrimidinyl, 6,7,8,9 - tetrahydro - 5H - cyclohepta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6,7,8 - tetrahydropyrido[4,5 - c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyryl, triazolyl, tetrazolyl, triazinyl, thieno[2,3 - d]pyrimidinyl, thieno[3,2 - d]pyrimidinyl, thieno[2,3 - c]pyridinyl, and thiophenyl (i.e., thienyl), but are not limited thereto. Unless otherwise specified herein, the heteroaryl moiety is independently alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilyl, -OR, a , -SR a , -S(O)t R a -(where t is 1 or 2), -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or is optionally substituted by one or more substituents that are PO(OR a )2, and each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0077] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents such as, for example, pyridinyl N-oxide.

[0078] “Heteroaryl alkyl” refers to a moiety having an aryl moiety as described herein attached to an alkylene moiety as described herein, and the attachment to the remainder of the molecule is via an alkylene group.

[0079] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears in this specification, a numerical range such as "3 to 18" refers to each integer within the specified range. For example, "3 to 18 ring atoms" means that a heterocycloalkyl group can be composed of 3 ring atoms, 4 ring atoms, etc., and contain up to 18 ring atoms. Unless otherwise explicitly stated in this specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include a fused or bridged ring system. The heteroatoms in a heterocycloalkyl radical can be optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. A heterocycloalkyl radical is partially or fully saturated. A heterocycloalkyl can be attached to the remainder of the molecule through any atom of the ring. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise stated in this specification, a heterocycloalkyl moiety is independently alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilyl, -OR a , -SR a , -S(O) t R a -(where t is 1 or 2), -OC(O)-R a, -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2(where t is 1 or 2), or is optionally substituted by one or more substituents that are PO(OR a )2, and each R a is, independently, hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0080] "Heterocycloalkyl" also includes a bicyclic ring system, where one non-aromatic ring usually has 3 to 7 ring atoms and, in addition to at least 2 carbon atoms, independently includes 1 to 3 heteroatoms selected from oxygen, sulfur, nitrogen, and combinations including at least 1 of the aforementioned heteroatoms, and the other ring usually has 3 to 7 ring atoms and optionally independently includes 1 to 3 non-aromatic heteroatoms selected from oxygen, sulfur, and nitrogen.

[0081] "Hydroxamate" refers to the -C(O)NR a OR a moiety, and each Ra independently is hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, or heteroaryl alkyl.

[0082] "Nitro" refers to the -NO2 radical.

[0083] "Oxa" refers to the -O- radical.

[0084] "Oxo" refers to the =O radical.

[0085] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space, i.e., they have different stereochemical configurations. "Enantiomers" are pairs of stereoisomers that are mirror images of each other and cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used, where appropriate, to refer to a racemic mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog priority rules R-S system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be assigned as either (R) or (S). A resolved compound of unknown absolute configuration can be assigned as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R) or (S) from the perspective of absolute stereochemistry. The chemical substances, pharmaceutical compositions, and methods of the present invention are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthesis or chiral reagents or can be resolved using conventional techniques. If the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, the compounds are intended to include both E and Z geometric isomers unless otherwise specified.

[0086] As used herein, "enantiomeric purity" refers to the relative amount, expressed as a percentage, of the amount of a particular enantiomer present compared to the other enantiomer. For example, if a compound that can have either an (R)- or (S)-isomeric configuration is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If the compound predominantly has one isomeric form, such as 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined by many methods known in the art, including but not limited to chromatography using a chiral support, polarimetry of the rotation of plane-polarized light, nuclear magnetic resonance spectroscopy using a chiral shift reagent including but not limited to lanthanide-containing chiral complexes or Mosher's acid, or derivatization of the compound using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0087] In some embodiments, an enantiomerically enriched composition has a higher potency per unit mass with respect to therapeutic utility than the racemic mixture of the composition. Enantiomers can be isolated from the mixture by methods known to those of skill in the art, including chiral high pressure liquid chromatography (HPLC), and formation and crystallization of chiral salts, or the preferred enantiomer can be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981), E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962), and E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

[0088] As used herein, the terms “enantiomerically enriched” and “non-racemic” refer to a composition in which the weight percentage of one enantiomer is greater than the amount of that one enantiomer in a control mixture of a racemic composition (e.g., greater than 1:1 weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of a compound having greater than 50% by weight of the (S)-enantiomer compared to the (R)-enantiomer, e.g., at least 75% by weight, or e.g., at least 80% by weight. In some embodiments, the enrichment is well in excess of 80% by weight, and a “substantially enantiomerically enriched” or “substantially non-racemic” preparation can be provided, which refers to a preparation of a composition containing at least 85% by weight, e.g., at least 90% by weight, or at least 95% by weight of one enantiomer compared to the other enantiomer. The terms “enantiomerically pure” or “substantially enantiomerically pure” refer to a composition containing at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0089] “Moiety” refers to a particular part or functional group of a molecule. Chemical moieties are often recognized as chemical substances embedded in or added to a molecule.

[0090] "Tautomers" are structurally different isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization that includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the movement of a proton with a change in bond order, often involving the replacement of a single bond adjacent to a double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0091] "Leaving group or leaving atom" refers to any group or atom that is cleaved from a starting material under selected reaction conditions and thus promotes reaction at a specific site. Examples of such groups include, unless otherwise specified, halogen atoms and mesyloxy groups, p-nitrobenzenesulfonyloxy groups, and tosyl-oxy groups.

[0092] "Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a polyfunctional compound, allows a chemical reaction to be carried out selectively at another unprotected reactive site, and can be easily removed or deprotected after the selective reaction is completed. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).

[0093] "Solvate" refers to a compound that is physically associated with one or more molecules of a pharmaceutically acceptable solvent.

[0094] "Substitution" means that one or more additional groups, radicals, or moieties independently selected individually from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino including mono- and disubstituted amino groups, and their protected derivatives may be attached. The substituents themselves may be substituted; for example, a cycloalkyl substituent itself may have a halide substituent on one or more of its ring carbons. The term "optionally substituted" means any substitution on the specified group, radical, or moiety.

[0095] "Sulfanyl" refers to a group including -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl).

[0096] "Sulfinyl" refers to a group including -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)-(optionally substituted heteroaryl), and -S(O)-(optionally substituted heterocycloalkyl).

[0097] "Sulfonyl" refers to a group including -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

[0098] "Sulfonamidyl" or "sulfonamide" refers to the -S(=O)2-NRR radical, where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical can together with the nitrogen to which it is attached form a 4-, 5-, 6-, or 7-membered ring. Each sulfonamide group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0099] "Sulfoxyl" refers to the -S(=O)2OH radical.

[0100] "Sulfonate" refers to the -S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon). Each sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0101] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrides), conformational polymorphs, and amorphous forms, and mixtures thereof. The terms "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrides), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a particular crystalline or amorphous form is recited.

[0102] The term "antibody" as used herein is used in the broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies).

[0103] Exemplary antibodies such as IgG contain two heavy chains and two light chains. Each heavy chain consists of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region. Each light chain consists of a light chain variable region (abbreviated as VL herein) and a light chain constant region. The VH region and the VL region can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0104] Hypervariable regions generally include amino acid residues 24 - 34 of the light chain variable region (LCDR1, "L" indicates light chain), 50 - 56 (LCDR2), and 89 - 97 (LCDR3), and amino acid residues 31 - 35B of the heavy chain variable region (HCDR1, "H" indicates heavy chain), 50 - 65 (HCDR2), and 95 - 102 (HCDR3); Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), and / or residues that form hypervariable loops (e.g., residues 26 - 32 (LCDR1), 50 - 52 (LCDR2), and 91 - 96 (LCDR3) of the light chain variable region, and residues 26 - 32 (HCDR1), 53 - 55 (HCDR2), and 96 - 101 (HCDR3) of the heavy chain variable region); Chothia and Lesk (1987) J. Mol. Biol. 196:901 - 917.

[0105] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, e.g., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variants that may occur during production of the monoclonal antibody preparation, such as those containing natural occurring mutations, and such variants generally are present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals that include all or part of the human immunoglobulin locus, and such methods and other exemplary methods for making monoclonal antibodies described herein are described herein.

[0106] The term "chimeric" antibody refers to a recombinant antibody in which a portion of the heavy and / or light chain is derived from a particular source or species and the remaining portion of the heavy and / or light chain is derived from a different source or species.

[0107] "Human antibody" refers to an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human, and / or an antibody produced using any of the techniques known to those skilled in the art for producing human antibodies. This definition of a human antibody clearly excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques well-known in the art, including the methods described in Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985), Boerner et al, J. Immunol, 147(I):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol, 5:368-74 (2001). Human antibodies are modified to produce such antibodies in response to antigen stimulation, but transgenic animals in which the endogenous locus has been inactivated, such as immunized HuMab mice (for HuMab mice, see, for example, Nils Lonberg et al., 1994, Nature 368:856-859, WO98 / 24884, WO94 / 25585, WO93 / 1227, WO92 / 22645, WO92 / 03918, and WO01 / 09187), xenomice (for XENOMOUSE (trademark) technology, see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584), or Trianni mice (for example, WO2013 / 063391, WO2017 / 035252, and WO2017 / 136734) can be prepared by administering an antigen thereto.

[0108] The term "humanized antibody" refers to an antibody designed to include one or more human framework regions in the variable region, together with non-human (e.g., mouse, rat, hamster) complementarity-determining regions (CDRs) of the heavy and / or light chains. In certain embodiments, a humanized antibody includes sequences that are completely human except for the CDR regions. Humanized antibodies provide therapeutic benefits in certain situations because they have lower immunogenicity in humans compared to non-humanized antibodies. Those skilled in the art will recognize humanized antibodies and the techniques suitable for their production. See, for example, Hwang, W.Y.K., et al., Methods 36:35, 2005, Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989, Jones et al., Nature, 321:522-25, 1986, Riechmann et al., Nature, 332:323-27, 1988, Verhoeyen et al., Science, 239:1534-36, 1988, Orlandi et al., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989, U.S. Patent Nos. 5,225,539, 5,530,101, 5,585,089, 5,693,761, 5,693,762, 6,180,370, and Selick et al., WO90 / 07861, each of which is incorporated herein by reference in its entirety.

[0109] The "class" of an antibody refers to the type of constant domain or constant region that its heavy chain has. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0110] The term "antigen-binding domain" (or simply "binding domain") of an antibody, or a similar term, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen complex. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include: (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH domains; (ii) F(ab’)2 fragments, divalent fragments containing two Fab fragments linked by disulfide bridges in the hinge region; (iii) Fd fragments consisting of VH and CH domains; (iv) Fv fragments consisting of VL and VH domains of a single arm of an antibody; (v) dAb fragments (Ward et al., (1989) Nature 341:544-546), consisting of VH domains; (vi) isolated complementarity determining regions (CDRs), and (vii) combinations of two or more isolated CDRs that may be optionally linked by a synthetic linker.

[0111] As used herein, the term "complementarity determining region" or "CDR" refers to short polypeptide sequences within both the variable regions of the heavy and light chain polypeptides that are primarily involved in mediating specific antigen recognition. There are three CDRs (referred to as CDR1, CDR2, and CDR3) within each VL and each VH.

[0112] As will be understood by those of skill in the art, the exact numbering and placement of CDRs can vary between different numbering systems. However, it should be understood that the disclosure of a variable heavy chain and / or variable light chain sequence includes the disclosure of the relevant CDRs. Thus, the disclosure of each variable heavy chain region is a disclosure of vhCDRs (e.g., vhCDR1, vhCDR2, and vhCDR3), and the disclosure of each variable light chain region is a disclosure of vlCDRs (e.g., vlCDR1, vlCDR2, and vlCDR3).

[0113] In certain embodiments, the CDRs of an antibody can be determined according to the IMGT numbering system described in Lefranc M-P, (1999) The Immunologist 7:132-136 and Lefranc M-P et al, (1999) Nucleic Acids Res 27:209-212, each of which is incorporated herein by reference in its entirety. Unless otherwise indicated herein, references to residue numbers in the variable domain of an antibody mean residue numbering according to the IMGT numbering system.

[0114] In other embodiments, the CDRs of an antibody can be determined according to MacCallum RM et al, (1996) J Mol Biol 262:732-745, which is incorporated herein by reference in its entirety. For example, reference is also made to Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Diibel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001), which is incorporated herein by reference in its entirety. In other embodiments, the CDRs of an antibody can be determined according to the AbM numbering scheme, which refers to the AbM hypervariable regions that represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.), which is incorporated herein by reference in its entirety

[0115] “Framework” or “framework region” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4.

[0116] The "human consensus framework" is a framework that represents the amino acid residues that most commonly occur in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), Vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I such as those in Kabat et al., described above. In one embodiment, for VH, the subgroup is subgroup Ill such as those in Kabat et al., described above.

[0117] The "hinge region" is generally defined as the region spanning residues 216-238 (EU numbering) or 226-251 (Kabat numbering) of human IgG1. The hinge can be further divided into three distinct regions: the upper, middle (e.g., core), and lower hinge.

[0118] The term "Fc region" as used herein is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991).

[0119] A "blocking" antibody or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. Certain blocking or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

[0120] An antibody that "binds to the same epitope as" a reference antibody refers to an antibody that contacts or blocks by 50% or more the binding of the reference antibody to its antigen in a competitive assay, with a set of overlapping amino acid residues of the antigen as compared to the reference antibody. The amino acid residues of the antibody that contact the antigen can be determined, for example, by determining the crystal structure of the antibody complexed with the antigen or by performing hydrogen / deuterium exchange. In some embodiments, residues of the antibody that are within 5 Å of the antigen are considered to contact the antigen. In some embodiments, an antibody that binds to the same epitope as a reference antibody blocks by 50% or more the binding of the reference antibody to its antigen in a competitive assay, and conversely, the reference antibody is blocked by 50% or more from binding to its antigen by the antibody in a competitive assay.

[0121] The term "antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds to an antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab)2, diabody, linear antibody, single-chain antibody molecule (e.g., scFv). Papain digestion of an antibody produces two identical binding fragments, called "Fab" fragments, and a residual Fc fragment, which is a designation that reflects the ability to readily crystallize. The Fab fragment consists of the variable region domain of the heavy chain (H) chain (VH) and the entire light chain (L) chain, together with the first constant domain of one heavy chain (CH1). Pepsin treatment of an antibody yields a single large F(ab)2 fragment that has bivalent antigen-binding activity and can still cross-link antigens. The Fab fragment differs from the Fab’ fragment by having several additional residues at the carboxy terminus of the CH1 domain that include one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for a Fab’ in which the cysteine residue of the constant domain has a free thiol group. F(ab’)2 antibody fragments are originally produced as pairs of Fab’ fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0122] "Fv" consists of a dimer of one heavy-chain variable region domain and one light-chain variable region domain in a tight non-covalent association. From the folding of these two domains, six hypervariable loops (three loops each from the H chain and the L chain) are generated that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody.

[0123] A "single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment that contains VH and VL antibody domains linked to a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH domain and the VL domain, thereby enabling the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0124] When used to describe the various antibodies disclosed herein, the term "isolated antibody" means an antibody that has been identified and separated and / or recovered from the cells or cell culture in which it was expressed. The contaminant components of its natural environment are typically substances that would interfere with the diagnostic or therapeutic use of the polypeptide and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to a purity of greater than 95% or 99% as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) approaches. For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). In one embodiment, the antibody is purified to at least the extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by use of a spinning cup sequencer or to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or preferably silver staining.

[0125] With respect to the binding of an antibody to a target molecule, the terms "specific binding" or "binds specifically" or "is specific for" a particular polypeptide or an epitope on a particular polypeptide target mean a binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule in comparison to the binding of a control molecule. For example, specific binding can be determined by competition with a control molecule similar to the target, e.g., an excess of unlabeled target. In this case, specific binding is indicated if the binding of a labeled target to a probe is competitively inhibited by an excess of unlabeled target. As used herein, the terms "specific binding" or "binds specifically" or "is specific for" a particular polypeptide or an epitope on a particular polypeptide target can be indicated by a molecule having a Kd for the target of, for example, 10-4 M or less, alternatively 10-5 M or less, alternatively 10-6 M or less, alternatively 10-7 M or less, alternatively 10-8 M or less, alternatively 10-9 M or less, alternatively 10-10 M or less, alternatively 10-11 M or less, alternatively 10-12 M or less, or having a Kd in the range of 10-4 M to 10-6 M or 10-6 M to 10-10 M or 10-7 M to 10-9 M. As will be understood by those skilled in the art, affinity and KD values are inversely proportional. High affinity for an antigen is measured by a low KD value. In one embodiment, the term "specific binding" refers to a binding in which a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. As used herein, the terms "specific binding", "binds specifically", and "binds selectively" refer to an antibody that binds to an epitope of CDCP1.

[0126] As used herein, the term "affinity" means the strength of binding of an antibody to an epitope. The affinity of an antibody is given by the dissociation constant Kd, defined as [Ab]×[Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of unbound antibody, and [Ag] is the molar concentration of unbound antigen. The affinity constant Ka is defined as 1 / Kd. Methods for determining the affinity of mAbs can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which are hereby incorporated by reference in their entirety. One standard method well known in the art for determining the affinity of mAbs is the use of surface plasmon resonance (SPR) screening (such as by analysis using a BIAcore™ SPR analyzer).

[0127] The term "epitope" is a technical term in the art that refers to the site or sites of interaction between an antibody and its antigen, as described in Janeway, C., Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3-8. New York, Garland Publishing, Inc. "Antibodies generally recognize only small regions on the surface of macromolecules such as proteins. [A particular epitope] is likely to be composed of amino acids from different parts of the [antigen] polypeptide chains brought together by protein folding. This type of antigenic determinant is known as a conformational or discontinuous epitope because the recognized structure is discontinuous in the amino acid sequence of the antigen but comes together in the three-dimensional structure. In contrast, an epitope composed of a single segment of a polypeptide chain is called a continuous or linear epitope (Janeway, C. Jr., P. Travers, et al. (2001). Immunobiology: the immune system in health and disease. Part II, Section 3-8. New York, Garland Publishing, Inc.).

[0128] As used herein, the term "KD" is intended to refer to the dissociation constant of a particular antibody-antigen interaction. This is calculated by the following equation: Koff / Kon = KD.

[0129] As used herein, the term "IC50" is intended to refer to the effective concentration of an antibody of the invention necessary to neutralize 50% of the biological activity of IL-23 on human lymphoma DB cells in the bioassay described in Example 5. Inhibition of STAT3 activation in the human DB cell assay.

[0130] "EC50" with respect to an agent and a specific activity (e.g., binding to cells, inhibition of enzyme activity, activation or inhibition of immune cells) refers to the effective concentration of the agent that produces 50% of its maximum response or effect with respect to such activity. "EC100" with respect to an agent and a specific activity refers to the effective concentration of the agent that produces substantially its maximum response with respect to such activity.

[0131] antibody In one aspect, the present disclosure provides antibody-drug conjugates (ADCs), linkers, and antibodies, antibody fragments useful within other compounds and / or conjugates described herein. In some embodiments, the antibody and / or antibody fragment binds to CDCP1. In some embodiments, the antibody and / or antibody fragment is a specific antibody for CDCP1 or an antigen-binding portion thereof.

[0132] CUB domain-containing protein 1 (CDCP1) CDCP1 (HGNC:24357; NCBI Entrez Gene:64866; Ensembl:ENSG00000163814; UniProtKB / Swiss-Prot:Q9H5V8) has a large extracellular domain (665 amino acids in size) containing three CUB domains that are likely to mediate protein-protein interactions and are involved in cell adhesion and interaction with the extracellular matrix. The CDCP1 gene has been found to be strongly expressed in cancer and has been previously disclosed as a therapeutic target at least in WO2020 / 097336 and WO2018 / 112334, which are hereby incorporated by reference in their entirety.

[0133] The transmembrane protein CDCP1 is associated with Src and PKCδ, and all three proteins show an increase in tyrosine phosphorylation when CDCP1 is activated. Src phosphorylates and binds to CDCP1, and subsequently CDCP1 binds to the C2 domain, which is part of the regulatory domain of PKCδ. Tyr-734 has been identified as the site phosphorylated by Src and Src family kinases, and thus, P-Tyr-734 is a biomarker for CDCP1 activation. The full-length CDCP1 protein is 135 kDa, but in some cells, the extracellular domain is proteolytically cleaved into a transmembrane protein of approximately 75 kDa. [Table 1]

[0134] In some embodiments, CDCP1 is human CDCP1. In some embodiments, CDCP1 is cynomolgus (Macaca fascicularis) CDCP1. In some embodiments, CDCP1 is mouse CDCP1. In some embodiments, CDCP1 is primate CDCP1. Exemplary CDCP1 sequences are provided in Table 1.

[0135] CDCP1 antibody As used herein, the term "antibody" encompasses the broadest meaning and specifically includes monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments as long as they exhibit the desired biological activity. Antibodies can be derived from mice, humans, humanized, chimeric, or other species. Antibodies are proteins produced by the immune system that can recognize and bind to specific antigens. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). The target antigen generally has multiple binding sites, also called epitopes, which are recognized by the CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen can have more than one corresponding antibody. Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules containing antigen-binding sites that immunospecifically bind to the target of interest or an antigenic part thereof, such targets including, but not limited to, cancer cells or cells that produce autoantibodies associated with autoimmune diseases.

[0136] The immunoglobulins disclosed herein can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule. Immunoglobulins can be derived from any species. However, in one aspect, the immunoglobulins are of human, murine, or rabbit origin.

[0137] The "binding fragment" of an antibody refers to a fragment of a full-length antibody that retains the ability to specifically bind to an antigen (preferably substantially the same binding affinity). Examples of such binding fragments include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab’)2 fragment, a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the VH domain and the CH1 domain; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain (Ward et al., 1989 Nature 341:544-546); and (vi) isolated complementarity determining regions (CDRs), disulfide-bonded Fv (dsFv), anti-idiotype (anti-Id) antibodies, and intrabodies. Further, the two domains of an Fv fragment, VL and VH, are encoded by separate genes but can be joined using recombinant methods (e.g., by a synthetic linker), thereby enabling them to be produced as a single protein chain (known as a single-chain Fv (scFv)) in which the VL and VH regions pair to form a monovalent molecule. See, for example, Bird et al., Science 242:423-426 (1988), and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883. Other forms of single-chain antibodies, such as diabodies, are also included. Diabodies are antibodies in which the VH and VL domains are expressed on a single polypeptide chain but use a linker that is too short to allow pairing between the two domains on the same chain, thereby causing the domains to pair with complementary domains on another chain to generate two antigen-binding sites, and are thus divalent bispecific antibodies (see, for example, Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448, Poljak et al., 1994, Structure 2:1121-1123).

[0138] The "variable domain" of an antibody refers to the variable region (VL) of the antibody light chain or the variable region (VH) of the antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs) and contribute to the formation of the antigen-binding site of the antibody.

[0139] The "complementarity-determining region" (CDR) can be identified according to the Kabat, Chothia definitions, the cumulative of both Kabat and Chothia, the AbM, contact, North, and / or conformational definitions, or any method of CDR determination well-known in the art. See, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions), Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The identity of the amino acid residues in a particular antibody that make up the CDR can be determined using methods well-known in the art. The AbM definition of the CDR is a compromise between Kabat and Chothia and uses the AbM antibody modeling software of Oxford Molecular (Accelrys®).

[0140] The definition of "contact" of CDR is based on the observation of antigen contact shown in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The definition of "conformation" of CDR is based on the residues that contribute enthalpically to antigen binding (see, for example, Makabe et al., 2008, J. Biol. Chem., 283:1156-1166). North identified the canonical CDR conformations using different sets of preferred CDR definitions (North et al., 2011, J. Mol. Biol. 406:228-256). In another approach herein referred to as the "conformational definition" of CDR, the positions of CDRs can be identified as residues that contribute enthalpically to antigen binding (Makabe et al., 2008, J Biol. Chem. 283:1156-1166).

[0141] Still other CDR boundary definitions may not strictly follow one of the above approaches, but may still overlap with at least a portion of the Kabat CDRs and can be shortened or extended taking into account predictions or experimental findings that a particular residue or group of residues, or even an entire CDR, does not significantly affect antigen binding.

[0142] As used herein, CDR can refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein can utilize CDRs defined according to any of these approaches. For any given embodiment that includes more than one CDR, the CDRs (or other residues of the antibody) can be defined according to any of the Kabat, Chothia, North, extended, AbM, contact, and / or conformational definitions.

[0143] Residues in the variable domain are numbered according to Kabat, a numbering system used for the heavy chain variable domain or the light chain variable domain in the compilation of antibodies. See Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to deletions or insertions in the FR or CDR of the variable domain. For example, the heavy chain variable domain may contain a single amino acid insertion (residue 52a according to Kabat) after residue 52 of H2, and residues inserted after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by aligning the homologous regions of the antibody's sequence with the "standard" Kabat numbering sequence. Various algorithms are available for assigning Kabat numbering. The algorithm implemented in version 2.3.3 release of Abysis (www.abysis.org) is used herein to assign Kabat numbering to the variable region CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3.

[0144] In some embodiments, specific amino acid residue positions in the antibody may also be numbered according to Kabat. In some embodiments, the anti - CDCP1 targeting agent comprises one or more of the CDRs listed in Table 2A and / or Table 2B.

[0145] "Framework" (FR) residues are antibody variable domain residues other than CDR residues. The VH or VL domain framework contains four framework sub - regions, FR1, FR2, FR3, FR4, in which the CDRs are interspersed in the following structure: FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4.

[0146] An "epitope" refers to the area or region of an antigen to which an antibody specifically binds, for example, the area or region containing residues that interact with the antibody. An epitope can be linear or conformational.

[0147] The term "paratope" is derived by reversing the perspective from the above definition of "epitope", and refers to the area or region of an antibody molecule involved in binding to an antigen, for example, the area or region containing residues that interact with the antigen. A paratope can be linear or conformational (such as discontinuous residues in a CDR).

[0148] The epitope / paratope of a given antigen / antibody binding pair can be defined and characterized at different levels of detail using various experimental and computational epitope mapping methods. Experimental methods include mutagenesis, X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, hydrogen / deuterium exchange mass spectrometry (HX-MS), and various competitive binding methods.

[0149] At its most detailed level, the epitope / paratope for the interaction between an antibody (Ab) and an antigen (Ag) can be defined by the spatial coordinates that define the atomic contacts present during the Ag-Ab interaction, as well as information about their relative contributions to the binding thermodynamics. At one level, the epitope / paratope residues can be characterized by the spatial coordinates that define the atomic contacts between the Ag and the Ab.

[0150] In one aspect, the epitope / paratope residues can be defined by specific criteria, such as the distance between atoms in the Ab and the Ag (e.g., a distance of about 4 Å or less from the heavy atoms of the homologous antibody and the heavy atoms of the antigen). In another aspect, the epitope / paratope residues can be characterized as those involved in hydrogen bond interactions with the homologous antibody / antigen, or hydrogen bond interactions with water molecules that also hydrogen bond with the homologous antibody / antigen (water-mediated hydrogen bonds). In another aspect, the epitope / paratope residues can be characterized as those forming salt bridges with the residues of the homologous antibody / antigen. In yet another aspect, the epitope / paratope residues can be characterized as residues having a non-zero change in buried surface area (BSA) due to the interaction with the homologous antibody / antigen.

[0151] At a less detailed level, the epitope / paratope can be characterized via function, e.g., by competitive binding with other Abs. The epitope / paratope can also be more generally defined as including amino acid residues where substitution by another amino acid changes the characteristics of the interaction between the Ab and the Ag (e.g., alanine scanning).

[0152] Epitopes and antibodies that "bind preferentially" or "bind specifically" (used interchangeably herein) are terms well understood in the art, and methods for determining such specific or preferential binding are well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or binds to a particular cell or substance more frequently, more rapidly, for a longer period of time, and / or with a higher affinity than to other cells or substances. An antibody "binds specifically" or "binds preferentially" if it binds to a target with a higher affinity, binding strength, more readily, and / or for a longer duration than it binds to other substances. In a non-limiting example, an antibody that binds specifically or preferentially to a CDCP1 epitope is an antibody that binds to this epitope with a higher affinity, binding strength, more readily, and / or for a longer duration than it binds to other CDCP1 epitopes or non-CDCP1 epitopes. Also, reading this definition, it is understood that, for example, an antibody (or portion, targeting agent, or epitope) that binds specifically or preferentially to a first target may or may not bind specifically or preferentially to a second target. Thus, "specific binding" or "preferential binding" does not necessarily (although it can include exclusive binding) require exclusive binding. Generally, although not necessarily, reference to binding means preferential binding.

[0153] "Specific binding" or "preferential binding" includes compounds that recognize and bind to a particular molecule but do not substantially recognize or bind to other molecules in a sample, such as proteins, nucleic acids, antibodies, and the like. For example, an antibody that recognizes and binds to its cognate antigen in a sample but does not substantially recognize or bind to other molecules in the sample binds specifically to its cognate antigen. Thus, under specified assay conditions, a specified binding moiety (e.g., an antibody or its antigen-binding portion) binds preferentially to a particular target molecule and does not bind in significant amounts to other components present in a test sample.

[0154] Using various assays, antibodies or peptides that specifically bind to a target molecule can be selected. For example, solid-phase ELISA immunoassays, immunoprecipitation, BIAcore™ (GE Healthcare, Piscataway, NJ), fluorescence-activated cell sorting (FACS), Octet™ (ForteBio, Inc., Menlo Park, CA), and Western blot analysis are among the many assays that can be used to identify an antigen or receptor that specifically binds to a cognate ligand or binding partner, or an antibody that specifically reacts with a ligand-binding portion thereof. Typically, a specific or selective reaction is at least two-fold background signal or noise, more typically greater than 10-fold background, and even more specifically, an antibody is said to "specifically bind" to an antigen when the equilibrium dissociation constant (K D ) value is ≤1 μM, e.g., ≤100 nM, ≤10 nM, ≤100 pM, ≤10 pM, or ≤1 pM.

[0155] As used herein with respect to antibodies, the term "compete" means that the binding of a first antibody or its antigen-binding portion to an antigen reduces the subsequent binding of the same antigen by a second antibody or its antigen-binding portion. Generally, binding of the first antibody results in steric hindrance, conformational changes, or binding to a common epitope (or a portion thereof), such that binding of the second antibody to the same antigen is reduced. Standard competition assays can be used to determine whether two antibodies compete with each other. One suitable assay for antibody competition involves the use of surface plasmon resonance (SPR) technology, typically a biosensor system (such as a BIACORE® system), to measure the extent of interaction. For example, SPR can be used in an in vitro competitive binding inhibition assay to determine the ability of one antibody to inhibit the binding of a second antibody. Another assay for measuring antibody competition uses an ELISA-based approach.

[0156] Furthermore, high-throughput processes for the binding of antibodies based on such competition are described in International Patent Application No. WO2003 / 48731, which is hereby incorporated by reference in its entirety. There is a case where one antibody (or fragment) reduces the binding of another antibody (or fragment) to its target (e.g., CDCP1). For example, a sequential binding competition assay can be used where different antibodies are added in sequence. The first antibody can be added to reach near-saturating binding. Then, the second antibody is added. In a non-limiting example, if the binding of the second antibody (e.g., binding to CDCP1) is not detected or is significantly reduced (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% reduced) compared to a parallel assay in the absence of the first antibody (this value can be set as 100%), the two antibodies are considered to be competing with each other.

[0157] An "antigen-binding portion" (or alternatively "its binding fragment") includes a portion of a full-length antibody, generally its antigen-binding region or variable region. Examples of antigen-binding portions include Fab, Fab’, F(ab’)2, and Fv fragments, diabodies, linear antibodies, fragments produced by a Fab expression library, anti-idiotype (anti-Id) antibodies, CDRs (complementary determining regions), and any of the above epitope-binding fragments that immunospecifically bind to a cancer cell antigen, viral antigen, or microbial antigen, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody or its antigen-binding portion is selected from monoclonal antibodies, polyclonal antibodies, antibody fragments, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, single-chain Fv, diabodies, linear antibodies, bispecific antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, and fusion proteins containing an antigen-binding portion of an antibody.

[0158] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations that include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they can be synthesized so as not to be contaminated with other antibodies. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used according to the present invention may be made by the hybridoma method first described by Kohler et al., (1975) Nature 256:495, or may be made by recombinant DNA methods.

[0159] Fv is the smallest antibody fragment that contains the complete antigen recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association. In this configuration, the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. The six hypervariable regions together confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only the three hypervariable regions specific for an antigen) has the ability to recognize and bind the antigen, although with a lower affinity than the entire binding site.

[0160] The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab’ fragment differs from the Fab fragment by adding several residues to the carboxy terminus of the heavy chain CH1 domain that includes one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for a Fab’ in which the cysteine residue of the constant domain has at least one free thiol group. F(ab’)2 antibody fragments were originally produced as pairs of Fab’ fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0161] The light chains of antibodies from any vertebrate species can be assigned to one of two distinct types called kappa (κ) and lambda (λ) based on the amino acid sequences of their constant domains.

[0162] Single-chain Fv or scFv refers to a single-chain variable region antibody fragment that contains the VH and VL domains of an antibody, and these domains are present within a single polypeptide chain. The Fv polypeptide may further include a polypeptide linker between the VH domain and the VL domain, which enables the scFv to form the desired structure for antigen binding.

[0163] The term “diabody” refers to a small antibody fragment that has two antigen-binding sites, and the fragment contains a variable heavy chain domain (VH) connected to a variable light chain domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains on another chain, creating two antigen-binding sites.

[0164] Humanized forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequences derived from non-human immunoglobulins. In most cases, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the hypervariable regions of the recipient have been replaced by residues from the hypervariable regions of a non-human species such as a mouse, rat, rabbit, or non-human primate (donor antibody) that have the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by the corresponding non-human residues.

[0165] Furthermore, a humanized antibody may contain residues not found in the recipient antibody or donor antibody. These modifications are made to further refine antibody performance. Generally, a humanized antibody contains substantially all of at least one, typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of the non-human immunoglobulin and all or substantially all of the FRs being of human immunoglobulin sequence.

[0166] An "isolated antibody" is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is (1) greater than 95% or greater than 99% by weight of the antibody as determined by the Lowry method, (2) sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by use of a spinning cup protein sequencer, or (3) homogeneous by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver staining. An isolated antibody includes an antibody contained in recombinant cells because it lacks at least one component of its natural environment. However, usually an isolated antibody is prepared by at least one purification step.

[0167] In some embodiments, the targeting agent, antibody, or binding fragment thereof disclosed herein may include one or more conservative amino acid substitutions. One of ordinary skill in the art will recognize that a conservative amino acid substitution is a substitution of one amino acid with another amino acid having similar structural or chemical properties, such as similar side chains. Exemplary conservative substitutions are described, for example, in the literature of Watson et al., Molecular Biology of the Gene, The Benjamin / Cummings Publication Company, 4th Ed. (1987).

[0168] In some embodiments, the targeting agent, antibody, or binding fragment thereof includes a variable heavy chain sequence that includes an amino acid sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In other embodiments, the targeting agent, antibody, or binding fragment thereof retains the binding and / or functional activity of a targeting agent, antibody, or binding fragment thereof that includes the variable heavy chain sequence of SEQ ID NO: 2, 3, or 4. In still further embodiments, the targeting agent, antibody, or binding fragment thereof includes the variable heavy chain sequence of SEQ ID NO: 1, 2, 3, or 4 and has one or more conservative amino acid substitutions, such as 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 conservative amino acid substitutions, in the heavy chain variable sequence. In still further embodiments, one or more conservative amino acid substitutions are included within one or more framework regions of SEQ ID NO: 1, 2, 3, or 4 (based on the Kabat numbering system).

[0169] In certain embodiments, the targeting agent, antibody, or binding fragment thereof includes a variable heavy chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the binding protein heavy chain variable region sequence set forth in SEQ ID NO: 1, 2, 3, or 4, includes one or more conservative amino acid substitutions in the framework region (based on the Kabat numbering system), and retains the binding and / or functional activity of a binding protein that includes the variable heavy chain sequence set forth in SEQ ID NO: 1, 2, 3, or 4 and the variable light chain sequence set forth in SEQ ID NO: 5, 6, 7, or 8.

[0170] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a variable light chain sequence having an amino acid sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 5. In other embodiments, the targeting agent, antibody, or binding fragment thereof retains the binding and / or functional activity of a targeting agent, antibody, or binding fragment thereof that comprises the variable light chain sequence of SEQ ID NO: 5, 6, 7, or 8. In still further embodiments, the targeting agent, antibody, or binding fragment thereof comprises the variable light chain sequence of SEQ ID NO: 5, 6, 7, or 8 and has one or more conservative amino acid substitutions in the light chain variable sequence, for example 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 conservative amino acid substitutions. In still further embodiments, one or more conservative amino acid substitutions are included within one or more framework regions of SEQ ID NO: 5, 6, 7, or 8 (based on the Kabat numbering system).

[0171] In certain embodiments, the targeting agent, antibody, or binding fragment thereof comprises a variable light chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the binding protein light chain variable region sequence set forth in SEQ ID NO: 5, 6, 7, or 8, comprises one or more conservative amino acid substitutions in the framework region (based on the Kabat numbering system), and retains the binding and / or functional activity of a binding protein that comprises the variable heavy chain sequence set forth in SEQ ID NO: 1, 2, 3, or 4 and the variable light chain sequence set forth in SEQ ID NO: 5, 6, 7, or 8.

[0172] In one aspect, the present disclosure provides targeting agents (e.g., antibodies and antibody fragments) useful within the complexes (e.g., antibody-drug conjugates) and compounds of the present disclosure. Any targeting agent (e.g., antibodies and antibody fragments) is contemplated by the present disclosure.

[0173] In some embodiments, the targeting agent (e.g., an antibody and its binding fragments) specifically binds to CDCP1. Exemplary antibody sequences are shown in WO2018 / 112334, which is hereby incorporated by reference in its entirety. In some embodiments, the ADC is used to treat cancer.

[0174] In some embodiments, the anti-CDCP1 targeting agent, antibody, or its binding fragment comprises a heavy chain variable region comprising a VH complementarity determining region 3 (CDRH3) having the amino acid sequence of SEQ ID NO: 4, and a light chain variable region comprising a VL complementarity determining region 3 (CDRL3) having the amino acid sequence of SEQ ID NO: 8.

[0175] In some embodiments, the anti-CDCP1 targeting agent, antibody, or its binding fragment further comprises a heavy chain variable region comprising a VH complementarity determining region 2 (CDRH2) having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a VL complementarity determining region 2 (CDRL2) having the amino acid sequence of SEQ ID NO: 7.

[0176] In some embodiments, the anti-CDCP1 targeting agent, antibody, or its binding fragment comprises a heavy chain variable region comprising a VH complementarity determining region 1 (CDRH1) having the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a VL complementarity determining region 1 (CDRH1) having any of the amino acid sequences of SEQ ID NO: 6. [Table 2] [Table 3]

[0177] In some embodiments, the targeting agent, antibody, or its binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 2.

[0178] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a VH comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 3.

[0179] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a VH comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 4.

[0180] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0181] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a light chain variable region (VL) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 7.

[0182] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 8.

[0183] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 12.

[0184] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a variable light chain (VL) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 13.

[0185] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 14.

[0186] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VH comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 1, and / or a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 5.

[0187] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VH comprising an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 1.

[0188] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VL comprising an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 5.

[0189] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16.

[0190] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a variable light chain (VL) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 17.

[0191] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 18.

[0192] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 20.

[0193] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a light chain variable region (VL) comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 21.

[0194] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0195] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VH comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15, and / or consists of a VL comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0196] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VH comprising an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 15.

[0197] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises and / or consists of a VL comprising an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0198] Any combination of the VH and VL sequences shown in Table A is also encompassed by the present disclosure.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

Table 4-54

Table 4-55

Table 4-56

Table 4-57

[0199] Several human, humanized, and chimeric anti-CDCP1 antibodies are disclosed in the patent literature (see, e.g., Table A above showing the heavy chain, heavy chain variable region, light chain, and / or light chain variable region of such antibodies. Such sequences can be found, for example, in Japanese Patent Application Publication No. JP2007 / 112734, PCT Patent Application Publication No. WO2022 / 212876, and U.S. Patent Application Publication Nos. 2023 / 0050380A1, 2022 / 0389113A1, 2022 / 011954A1, 2008 / 0008719A1, and U.S. Patent No. 9,346,886, which are hereby incorporated by reference in their entirety).

[0200] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a heavy chain (or heavy chain variable region) having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to any one of the amino acid sequences of SEQ ID NOs: 23-158, and a light chain (or light chain variable region) having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NOs: 159-295.

[0201] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 1.

[0202] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a light chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 5.

[0203] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 10.

[0204] In some embodiments, the targeting agent, antibody, or binding fragment thereof comprises a light chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 11.

[0205] In some embodiments, the targeting agent, antibody, or binding fragment thereof (i) (a) a CDRH1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a CDRH2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a CDRH3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, a heavy chain variable region (VH), and (ii) (a) a CDRL1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a CDRL2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A light chain variable region (VL) comprising a CDRL3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8.

[0206] In some embodiments, the targeting factor, antibody, or binding fragment thereof (i) (a) A CDRH1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) A CDRH2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) A heavy chain variable region (VH) comprising a CDRH3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, (ii) (a) A CDRL1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) A CDRL2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A light chain variable region (VL) comprising a CDRL3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8.

[0207] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16, 17, and / or 18.

[0208] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 15.

[0209] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 20, 21, and / or 22.

[0210] In some embodiments, the targeting factor, antibody, or binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 19.

[0211] In some embodiments, the targeting factor, antibody, or binding fragment thereof (i) (a) a CDRH1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 16, (b) a CDRH2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 17, and (c) a CDRH3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 18, a heavy chain variable region (VH), and (ii) (a) a CDRL1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 20, (b) a CDRL2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 21, and (c) a CDRL3 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 22, a light chain variable region (VL).

[0212] In certain embodiments, the targeting factor, antibody, or binding fragment thereof described herein comprises an Fc domain. The Fc domain can be derived from IgA (e.g., IgA1 or IgA2), IgG, IgE, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the Fc domain comprises the wild-type sequence of the Fc domain. In some embodiments, the Fc domain comprises one or more mutations that result in an altered biological activity. For example, the mutations can be introduced into the Fc domain to increase homogeneity during production of the recombinant protein. In some embodiments, the Fc domain is the Fc domain of human IgG. In some embodiments, a lysine at the C-terminal position of the Fc domain is deleted to increase homogeneity during production of the recombinant protein. In some embodiments, a lysine is present at the C-terminal position of the Fc domain.

[0213] In certain embodiments, the polypeptide comprising the targeting factor, antibody, or binding fragment thereof described herein is encoded by a cDNA polynucleotide sequence. As is well understood in the art, introduction of the cDNA into competent mammalian cells results in the production of a polypeptide comprising the targeting factor, antibody, or binding fragment thereof. Exemplary methods of antibody production by these means are described in at least U.S. Patent Nos. 8,008,449, 10,934,571, and 11,339,215, which are incorporated herein by reference.

[0214] In one embodiment, the cDNA comprises a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR H1, H2, and H3 having the amino acid sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively.

[0215] In one embodiment, the cDNA comprises a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH having the amino acid sequence set forth in SEQ ID NO: 1.

[0216] In one embodiment, the cDNA comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof that comprises a VL comprising CDR L1, L2, and L3 having the amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8, respectively.

[0217] In one embodiment, the cDNA comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or a fragment thereof that comprises a VL having the amino acid sequence set forth in SEQ ID NO: 5.

[0218] Also provided by the present disclosure are targeting agents, antibodies, or binding fragments thereof that bind to the same epitope (e.g., CDCP1) as any of the antibodies or binding fragments thereof described herein. For example, antibody competition assays (and overlapping epitope analysis) can be evaluated by surface plasmon resonance (SPR) or biolayer interferometry (BLI) as described in detail herein.

[0219] The antibodies and binding fragments thereof provided by the present invention include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab’, F(ab’)2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, hetero-complex antibodies (e.g., antibody-drug conjugates), single-chain (ScFv), variants thereof, fusion proteins comprising antibody portions, domain antibodies (dAb), humanized antibodies, and any other modified structures of immunoglobulin molecules comprising an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies and binding fragments thereof can be of mouse, rat, human, or any other origin (including chimeric or humanized antibodies). In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody, a humanized antibody, or a human antibody. In certain embodiments, the antibody is an antibody-drug conjugate.

[0220] In some embodiments, the anti-CDCP1 antibody or antibody fragment thereof comprises one or more conservative amino acid substitutions. One of ordinary skill in the art will recognize that a conservative amino acid substitution is a substitution of one amino acid with another amino acid that has similar structural or chemical properties, such as similar side chains. Exemplary conservative substitutions are described, for example, in the literature of Watson et al., Molecular Biology of the Gene, The Benjamin / Cummings Publication Company, 4th Ed. (1987).

[0221] "Conservative modification" refers to amino acid modifications that do not significantly affect or alter the binding properties of an antibody containing the amino acid sequence. Conservative modifications include amino acid substitutions, additions, and deletions. Conservative substitutions are those in which an amino acid is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are clearly defined and include amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine), amides (e.g., asparagine, glutamine), beta-branched side chains (e.g., threonine, valine, isoleucine), and sulfur-containing side chains (cysteine, methionine). Further, any natural residue in a polypeptide can also be substituted with alanine, as described above for alanine scanning mutagenesis (MacLennan et al. (1998) Acta Physiol Scand Suppl 643:55-67, Sasaki et al. (1998) Adv Biophys 35:1-24). Amino acid substitutions to the antibodies of the present invention can be made by known methods, such as PCR mutagenesis (U.S. Patent No. 4,683,195).

[0222] In some embodiments, the antibody or fragment thereof comprises a variable heavy chain sequence comprising an amino acid sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the amino acid sequences set forth in SEQ ID NOs: 1, 15, 23-158. In other embodiments, the antibody or fragment thereof retains the binding and / or functional activity of an antibody or fragment thereof comprising the variable heavy chain sequence of SEQ ID NOs: 1, 15, 23-158. In still further embodiments, the antibody or fragment thereof comprises the variable heavy chain sequence of SEQ ID NOs: 1, 15, 23-158 and has one or more conservative amino acid substitutions in the heavy chain variable sequence, for example, 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 conservative amino acid substitutions.

[0223] In certain embodiments, the antibody or fragment thereof comprises a variable heavy chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the variable heavy chain region sequence of an antibody or fragment thereof set forth in SEQ ID NOs: 1, 15, 23-158, comprises one or more conservative amino acid substitutions in the framework region (based on the Kabat numbering system), the variable heavy chain sequence set forth in SEQ ID NOs: 1, 15, 23-158, and the variable light chain sequence set forth in SEQ ID NOs: 5, 19, 159-295, and retains the binding and / or functional activity of an antibody or fragment thereof.

[0224] In some embodiments, the antibody or fragment thereof comprises a variable light chain sequence comprising an amino acid sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the amino acid sequences set forth in SEQ ID NOs: 5, 19, 159-295. In other embodiments, the antibody or fragment thereof retains the binding and / or functional activity of an antibody or fragment thereof comprising the variable light chain sequence of SEQ ID NOs: 5, 19, 159-295. In still further embodiments, the antibody or fragment thereof comprises the variable light chain sequence of SEQ ID NOs: 5, 19, 159-295 and has one or more conservative amino acid substitutions in the light chain variable sequence, for example, 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, or 1-5 conservative amino acid substitutions.

[0225] In certain embodiments, the antibody or fragment thereof comprises a variable light chain sequence having at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the variable light chain sequence of the antibody or fragment thereof set forth in SEQ ID NOs: 5, 19, 159 - 295, and comprising one or more conservative amino acid substitutions in the framework region (based on the Kabat numbering system), and retains the binding and / or functional activity of the antibody or fragment thereof comprising the variable heavy chain sequence set forth in SEQ ID NOs: 1, 15, 23 - 158 and the variable light chain sequence set forth in SEQ ID NOs: 5, 19, 159 - 295.

[0226] The binding affinity of the targeting agent or antibody can be expressed as an equilibrium dissociation constant (K D ), which refers to the dissociation rate of a particular antigen - antibody interaction. K D is the ratio of the dissociation rate (also called the "off - rate (k off )") to the association rate (also called the "on - rate (k on )"). Thus, K D is equal to k off / k on (dissociation / association), is expressed in molar concentration (M), and the smaller the K D , the stronger the binding affinity. The K D value of an antibody can be determined using well - established methods in the art. Unless otherwise specified, "binding affinity" refers to a monovalent interaction (intrinsic activity, e.g., the binding of an antibody to an antigen via a monovalent interaction).

[0227] In certain embodiments, the targeting agent, antibody, or binding fragment thereof of the present invention has an affinity (K D ) value of about 350 nM, about 325 nM, about 323.10 nM, about 300 nM, about 286.44 nM, about 275 nM, about 250 nM, about 232.13 nM, about 225 nM, about 219.13 nM, about 200 nM, about 195.54 nM, about 175 nM, about 158 nM, about 150 nM, about 125 nM, or about 100 nM or less.

[0228] In some embodiments, the targeting agent, antibody, or binding fragment thereof binds to an epitope (e.g., CDCP1) with a K D value of about 95 nM, about 90 nM, about 80 nM, about 79.89 nM, about 75 nM, about 70 nM, about 69.50 nM, about 65 nM, about 63.44 nM, about 60 nM, about 55 nM, about 52.88 nM, about 50 nM, about 45 nM, about 44.50 nM, about 41.99 nM, about 40 nM, about 35 nM, about 30 nM, about 25 nM, about 20 nM, about 10 nM, about 5 nM, or about 1 nM or less.

[0229] In some embodiments, the targeting agent, antibody, or binding fragment thereof binds to an epitope (e.g., CDCP1) with a K D value of about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3.12 nM, about 3 nM, about 2.90 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, about 900 pM, about 800 pM, about 700 pM, about 600 pM, about 500 pM, about 400 pM, about 300 pM, about 250 pM, about 200 pM, about 150 pM, about 100 pM, about 50 pM, about 40 pM, about 30 pM, about 25 pM, about 20 pM, about 15 pM, about 10 pM, about 5 pM, or about 1 pM or less.

[0230] The K D value can be determined directly by well-known methods and can be calculated even for complex mixtures, for example, by methods such as those described in Caceci et al., (1984, Byte 9:340-362). For example, K D can be established using a double-filter nitrocellulose filter binding assay as disclosed by Wong & Lohman (1993, Proc. Natl. Acad. Sci. USA 90:5428-5432). Other standard assays for evaluating the binding ability of a ligand, such as an antibody, to its target antigen are known in the art and include, for example, ELISA, Western blot, RIA, and flow cytometry analysis, as well as other assays exemplified elsewhere in this specification.

[0231] The binding affinity (K D)One exemplary method for measuring values is surface plasmon resonance (SPR), which typically uses a biosensor system such as a BIACORE® system. SPR refers to an optical phenomenon that enables the analysis of real-time biospecific interactions, for example, by detecting changes in protein concentration within a biosensor matrix using a BIACORE® system. BIAcore kinetic analysis involves analyzing the binding and dissociation of an antigen from a chip containing a molecule immobilized on its surface (e.g., a molecule containing an antigen-binding domain), or the dissociation of an antibody or its binding fragment from a chip containing an immobilized antigen.

[0232] In certain embodiments, SPR measurements are performed using a BIACORE® T100 or T200 instrument. For example, standard assay conditions for surface plasmon resonance can be based on antibody immobilization of approximately 100 - 500 response units (RU) of IgG on the SPR chip. The purified target protein is diluted in buffer to the range of final concentrations and injected at the required flow rate (e.g., 10 - 100 μl / min) to enable the calculation of Ka. Dissociation is allowed to proceed to establish the off-rate, and subsequently the chip surface is regenerated with 3M MgCl2 (or 20 mM NaOH). The sensorgram is then analyzed using a kinetic evaluation software package. In an exemplary embodiment, the SPR assay follows the conditions described in the examples.

[0233] In certain embodiments, the binding affinity (K D ) value is measured using a solution-based kinetic exclusion assay (KinExA™). In certain embodiments, KinExA measurements are performed using a KinExA™ 3200 instrument (Sapidyne). The kinetic exclusion assay (KinExA™) is a general-purpose immunoassay platform (basically a flow fluorometer) that can measure the equilibrium dissociation constant of an antigen / antibody interaction, as well as the association and dissociation rate constants. Since KinExA™ is performed after equilibrium is obtained, the K of high-affinity interactions where the off-rate of the interaction can be very slow DIt is an advantageous technique used to measure. The KinExA (trademark) method can generally be implemented as described in Drake et al., (2004) Analytical Biochem. 328, 35-43.

[0234] The K of the antibody D Another method for determining is typically by using Bio-Layer Interferometry (BLI) which uses the OCTET (registered trademark) technology from ForteBio (e.g., Octet QKe system). In certain embodiments, the BLI measurement is performed as follows: A sensor chip coated with a proprietary anti-human antibody (ForteBio) is subjected to BLI signal stabilization by immersion in a running buffer (such as 10 mM Hepes buffered saline (HBS) containing 0.05% tween-20) for 120 seconds. Then the antibody is captured by immersing the sensor in the running buffer (the buffer may contain 1-10 ug / mL of the antibody) for 300 seconds. Then the signal is stabilized by immersing the sensor tip in the running buffer for 120 seconds. Then the tip is transferred to a solution containing the cognate antigen. The antibody-antigen binding is measured for 180 seconds prior to transferring the sensor tip to the running buffer to monitor receptor dissociation over 180 seconds.

[0235] In the case of CDCP1, typically, a 7-point dose response of the antigen (which can be in the range of 1-2 nM in serial dilution) is measured. Additionally, a sensor tip without the antibody captured is exposed to the antigen and non-specific binding to the sensor tip of the receptor is monitored. A second reference type also includes a tip with the antibody captured thereon, which is then exposed to a running buffer without the antigen. This allows for a double reference that removes both non-specific binding and the underlying baseline drift due to system noise and dissociation of the antibody from the anti-human Fc sensor tip. The raw data is subjected to double reference subtraction and then fit to a 1:1 Langmuir-type binding model to determine the affinity and kinetic parameters.

[0236] In some embodiments, CDCP1 is human CDCP1, cynomolgus monkey CDCP1, or mouse CDCP1. Generally, the anti-CDCP1 antibody should bind to CDCP1 with high affinity. The anti-CDCP1 antibody should have a binding affinity (K D ) for human CDCP1 in the low nanomolar range, such as about 40 nM or less. In some embodiments, CDCP1 is human CDCP1 and the K D value is about 40 nM, about 45 nM, or about 50 nM. In some embodiments, CDCP1 is cynomolgus monkey CDCP1 and the K D value is about 62 nM, about 64 nM, about 66 nM, about 68 nM, or about 70 nM.

[0237] Drug moiety In some embodiments, the drug moiety is a cytotoxic agent, an immunomodulatory agent, a contrast agent, a chemotherapeutic agent, or a therapeutic protein.

[0238] In some embodiments, the drug moiety is preferably a small molecule having a molecular weight of < about 5 kDa, more preferably < about 4 kDa, more preferably < about 3 kDa, most preferably < about 1.5 kDa or < about 1 kDa.

[0239] In some embodiments, the drug moiety has an IC 50 of less than about 1 nM.

[0240] In some embodiments, the drug moiety has an IC 50 greater than about 1 nM. For example, the therapeutic agent has an IC 50 of about 1 to about 50 nM.

[0241] IC greater than about 1 nM 50Some drug moieties having (e.g., "low potency drugs") are inappropriate for conjugation with antibodies using composite techniques recognized in the art. Without wishing to be bound by theory, such drug moieties cannot be conjugated using techniques recognized in the art without a sufficient copy of the drug (i.e., more than 8) resulting in a decrease in the pharmacokinetics and physiochemical properties of the conjugate, and thus have insufficient potency for use in targeted antibody-drug conjugates using conventional techniques. However, using the conjugation strategies described herein, a sufficiently high loading of these less potent agents can be achieved, thereby resulting in a high loading of the therapeutic agent while maintaining desirable pharmacokinetic and physiochemical properties. Thus, in some embodiments, the disclosure also relates to an antibody-drug conjugate comprising an antibody, a linker, and at least eight drug moieties, wherein the therapeutic agent has an IC 50 having.

[0242] In some embodiments, the small molecule therapeutic agents used in the present disclosure (e.g., anti-proliferative agents (cytotoxic and cytostatic agents) that can be linked to a targeting moiety via a linker of the present disclosure) include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, cell cycle progression inhibitors, PI3K / m-TOR / AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperone inhibitors, HDAC inhibitors, PARP inhibitors, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, Wnt hedgehog signaling pathway inhibitors, and RNA polymerase inhibitors.

[0243] Examples of a wide range of cytotoxins include, but are not limited to, DNA binders, intercalating agents or alkylating agents, microtubule stabilizers and destabilizers, platinum compounds, topoisomerase inhibitors (including topoisomerase I inhibitors and topoisomerase II inhibitors), and protein synthesis inhibitors.

[0244] In some embodiments, the drug moiety comprises one or more cGAS / interferon gene stimulator (STING) pathway agonists. Non-limiting examples of STING agonists include DMXAA, ADUS100 / MIW815, MK-1454, MK-2118, SB11285, GSK3745417, BMS-986301, BI-STING (BI1387446), E7766, TAK-676, SNX281, SYNB1891. Additional non-limiting examples of STING agonists, as well as combinations with other cytotoxic agents and / or ENPP1 inhibitors, can be found in Amouzegar et al., Cancers 13:2695 (2021), which is hereby incorporated by reference in its entirety.

[0245] Exemplary DNA binders, intercalators or alkylating agents include CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin, nemorubicin, and their derivatives, PNU-159682), bisnaphthalimide compounds such as elinafide (LU79553), and its analogs, alkylating agents such as calicheamicin, dactinomycin, mitomycin, pyrrolobenzodiazepine, indolinobenzodiazepine, etc., but are not limited thereto. Exemplary CC-1065 analogs include duocarmycin SA, duocarmycin A, duocarmycin CI, duocarmycin C2, duocarmycin Bl, duocarmycin B2, duocarmycin D, DU-86, KW-2189, adozelesin, bisucaberin, carzelesin, seco-adozelesin, and related analogs and prodrug forms, examples of which are described in U.S. Patent Nos. 5,475,092, 5,595,499, 5,846,545, 6,534,660, 6,586,618, 6,756,397, and 7,049,316. Doxorubicin and its analogs include those described in U.S. Patent No. 6,630,579. Calicheamicin includes, for example, enediynes such as esperamicin, and those described in U.S. Patent Nos. 5,714,586 and 5,739,116. Duocarmycin includes those described in U.S. Patent Nos. 5,070,092, 5,101,038, 5,187,186, 6,548,530, 6,660,742, and 7,553,816B2, and Li et al., Tel Letts., 50: 2932-2935 (2009), the entire disclosures of which are incorporated herein by reference in their entirety.

[0246] Exemplary topoisomerase inhibitors (e.g., topoisomerase I and / or topoisomerase II) include camptothecin, camptothecin derivatives, camptothecin analogs, and non-natural camptothecins, such as exatecan, Dxd, Sn-38 (7-ethyl-10-hydroxy-camptothecin), CPT-11 (irinotecan), GI-147211C, topotecan, 9-aminocamptothecin, 7-hydroxymethylcamptothecin, 7-aminomethylcamptothecin, 10-hydroxycamptothecin, (20S)-camptothecin, rubitecan, gimatecan, carotenotecan, silatecan, larototecan, diflomotecan, verotecan, lutotecan, and S39625, and any analogs thereof, but are not limited thereto. Non-limiting examples of other topoisomerase inhibitors (e.g., topoisomerase I and / or topoisomerase II) that can be used in the present disclosure include those described in WO2020 / 00880 and WO2021 / 148501, the disclosures of each of which are hereby incorporated by reference in their entirety. Non-limiting examples of other camptothecin compounds that can be used in the present disclosure include those described in J.Med.Chem., 29:2358-2363 (1986), J.Med.Chem., 23:554 (1980), J.Med.Chem., 30:1774 (1987), the disclosures of each of which are hereby incorporated by reference in their entirety. In some embodiments, the drug moiety is exatecan and / or an analog thereof. In some embodiments, the drug moiety is Dxd and / or an analog thereof.

[0247] Non-limiting examples of pyrrolobenzodiazepines (PBDs) and their analogs include those described in Denny, Exp. Opin. Ther. Patents., 10(4):459-474 (2000), Antonow and Thurston, Chem Rev., 2815-2864 (2010), Min et al., ACS Omega 5:25798-25809 (2020), and Hartley Exp. Opin. Biol. Therapy 7:931-943 (2020), but are not limited thereto, and the disclosure of each of them is hereby incorporated by reference in its entirety.

[0248] Exemplary microtubule stabilizers and destabilizers include taxane compounds such as paclitaxel, docetaxel, tesetaxel, and cabazitaxel, maytansinoids, auristatins, and their analogs, vinca alkaloid derivatives, epothilones, and cryptophycins, but are not limited thereto.

[0249] Exemplary mitansinoids or mitansinoid analogs include, but are not limited to, mitansinol and mitansinol analogs, mitansine or DM-i and DM-4, those described in U.S. Patent Nos. 5,208,020, 5,416,064, 6,333,410, 6,441,163, 6,716,821, RE39,151, and 7,276,497. In certain embodiments, the cytotoxic agent is a mitansinoid, another group of anti-tubulin agents (see also ImmunoGen, Inc., Chari et al., 1992, Cancer Res. 52:127-131), a mitansinoid, or a mitansinoid analog. Examples of suitable mitansinoids include, but are not limited to, mitansinol and mitansinol analogs. Non-limiting examples of suitable mitansinoids are those described in U.S. Patent Nos. 4,424,219, 4,256,746, 4,294,757, 4,307,016, 4,313,946, 4,315,929, 4,331,598, 4,361,650, 4,362,663, 4,364,866, 4,450,254, 4,322,348, 4,371,533, 6,333,410, 5,475,092, 5,585,499, and 5,846,545, which are hereby incorporated by reference in their entirety.

[0250] Exemplary auristatins include, but are not limited to, auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F, auristatin F phenylenediamine (AFP), auristatin F hydroxylpropylamide (AF FTP A), monomethyl auristatin F hydroxylpropylamide (MMAF HP A), and dolastatin. Non-limiting examples of suitable auristatins are also described in U.S. Patent Publication Nos. 2003 / 0083263, 2011 / 0020343, and 2011 / 0070248, PCT Application Publication Nos. WO09 / 117531, WO2005 / 081711, WO04 / 010957, WO02 / 088172, and WO01 / 24763, and U.S. Patent Nos. 7,498,298, 6,884,869, 6,323,315, 6,239,104, 6,124,431, 6,034,065, 5,780,588, 5,767,237, 5,665,860, 5,663,149, 5,635,483, 5,599,902, 5,554,725, 5,530,097, 5,521,284, 5,504,191, 5,410,024, 5,138,036, 5,076,973, 4,986,988, 4,978,744, 4,879,278, 4,816,444, and 4,486,414, the disclosures of each of which are hereby incorporated by reference in their entirety. In some embodiments, the drug moiety is monomethyl auristatin E (MMAE) and / or an analog thereof.

[0251] Exemplary vinca alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, and navelbine (vinorelbine). Suitable vinca alkaloids that can be used in the present disclosure are also disclosed in U.S. Published Application Nos. 2002 / 0103136 and 2010 / 0305149, and U.S. Patent No. 7,303,749B1, the disclosures of each of which are incorporated herein by reference in their entirety.

[0252] Exemplary epothilone compounds include, but are not limited to, epothilone A, B, C, D, E, and F, and derivatives thereof. Suitable epothilone compounds and their derivatives are described, for example, in U.S. Patent Nos. 6,956,036, 6,989,450, 6,121,029, 6,117,659, 6,096,757, 6,043,372, 5,969,145, and 5,886,026, and WO97 / 19086, WO98 / 08849, WO98 / 22461, WO98 / 25929, WO98 / 38192, WO99 / 01124, WO99 / 02514, WO99 / 03848, WO99 / 07692, WO99 / 27890, and WO99 / 28324, the disclosures of all of which are incorporated herein by reference in their entirety.

[0253] Non-limiting examples of cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021, the disclosures of each of which are incorporated herein by reference in their entirety.

[0254] Exemplary platinum compounds include, but are not limited to, cisplatin (PLATINOL®), carboplatin (PARAPLATIN®), oxaliplatin (ELOXATIN®), iproplatin, ormaplatin, and tetraplatin.

[0255] Compounds of other classes, or non-limiting examples of these or other compounds having a cytotoxic mode of action may be selected, for example, mitomycin C, mitomycin A, daunorubicin, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, aminopterin, bleomycin, l-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol, pyridinobenzodiazepine (PDD), pyrrolobenzodiazepine (PBD), and polyamides and their dimers are included. Non-limiting examples of other suitable cytotoxic agents include puromycin, topotecan, lysocine, echinomycin, combretastatin, netropsin, estramustine, cryptophycin, semadotin, discodermide, eribulin, and mitoxantrone.

[0256] Examples of angiogenesis inhibitors include, but are not limited to, MetAP2 inhibitors, VEGF inhibitors, PIGF inhibitors, VGFR inhibitors, PDGFR inhibitors, and MetAP2 inhibitors. Exemplary VGFR and PDGFR inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent), and brivanib. Exemplary MetAP2 inhibitors include compounds that inhibit the ability of MetAP-2 to remove the NH2-terminal methionine from a protein, including fumagillamine, i.e., compounds that contain a fumagillin core structure, as described in Rodeschini et al., J. Org. Chem., 69, 357-373, 2004 and Liu, et al., Science 282, 1324-1327, 1998. Non-limiting examples of "fumagillol analogs" are disclosed in J Org. Chem., 69, 357, 2004, J. Org. Chem., 70, 6870, 2005, European Patent Application No. 0354787, J. Med.Chem., 49, 5645, 2006, Bioorg. Med.Chem., 1 1, 5051, 2003, Bioorg. Med.Chem., 14, 91, 2004, Tel Lett 40, 4797, 1999, WO99 / 61432, U.S. Patent Nos. 6,603,812, 5,789,405, 5,767,293, 6,566,541, and 6,207,704, the entire disclosures of which are hereby incorporated by reference in their entirety.

[0257] Exemplary cell cycle progression inhibitors include CDK inhibitors such as BMS-387032 and PD0332991, Rho kinase inhibitors such as GSK429286, checkpoint kinase inhibitors such as AZD7762, aurora kinase inhibitors such as AZD1152, MLN8054, and MLN8237, PLK inhibitors such as BI2536, BI6727 (volasertib), GSK461364, ON-01910 (Estybon), and KSP inhibitors such as SB743921, SB715992 (ispirosib), MK-0731, AZD8477, AZ3146, and ARRY-520, but are not limited thereto.

[0258] Exemplary PBK / m-TOR / AKT signaling pathway inhibitors include phosphoinositide 3-kinase (PI3K) inhibitors, GSK-3 inhibitors, ATM inhibitors, DNA-PK inhibitors, and PDK-1 inhibitors, but are not limited thereto.

[0259] Non-limiting examples of exemplary PI3 kinase inhibitors are disclosed in U.S. Patent No. 6,608,053, the disclosure of which is hereby incorporated by reference in its entirety, and include BEZ235, BGT226, BKM120, CAL101, CAL263, demethoxybiridin, GDC-0941, GSK615, IC87114, LY294002, Pafomid 529, perifosine, PI-103, PF-04691502, PX-866, SAR245408, SAR245409, SF1126, wortmannin, XL147, and XL765.

[0260] Exemplary AKT inhibitors include AT7867, but are not limited thereto.

[0261] Exemplary MAPK signaling pathway inhibitors include MEK, Ras, JNK, B-Raf, and p38MAPK inhibitors, but are not limited thereto.

[0262] Non-limiting examples of MEK inhibitors are disclosed in U.S. Patent No. 7,517,994, the disclosure of which is incorporated herein by reference in its entirety, and include GDC-0973, GSK1120212, MSC1936369B, AS703026, R05126766, and R04987655, PD0325901, AZD6244, AZD8330, and GDC-0973.

[0263] Exemplary B-raf inhibitors include, but are not limited to, CDC-0879, PLX-4032, and SB590885.

[0264] Exemplary B p38 M APK inhibitors include, but are not limited to, BIRB796, LY2228820, and SB202190.

[0265] Receptor tyrosine kinases (RTKs) are cell surface receptors often associated with signaling pathways that stimulate uncontrolled growth and angiogenesis of cancer cells. Many RTKs have been identified that overexpress or have mutations leading to constitutive activation of the receptor, including, but not limited to, the VEGFR, EGFR, FGFR, PDGFR, EphR, and RET receptor family receptors. Exemplary specific RTK targets include, but are not limited to, ErbB2, FLT-3, c-Kit, and c-Met.

[0266] Exemplary inhibitors of the ErbB2 receptor (EGFR family) include, but are not limited to, AEE788 (NVP-AEE788), BIBW2992, (afatinib), lapatinib, erlotinib (Tarceva), and gefitinib (Iressa).

[0267] Exemplary RTK inhibitors (multi-target kinase inhibitors) that target more than one signaling pathway include, but are not limited to, AP24534 (ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR, and Bcr-Abl receptors; ABT-869 (lenvatinib) that targets FLT-3 and VEGFR-PDGFR receptors; AZD2171 that targets VEGFR-PDGFR, Flt-1, and VEGF receptors; CHR-258 (dovitinib) that targets VEGFR-PDGFR, FGFR, Flt-3, and c-Kit receptors; sunitinib (Sutent) that targets VEGFR, PDGFR, KIT, FLT-3, and CSF-IR; sorafenib (Nexavar) and brivanib that target VEGFR, PDGFR, and intracellular serine / threonine kinases in the Raf / Mek / Erk pathway.

[0268] Exemplary protein chaperone inhibitors include, but are not limited to, HSP90 inhibitors.

[0269] Examples of HSP90 inhibitors include, but are not limited to, 17AAG derivatives, BIIB021, BIIB028, S X-5422, NVP-AUY-922, and KW-2478.

[0270] Exemplary WD AC inhibitors include, but are not limited to, vorinostat (PXD101), CUDC-101, droxinostat, ITF2357 (givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP-LAQ824, dacinostat), LBH-589 (panobinostat), MC I 568, MGCD0103 (mocetinostat), M S -275 (entinostat), PCI-24781, pyroxamide (NSC696085), SB939, trichostatin A, and vorinostat (SAHA).

[0271] Exemplary PARP inhibitors include, but are not limited to, iniparib (BSI201), olaparib (AZD-2281), ABT-888 (veliparib), AG014699, CEP9722, MK4827, KU-0059436 (AZD2281), LT-673, 3-aminobenzamide, A-966492, and AZD2461.

[0272] Exemplary NAMPT inhibitors include, but are not limited to, FK866 (AP0866) and CHS828, GPP78, GMX1778 (CHS828), STF-118804, STF-31, CB300919, CB30865, GNE-617, IS001, TP201565, Nampt-IN-1, P7C3, MPC-9528, CB30865, MPI0479883, and

Number

[0273] Exemplary Wnt / hedgehog signaling pathway inhibitors include, but are not limited to, vismodegib (RG3616 / GDC-0449), cyclopamine (11-deoxojervine) (hedgehog pathway inhibitor), and XAV-939 (Wnt pathway inhibitor).

[0274] Exemplary RNA polymerase inhibitors include, but are not limited to, amatoxins. Exemplary amatoxins include α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amaniline, amanolic acid, amaninamide, amanin, and proamanullin.

[0275] Exemplary protein synthesis inhibitors include, but are not limited to, trichothene compounds.

[0276] In some embodiments, the drug moiety is a topoisomerase inhibitor (e.g., a non-natural camptothecin compound, a vinca alkaloid, a kinase inhibitor (e.g., a PI3 kinase inhibitor (GDC-0941 and PI-103)), a MEK inhibitor, a KSP inhibitor, an RNA polymerase inhibitor, a protein synthesis inhibitor, a PARP inhibitor, a NAMPT inhibitor, docetaxel, paclitaxel, doxorubicin, duocarmycin, auristatin, dolastatin, calicheamicin, topotecan, SN38, camptothecin, exatecan, nemorubicin and its derivatives, PNU-1.59682, CC1065, ellipticine, trichothecene, pyrrolobenzodiazepine, maytansinoid, a DNA binding agent or a platinum compound, and analogs thereof. In some embodiments, the drug is Sn-38, camptothecin, topotecan, exatecan, calicheamicin, nemorubicin, PNU-159682, anthracycline, maytansinoid, taxane, tincothecene, CC1065, ellipticine, vindesine, vinblastine, PI-103, AZD8330, dolastatin, auristatin E, auristatin F, duocarmycin compounds, isopinosine, pyrrolobenzodiazepine, ARRY-520, and derivatives of stereoisomers, isotars, and analogs thereof.

[0277] In some embodiments, the drug moiety D has the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0278] In some embodiments, the drug moiety used in the present disclosure is, for example, a combination of two or more drugs such as a PI3 kinase inhibitor and a MEK inhibitor, a broad-spectrum cytotoxic compound and a platinum compound, a PARI 3 inhibitor, a NAMPT inhibitor and a platinum compound, a broad-spectrum cytotoxic compound and a PARP inhibitor, and the like.

[0279] In some embodiments, the drug moiety used in the present disclosure is auristatin F-hydroxypropylamide-L-alanine.

[0280] Linker In one aspect, the drug moiety can be directly or indirectly linked to a targeting agent (e.g., an antibody or an antibody-binding fragment) to provide a targeted conjugate. In some embodiments, the antibody-drug conjugate (ADC) of the present disclosure (e.g., the ADC of formula (I)) comprises a linker group, and the targeting agent (e.g., an antibody or an antibody-binding fragment) is bound to the drug moiety via the linker group. In some embodiments, the compounds of the present disclosure (e.g., formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof) comprise a linker group, and the targeting agent (e.g., an antibody or an antibody-binding fragment) is bound to the drug moiety via the linker group. In some embodiments, the linker is a single bond. In a non-limiting example, when the linker is a single bond, the drug moiety is directly bound to the targeting agent (e.g., an antibody or an antibody-binding fragment). In some embodiments, various targeted conjugates are known in the art and can be used with the compounds of formula (III) and their salts or solvates. In a non-limiting example, the targeted conjugate is an antibody-drug conjugate, and one or more compounds of formula (III) are linked to the antibody. In embodiments, the antibody-drug conjugate of the present disclosure comprises one or more compounds of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof.

[0281] Any linker suitable for binding the drug moiety to a targeting agent (e.g., an antibody or an antibody-binding fragment) is contemplated by the present disclosure, as will be understood by those skilled in the art.

[0282] In some embodiments, the linker is a bond or a moiety having from 1 to 200 non-hydrogen atoms selected from C, N, O, S, or halogen, optionally incorporating alkyl, ether, oxo, carboxyl, carboxamide, carboximidyl, ester, urethane, branched, cyclic, unsaturated, amino acid, heterocyclyl, aryl, or heteroaryl moieties. In embodiments, the linker is unbranched or branched, flexible or rigid, short or long, and optionally incorporates any combination of moieties that are considered useful. In some embodiments, at least a portion of the linker has a polyalkylene oxide polymer region. In non-limiting examples, the polyalkylene oxide polymer region can enhance the solubility of the drug moiety. In some embodiments, the linker has repeating units of ethylene glycol.

[0283] In some embodiments, the linker has from about 1 to about 25, or any number of repeating ethylene glycol units therebetween. In some embodiments, the linker comprises from about 3 to about 20, about 3 to about 5, about 4 to about 15, about 4 to about 8, about 4 to about 6, about 5 to about 12, about 6 to about 10, or about 7 to about 9 ethylene glycol units. In some embodiments, the linker comprises about 8 ethylene glycol units.

[0284] In some embodiments, at least a portion of the linker comprises one or more amino acid moieties. In non-limiting examples, the one or more amino acid moieties provide enhanced solubility for the drug moiety and / or enhanced target binding, enhanced compatibility with a targeting agent, and / or provide an amino acid sequence for enhancing target binding recognition. In some embodiments, the linker comprises one or more amino acid moieties that provide a substrate motif suitable for a protease. In non-limiting examples, when a set of amino acid moieties are incorporated into a linker that provides a specific substrate motif for a selected protease, the drug moiety can be released from the target-bound complex to provide a local cytotoxic effect.

[0285] In some embodiments, the linker comprises an alkylene chain. In some embodiments, the alkylene chain has a length of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons, and preferably, the alkylene chain contains -CH2- groups. In some embodiments, these substrate motifs are known in the art and are incorporated into the linker as needed to provide for selective release from the complex bound to the target. In non-limiting examples, this selectivity is based on the known presence of a desired protease within the local delivery region of the complex drug. In some embodiments, other polymer type moieties, including but not limited to polyacids, polysaccharides, or polyamines, can be incorporated into the linker. In some embodiments, other moieties such as substituted aromatic or heteroaromatic moieties are used to enhance rigidity or provide synthetically accessible sites on substituents therein for attachment to reactive or drug moieties.

[0286] In non-limiting examples, the linker contains ethylene glycol repeat units and / or an amino acid sequence.

[0287] In some embodiments, the linker has the formula: -[CH2CH2O] p -X AA - and comprises or consists of, wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0288] In some embodiments, the linker has the formula: -[CH2CH2O] p -X AA - and comprises or consists of, wherein X AAis an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0289] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA - and comprises or consists of, wherein X AA is an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0290] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA - and comprises or consists of, wherein X AA is an amino acid sequence, p is an integer from 0 to 50, and X AA is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8. In some embodiments, -(CH2) 1-5 - is -(CH2) 1-3 .

[0291] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2) 1-3 -C(O)-X AA - and comprises or consists of, wherein X AAis an amino acid sequence, and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0292] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2) 1-3 -C(O)-X AA - and comprises or consists of, where X AA is an amino acid sequence, p is an integer from 0 to 50, and X AA is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0293] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2)2-C(O)-X AA - and comprises or consists of, wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0294] In some embodiments, the linker (e.g., L A ) has the formula: -[CH2CH2O] p -(CH2)2-C(O)-X AA - and comprises or consists of, wherein X AA is an amino acid sequence and p is an integer from 0 to 50, and X AAIt is not Val-Cit or Phe-Lys. In some embodiments, p is an integer from 1 to 40. In some embodiments, p is an integer from 1 to 30. In some embodiments, p is an integer from 6 to 40. In some embodiments, p is an integer from 8 to 30. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 6 to 20. In some embodiments, p is an integer from 8 to 20. In some embodiments, p is an integer from 10 to 30. In some embodiments, p is an integer from 10 to 20. In some embodiments, p is an integer from 1 to 25, 4 to 20, 5 to 15, 6 to 12, or 5 to 10. In some embodiments, p is an integer from 1 to 10, 4 to 10, 6 to 10, or 7 to 9. In some embodiments, p is 8.

[0295] In some embodiments, a suitable number of ethylene glycol units can be used for the linker. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 19, 20, 23, 24, 35, 36, 37, 48, 49, or more ethylene glycol units. In some embodiments, the linker comprises 1 to 10, 4 to 10, 6 to 10, or 7 to 9 ethylene glycol units. In some embodiments, the linker comprises 8 ethylene glycol units. Non-limiting examples of commercially available ethylene glycol groups (polyethylene glycol, PEG) suitable for the linker include H2N-dPEG®8-C(O)OH having an individual ("d") polyethylene glycol with 8 ethylene glycol repeat units. Non-limiting examples of other individual PEG units are commercially available from, for example, Advanced ChemTech and are well known to those skilled in the art. In some embodiments, the linker has the formula: -HN-PEG-C(O)-X AA - and comprises wherein PEG has 1 to 50 ethylene glycol units and X AAis an amino acid sequence. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0296] In some embodiments, the linker has the formula: -HN-PEG-C(O)-X AA - wherein PEG has 1 to 50 ethylene glycol units and X AA is an amino acid sequence, provided that X AA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0297] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2) 1-5 -C(O)-X AA - wherein PEG has 1 to 50 ethylene glycol units and X AA is an amino acid sequence. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units. In some embodiments, p is 8.

[0298] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2) 1-5 -C(O)-X AA - wherein PEG has 1 to 50 ethylene glycol units and X AAis an amino acid sequence, provided that X AA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0299] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2) 1-3 -C(O)-X AA - wherein PEG has 1 to 50 ethylene glycol units and X AA is an amino acid sequence. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units. In some embodiments, p is 8.

[0300] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2) 1-3 -C(O)-X AA - wherein PEG has 1 to 50 ethylene glycol units and X AA is an amino acid sequence, provided that X AA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0301] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2)2-C(O)-X AA- comprising, wherein PEG has 1 to 50 ethylene glycol units, and X AA is an amino acid sequence. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0302] In some embodiments, the linker (e.g., L A ) has the formula: -HN-PEG-(CH2)2-C(O)-X AA - comprising, wherein PEG has 1 to 50 ethylene glycol units, and X AA is an amino acid sequence, provided that X AA is not Val-Cit or Phe-Lys. In some embodiments, PEG has 1 to 10 ethylene glycol units, about 4 to 10 ethylene glycol units, or about 7 to 9 ethylene glycol units. In some embodiments, PEG has 8 ethylene glycol units.

[0303] In another non-limiting example, the linker comprises an alkylene chain and / or an amino acid sequence. In some embodiments, the linker has the formula: -[CH2] 0-12 -X AA - comprising, wherein X AA is an amino acid sequence, and the linker comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 -CH2- units.

[0304] In another non-limiting example, the linker comprises an alkylene chain and / or an amino acid sequence. In some embodiments, the linker has the formula: -[CH2] 0-12 -X AA - comprising, wherein X AAis an amino acid sequence, and the linker contains 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 -CH2- units, provided that X AA is not Val-Cit or Phe-Lys.

[0305] In some embodiments, the linker has the formula: -[CH2] 0-12 -X AA - wherein X AA is an amino acid sequence, and the linker contains 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 -CH2- units, provided that X AA is not Val-Cit or Phe-Lys.

[0306] In some embodiments, the linker has the formula: -HN-PEG8-C(O)-Val-Ala- where PEG has 8 ethylene glycol units.

[0307] In some embodiments, the linker has the formula: -HN-PEG8-(CH2) 1-5 -C(O)-Val-Ala- where PEG has 8 ethylene glycol units.

[0308] In some embodiments, the linker has the formula: -HN-PEG8-(CH2) 1-3 -C(O)-Val-Ala- where PEG has 8 ethylene glycol units.

[0309] In some embodiments, the linker has the formula: -HN-PEG8-(CH2)2-C(O)-Val-Ala- where PEG has 8 ethylene glycol units.

[0310] In some embodiments, the linker also includes various other linking groups that connect an ethylene glycol moiety to an amino acid sequence, or connect ethylene glycol or an amino acid sequence to a targeting agent (e.g., an antibody or antibody binding fragment) or a drug moiety. For example, the amino acid sequence can be connected to the drug moiety via a 4-aminobenzyl carboxylate group. In some embodiments, the ethylene glycol moiety is directly linked to a targeting agent (e.g., an antibody or antibody binding fragment). In some embodiments, the linker has the formula:

Chemical formula

[0311] In an embodiment, the linker is

Chemical formula

[0312] In an embodiment, the linker is

Chemical formula

[0313] In some embodiments, the linker is

Chemical formula

[0314] In some embodiments, the linker includes an amino acid moiety, which includes any suitable number of the above -mentioned amino acid moieties. By way of non - limiting example, the amino acid sequence X AA includes from 1 to 100 amino acid moieties, or from 1 to 10 amino acid moieties, or from 1 to 5 amino acid moieties. In some embodiments, the linker includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid moieties. In some embodiments, the linker includes 2 amino acid moieties. In some embodiments, X AA is valine - alanine.

[0315] In some embodiments, the amino acid sequence X AA is

Chemical formula

[0316] In some embodiments, the amino acid sequence X AA is [Chem.] is.

[0317] In some embodiments, the linker is C1-C6 alkyl, C=O, -NH-, ethylene glycol, optionally, 2-10 ethylene glycol units, valine-citrulline (val-cit), 6-maleimidocaproyl (mc), 6-succinimidylcaproyl, 6-(2,5-dioxo-3λ 3 -pyrrolidin-1-yl)caproyl, methoxy-polyethylene glycol maleimide 6 (MalPeg6), p-aminobenzyl carbamate (PABC), dimethylaminoethanol (DMAE), 3-maleimidopropanoyl (MP), 3-succinimidylpropanoyl, 3-(2,5-dioxo-3λ 3 -pyrrolidin-1-yl)propanoyl, hydrolyzed Peg-maleimide, hydrolyzed maleimide, hydrolyzed succinimide, valine-alanine (Val-Ala), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-succinimidyl 4-(2-pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), N-succinimidyl (4-iodo-acetyl)aminobenzoate (SIAB), 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-val-cit-PAB), and 6-maleimidocaproyl-valine-citrulline-p-aminobenzyl carbamate (mc-val-cit-PABC), amino acids, optionally, (D)-valine, (L)-valine, (D)-alanine, and / or (L)-alanine, and one or more groups selected from maleimide.

[0318] In some embodiments, the linker is C1-C6 alkyl, C=O, -NH-, polyethylene glycol (PEG), optionally 2 to 10 PEG groups, an amino acid, optionally (D)-valine, (L)-valine, (D)-alanine, and / or (L)-alanine, and maleimide, succinimide, or 2,5-dioxo-3λ 3 -pyrrolidin-1-yl, and the like. In some embodiments, the linker comprises, and / or consists of, val-cit. In some embodiments, the linker comprises, and / or consists of, val-cit-p-aminobenzyloxycarbonyl (PAB).

[0319] In some embodiments, the linker comprises one or more reactive moieties capable of reacting with a targeting agent and / or a targeting agent (e.g., an antibody or antibody fragment). Non-limiting examples of reactive moieties include azide, alkyne, bissulfone, carbohydrazide, hydrazine, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, pyridopyridazine, semicarbazide, succinimidyl ester, sulfodichlorophenol ester, sulfonyl halide, sulfosuccinimidyl ester, 4-sulfotetrafluorophenyl ester, tetrafluorophenyl ester, thiazole, and NHNH2. Non-limiting examples of targeting agents include proteins, portions of proteins, polypeptides, nucleic acids, hormones, antibodies or antibody fragments. In some embodiments, the targeting agent is an antibody or antibody fragment.

[0320] In some embodiments, the linker comprises R*, where R* is a reactive moiety capable of reacting with a targeting agent, a linking moiety that links the linker to the targeting agent, or a targeting agent. In some embodiments, the linker comprises, or consists of, the following formula: R*-L where R* is a reactive moiety, a linking moiety, or a targeting agent.

[0321] In some embodiments, R* is a reactive moiety that can react with functional groups such as aldehydes, amines, disulfides, ketones, thiols, etc. in the targeting agent, or can react in a Staudinger reaction, Pictet-Spengler reaction, and / or click chemistry reaction with the targeting agent. For some reactive moieties, a suitable coupling reagent can be used to react the reactive moiety with the targeting agent. For example, when R* is a carboxylic acid, a carbodiimide coupling reagent can be used. In some embodiments, R* is selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide.

[0322] In some embodiments, R* is maleimide:

Chemical formula

Chemical formula

Chemical formula

[0323] In some embodiments, R* is azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide or includes it.

[0324] Non-limiting examples of other chemical substances for the binding of a compound to an antibody are known. US7,595,292 (Brocchini et al.) refers to linkers that form sulfur and thioesters in the disulfide bonds of antibodies. US7,985,783 (Carico et al.) refers to the introduction of aldehyde residues into antibodies, which are used to bind a compound to an antibody, all of which are hereby incorporated by reference in their entirety.

[0325] In some embodiments, R* is a targeting agent, and the targeting agent is selected from a protein, a portion of a protein, a peptide, a nucleic acid, a hormone, an antibody, or an antibody fragment. In some embodiments, the targeting agent binds to a tumor-associated antigen, a cancer stem cell-associated antigen, or a viral antigen.

[0326] In some embodiments, the targeting agent is selected from a protein, a portion of a protein, a polypeptide, a nucleic acid, an antibody, or an antibody fragment. In some embodiments, the targeting agent is an antibody or an antibody fragment. In some embodiments, the targeting agent is an antibody.

[0327] In various embodiments, the targeting agent can bind to a target selected from acute myeloid leukemia (AML M4) cells, acute promyelocytic leukemia cells, acute lymphoblastic leukemia cells, acute lymphocytic leukemia cells, chronic lymphocytic leukemia cells, chronic myelogenous leukemia cells, chronic T cell lymphocytic leukemia, myelodysplastic syndrome cells, multiple myeloma cells, prostate cancer tumor cells, renal cell adenocarcinoma cells, pancreatic adenocarcinoma cells, lung cancer tumor cells or gastric adenocarcinoma cells, gastric adenocarcinoma cells, breast cancer cells, colorectal cancer cells, melanoma cells, thyroid cancer cells, ovarian cancer cells, bladder cancer cells, liver cancer cells, head and neck cancer cells, esophageal cancer cells, Hodgkin lymphoma cells, non-Hodgkin lymphoma cells, mesothelioma cells, neuroblastoma cells, neuroendocrine tumor cells, neurofibromatosis type 1 (NF1) cells, neurofibromatosis type 2 (NF2) cells, or osteosarcoma cells.

[0328] In some embodiments, the reactive moiety and / or targeting agent further comprises a linking moiety. In some embodiments, the linking moiety binds to the reactive moiety and / or targeting agent and the linker to couple the reactive moiety and / or targeting agent to the linker. In some embodiments, the linking moiety is selected from -[CH2] 0-12 , -[CH2CH2O] 0-50 -, and -[CH2] 0-12 -C(O)NH- and comprises one or more groups selected therefrom.

[0329] In some embodiments, the linker has the formula: R*-L1-L A - wherein L A is the linker, L1 is the linking moiety, and R* is the reactive moiety or targeting agent. In some embodiments, the linker L A is complexed with the drug moiety.

[0330] In some embodiments, the linker L A has the formula: -[CH2CH2O] p -X AA - wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, the linker L A further comprises

Chemical formula

[0331] In some embodiments, the linker L A has the formula: -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA - wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, the linker L A further comprises [Chem.] further comprises.

[0332] In some embodiments, linker L A is of the formula: -[CH2CH2O] p -(CH2) 1-3 -C(O)-X AA - comprises or consists of, wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, linker L A is [Chem.] further comprises.

[0333] In some embodiments, linker L A is of the formula: -[CH2CH2O] p -(CH2)2-C(O)-X AA - comprises or consists of, wherein X AA is an amino acid sequence and p is an integer from 0 to 50. In some embodiments, linker L A is [Chem.] further comprises.

[0334] In some embodiments, R* is a reactive moiety. In some embodiments, the reactive moiety is maleimide. In some embodiments, the reactive moiety is bisulfone.

[0335] In some embodiments, L1 is selected from one or more groups including -[CH2] 0-12 , -[CH2CH2O] 0-50 -, and -[CH2] 0-12 -C(O)NH-. In some embodiments, L1 is -[CH2]0-12 -C(O)NH-. In some embodiments, L1 is -[CH2]2-C(O)NH-. In some embodiments, it is -[CH2]5-C(O)NH-.

[0336] In some embodiments, L1 is -[CH2] 1-3 -C(O)NH-.

[0337] In some embodiments, L1 further comprises a binding moiety resulting from the reaction of a reactive moiety in the targeting agent with a functional group such as aldehyde, amine, disulfide, ketone, thiol, or the Staudinger reaction, Pictet-Spengler reaction, and / or click chemistry reaction of the targeting agent. In some embodiments, L1 further comprises a binding moiety selected from triazole, amide, thioether, and succinimide.

[0338] In some embodiments, L1 is succinimide (i.e., succinimidyl moiety, "2,5-dioxo-3λ 3 -pyrrolidin-1-yl"):

Chemical formula

[0339] In some embodiments, L1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0340] In some embodiments, R* is a reactive moiety that has reacted with a functional group such as an aldehyde, amine, disulfide, ketone, thiol, etc. in a targeting agent (e.g., Ab of formula (I)), or has reacted in a Staudinger reaction, Pictet-Spengler reaction, and / or click chemistry reaction of a targeting agent (e.g., Ab of formula (I)). In some embodiments, R* is selected from succinimide, triazole, amide, and thioether.

[0341] In some embodiments, L is a linker of the formula -R * -L1-L A Non-limiting examples include that R* reacts with a functional group of a targeting agent (e.g., with a cysteine moiety of an antibody or antibody fragment such as formula (I)). In some embodiments, R* is selected from succinimide, triazole, amide, and thioether.

[0342] In some embodiments, R* is succinimide (i.e., succinimidyl moiety, "2,5-dioxo-3λ 3 -pyrrolidin-1-yl").

Chemical formula

[0343] In some embodiments, R* is

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

[0344] In some embodiments, the linker is of the formula:

Chem.

[0345] In some embodiments, the linker is of the formula:

Chem.

[0346] In some embodiments, the linker is of the formula:

Chem.

[0347] In some embodiments, the linker is of the formula:

Chem.

[0348] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0349] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0350] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0351] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0352] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0353] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0354] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0355] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0356] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0357] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0358] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0359] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0360] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0361] In some embodiments, the linker has the formula: [Chemical formula] and comprises or consists of.

[0362] In some embodiments, the linker has the formula:

Chemical formula

[0363] In some embodiments, R* is a targeting factor. In some embodiments, the targeting factor is an antibody or an antibody fragment. In some embodiments, the targeting factor is an antibody.

[0364] Compound In one aspect, the present disclosure provides a compound comprising one or more linkers and one or more drug moieties. In some embodiments, the antibody-drug conjugate of the present disclosure (e.g., of formula (I)) comprises a compound of formula (III).

[0365] In some embodiments, the compound is a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D comprises a drug moiety.

[0366] In some embodiments, the linker L of formula (III) reacts with a target moiety to form a covalent bond with a targeting moiety, and reacts with a target moiety (e.g., an antibody or an antibody-binding fragment, including but not limited to Ab of formula (III)). In a non-limiting example, the linker L of formula (III) comprises a reactive group R* that reacts with an antibody or antibody fragment Ab to provide a conjugate of formula (I), and the linker L of formula (I) is a linker of formula (III) that comprises the product of the reaction of R* with the targeting moiety (e.g., R* is maleimide in formula (III) and succinimide in formula (I), or otherwise L is equivalent in each of formula (I) and formula (III)).

[0367] In some embodiments, the antibody is any antibody or antibody fragment disclosed herein. In some embodiments, the antibody or antibody fragment is an anti-CDCP1 antibody.

[0368] In some embodiments, the drug moiety D is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridobenzodiazepine (PDD). In some embodiments, exatecan has the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0369] In some embodiments, the compound has the formula:

Chemical formula

[0370] In some embodiments, the compound has the formula:

Chemical formula

[0371] In some embodiments, the linker has the formula:

Chemical formula

[0372] In some embodiments, the linker has the formula:

Chemical formula

[0373] In some embodiments, the linker has the formula:

Chemical formula

[0374] In some embodiments, the linker has the formula:

Chemical formula

[0375] In some embodiments, the linker has the formula:

Chemical formula

[0376] In some embodiments, the linker has the formula:

Chemical formula

[0377] In some embodiments, the linker has the formula:

Chemical formula

[0378] In some embodiments, the linker has the formula:

Chemical formula

[0379] In some embodiments, L-D has the formula:

Chemical formula

[0380] In some embodiments, L-D has the formula:

Chemical formula

[0381] In some embodiments, L-D has the formula:

Chemical formula

[0382] In some embodiments, L-D has the formula:

Chemical formula

[0383] In some embodiments, L-D has the formula:

Chemical formula

[0384] In some embodiments, L-D has the formula:

Chemical formula

[0385] In some embodiments, L-D has the formula:

Chemical formula

[0386] In some embodiments, L-D has the formula:

Chemical formula

[0387] In some embodiments, L-D has the formula:

Chemical formula

[0388] In some embodiments, L-D has the formula:

Chemical formula

[0389] In some embodiments, the compound is a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker of the formula R*-L1-L A -, R* is maleimide, L1 is -[CH2] 1-3 -C(O)NH-, L A is -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA -, optionally, -[CH2CH2O] p -(CH2) 1-3 -C(O)-X AA -, optionally, -[CH2CH2O] p -(CH2)2-C(O)-X AA -, where p is an integer from 5 to 10, and X AA is an amino acid sequence having two amino acid moieties, D is [Chemistry] and is Dxd, or Sn-38.

[0390] In some embodiments, the compound is a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker of the formula R*-L1-L A - R* is maleimide, L1 is -[CH2] 1-3 -C(O)NH-. L A is -[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA -, optionally, -[CH2CH2O] p -(CH2) 1-3 -C(O)-X AA -, optionally, -[CH2CH2O] p -(CH2)2-C(O)-X AA -, where p is an integer from 5 to 10, and X AA is an amino acid sequence having two amino acid moieties, D is [Chemistry] [Chemistry] [Chemistry] [Chemistry] is selected from

[0391] In some embodiments, X AAis selected from Val-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gln, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Val-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.

[0392] In some embodiments, X AA is Val-Ala.

[0393] In some embodiments, the compound is a compound of formula (III-A), or a salt, solvate, tautomer, isomer, or mixture thereof, R*-L1-[CH2CH2O] p -(CH2) 1-5 -C(O)-X AA 1 -X AA 2 -D Formula (III-A) In formula (III-A), R* is

Chemical formula

[0394] In some embodiments, formula (III-A) has the formula -[CH2CH2O] p -(CH2) 1-3. -C(O)-X AA -. In some embodiments, formula (III-A) has the formula -[CH2CH2O] p -(CH2)2-C(O)-XAA - has.

[0395] In some embodiments, X AA 1 is selected from Val, Tyr, Phe, Leu, Met, Thr, Ala, D-Val, and D-Ala. In some embodiments, X AA 1 is Val.

[0396] In some embodiments, X AA 2 is selected from Ala, Arg, Gln, Cit, Met, Thr, Asn, D-Gln, and D-Ala. In some embodiments, X AA 2 is Ala.

[0397] In some embodiments, -X AA 1 -X AA 2 - is selected from Val-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gln, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Val-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.

[0398] In some embodiments, -X AA 1 -X AA 2 - is Val-Ala.

[0399] In some embodiments, the compound of formula (III) or the compound of formula (III-A) is selected from any one of the compounds of formula 30 or 3031 to 3064, or a salt, solvate, tautomer, isomer, or mixture thereof:

Chemical formula

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

[0400] In some embodiments, the compound of formula (III) or the compound of formula (III-A) is selected from any one of the compounds of formula 30 or 3100 - 3118, or a salt, solvate, tautomer, isomer, or mixture thereof:

Chemical formula

Chemical formula

Table 6

[0401] In one embodiment (CI), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - and in the formula, LA is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. Linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - wherein, Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or contains this, and optionally, the bisulfone is

Chemical formula

Chemical formula

[0402] In one embodiment (CI), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - having, wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2) 1-3 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or contains this, and optionally, the bisulfone is

Chemical formula

Chemical formula

[0403] In one embodiment (CIb), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - has, in which L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. Linker L A is of the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - and has, in which Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or contains this, and optionally, the bisulfone is

Chemical formula

Chemical formula

[0404] In one embodiment (CII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker is of the following formula: R*-L1-L A - having, wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A is of the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - having, wherein Alk represents C2-C-4 alkylene, X AA is a dipeptide, and p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0405] In one embodiment (CIIa), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof. L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2) 1-3 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or contains this, and optionally, the bisulfone is

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0406] In one embodiment (CIIb), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbohydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or contains this, and optionally, the bisulfone is

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

[0407] In one embodiment (CIII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein, X AA is a nonpolar dipeptide, p is an integer from 5 to 10, such as 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semicarbazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is

Chem.

Chem.

[0408] In formula (III), L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is maleimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridobenzodiazepine (PDD) having the formula:

Chem.

[0409] In one embodiment (CV), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein X AA is a nonpolar dipeptide, p is an integer from 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is maleimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0410] In one embodiment (CVI), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker has the following formula: R*-L1-L A - having, wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A is of the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - having, wherein Alk represents C2-C4-alkylene, X AA is Val-Ala, and p is 7 or 8. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is

Chemical formula

Chemical formula

[0411] In one embodiment (CVII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D [[ID=S3]]Formula (III) In formula (III), L is a linker, and D includes a drug moiety. The linker is of the following formula: R*-L1-LA - having, wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. Linker L A is of the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - having, wherein X AA is Val-Ala, p is 7 or 8. R* is a reactive moiety selected from azide, alkyne, bisulfone, carbohydrazide, hydroxylamine, iodoacetamide, isothiocyanate, maleimide, phosphine, semihydrazide, succinimidyl ester, and sulfonyl halide. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is

Chemical formula

Chemical formula

[0412] In one embodiment (CVIII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) In formula (III), L is a linker, D contains a drug moiety. The linker is of the following formula: R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or targeting agent. Linker L A is the expression: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk denotes C2-C4-alkylene, X AA is Val-Ala, p is 7 or 8. R* is maleimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety has the formula: [ka] exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridinobenzodiazepine (PDD).

[0413] In one embodiment (CIX), the disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof: LD Formula (III) In formula (III), L is a linker, D comprises a drug moiety. The linker has the following formula: R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or targeting agent. Linker L A is the expression: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein XAA is Val - Ala, p is 7 or 8. R* is maleimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety is of the formula:

Chemical formula

[0414] In one embodiment (CX), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L - D Formula (III) as defined in any one of embodiments (CI) - (CX), and the index p is 8.

[0415] In one embodiment (CXI), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L - D Formula (III) as defined in any one of embodiments (CI) - (CX), and L1 is -[CH2]2 - C(O)NH-.

[0416] In one embodiment (CXII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L - D Formula (III) as defined in any one of embodiments (CI) - (CXI), and the drug moiety is of the formula:

Chemical formula

[0417] In one embodiment (XIII), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) is as defined in any one of embodiments (CI) to (CXII), and the drug moiety is of the formula:

Chemical formula

[0418] In one embodiment (XIV), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) is as defined in any one of embodiments (CI) to (CXIII), and the drug moiety is of the formula:

Chemical formula

[0419] In one embodiment (CXV), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) is as defined in any one of embodiments (CI) to (CXIV), and X AA is not Val-Cit or Phe-Lys.

[0420] In one embodiment (CXVI), the present disclosure provides a compound of formula (III), or a salt, solvate, tautomer, isomer, or mixture thereof, L-D Formula (III) wherein the moiety L-D has the following structure

Chemical formula

[0421] In one aspect, the present disclosure provides a complex of formula (II), Ab-L- Formula (II) wherein Ab is an antibody or an antibody fragment, and L is a linker.

[0422] Any antibody, antibody fragment, and / or linker disclosed herein is contemplated within formula (II). In some embodiments, the linker comprises and / or consists of a substructure that is further complexed with a drug moiety. In some embodiments, the linker comprises and / or consists of a complete structure that can be further complexed with a drug moiety.

[0423] In some embodiments, the linker has the formula:

Chemical formula

[0424] In some embodiments, the linker has the formula:

Chemical formula

[0425] In some embodiments, the linker has the formula:

Chemical formula

[0426] In some embodiments, the linker has the formula:

Chemical formula

[0427] In some embodiments, the linker has the formula:

Chemical formula

[0428] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0429] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0430] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0431] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0432] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0433] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0434] In some embodiments, the linker has the formula: [Chemical formula] comprises or consists of.

[0435] In some embodiments, the linker has the formula:

Chemical formula

[0436] In some embodiments, the antibody or binding fragment thereof Ab specifically binds to CUB domain-containing protein 1 (CDCP1).

[0437] In some embodiments, the antibody or binding fragment thereof Ab (i) (a) a CDRH1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a CDRH2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising one or more of CDRH3s comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and / or (ii) (a) a CDRL1 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a CDRL2 comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising one or more of CDRL3s comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8.

[0438] In some embodiments, the antibody or binding fragment thereof Ab comprises a VH comprising and / or consisting of the amino acid sequence of SEQ ID NO: 1, and / or a VL comprising and / or consisting of the amino acid sequence of SEQ ID NO: 5.

[0439] In some embodiments, the antibody or binding fragment thereof Ab comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and / or a light chain comprising the amino acid sequence of SEQ ID NO: 5. Antibody-drug conjugate

[0440] In one aspect, the present disclosure provides an antibody-drug conjugate comprising one or more linkers and one or more drug moieties. In some embodiments, the antibody-drug conjugate comprises an antibody, an antibody fragment, a linker, and / or a drug moiety described herein (e.g., of formula (II) and / or formula (III)). In some embodiments, the antibody and / or antibody fragment is conjugated to the linker-drug moiety via a sulfur-containing moiety (e.g., thiol) on the antibody and / or antibody fragment. In some embodiments, the sulfur-containing moiety comprises and / or consists of the sulfur moieties of one or more interchain disulfide bridges of the antibody and / or antibody fragment. In a non-limiting example, the interchain disulfide bridge that holds together the arms of an antibody (e.g., mAb) and / or antibody fragment is broken using a reducing agent, and the linker and / or payload is conjugated to the sulfur moiety of the disulfide bridge. In a non-limiting example, all available thiols from the interchain disulfide account for a loading (DAR) of 8 since there are four interchain disulfides in an antibody (e.g., mAb). In some embodiments, the antibody and / or antibody fragment is conjugated to the linker-drug moiety via one or more amino acid residues on the antibody and / or antibody fragment including, but not limited to, amino acid residues containing sulfur-containing side chains (e.g., cysteine and / or methionine). In some embodiments, the antibody and / or antibody fragment is conjugated to the linker-drug moiety via one or more cysteine residues on the antibody and / or antibody fragment. In some embodiments, the antibody and / or antibody fragment is conjugated to the linker-drug moiety via one or more cysteine residues on the antibody. In some embodiments, the amino acid residues are unengineered (e.g., unengineered cysteine and / or unengineered methionine residues). In some embodiments, the amino acid residues are engineered (e.g., engineered cysteine and / or engineered methionine residues). In some embodiments, the linker is selected from any of the linkers described herein. In some embodiments, the drug moiety is selected from any of the drug moieties described herein.

[0441] In one aspect, the present disclosure provides an antibody-drug conjugate (ADC) having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, L is a linker, D comprises a drug moiety, n is an integer from 1 to 20.

[0442] Any antibody, antibody fragment, linker, and / or drug moiety disclosed herein is contemplated within formula (III).

[0443] In some embodiments, the linker L of formula (I) is a linker of formula (III) that has reacted with an antibody or a binding fragment thereof Ab (e.g., the linker comprises a reactive group R* that reacts with an antibody or antibody fragment Ab).

[0444] In some embodiments, the linker has the formula:

Chemical formula

[0445] In some embodiments, the linker has the formula:

Chemical formula

[0446] In some embodiments, the linker has the formula:

Chemical formula

[0447] In some embodiments, the linker has the formula:

Chemical formula

[0448] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0449] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0450] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0451] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0452] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0453] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0454] In some embodiments, the linker has the formula: [ka] It comprises or consists of:

[0455] In some embodiments, the linker comprises or consists of valine-citrulline.

[0456] In some embodiments, the drug moiety D is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridobenzodiazepine (PDD). In some embodiments, exatecan has the formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0457] In some embodiments, L-D has the formula:

Chemical formula

[0458] In some embodiments, L-D has the formula:

Chemical formula

[0459] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0460] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0461] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0462] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0463] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0464] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0465] In some embodiments, L-D has the formula: [Chemical Formula] and has.

[0466] In some embodiments, L-D has the formula: [Chemical Formula] has.

[0467] In some embodiments, L-D has the formula:

Chemical formula

[0468] In some embodiments, L-D has the formula:

Chemical formula

[0469] In some embodiments, L-D has the formula -val-cit-MMAE.

[0470] In some embodiments, L-D has the formula -val-cit.PAB-MMAE.

[0471] In some embodiments, the antibody-drug conjugate is of formula (I-A), Ab-[L1-(CH2CH2O) p -X AA 1 -X AA 2 -D] n Formula (I-A) In formula (I-A), Ab contains an antibody or an antibody binding fragment, L1 is

Chemical formula

[0472] In some embodiments, the complex of formula (I) or the complex of formula (I-A) is selected from any one of the complexes of formulas 1030 to 1064:

Chemical formula

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

[0473] In some embodiments, the complex of formula (I) or the complex of formula (I-A) is selected from any one of the complexes of formula 1030 or 1100 to 1118:

Chemical formula

Chemical formula

Table 8

[0474] In some embodiments, n is an integer from 1 to 10. In some embodiments, n is an integer from 4 to 8. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0475] In one embodiment (I), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridinobenzodiazepine (PDD) having the formula:

Chem.

[0476] In one embodiment (I), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2) 1-3 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chem.

[0477] In one embodiment (Ib), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - having, wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - having, wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0478] In one embodiment (Ic), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0479] In one embodiment, the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2) 1-3 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0480] In one embodiment (Ie), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody-binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0481] In one embodiment (II), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody-binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. Ab is an antibody or a binding fragment thereof that specifically binds to CUB domain-containing protein 1 (CDCP1). The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is [Chemistry] or includes this. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula: [Chemical formula] It is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridobenzodiazepine (PDD) having

[0482] In one embodiment (IIa), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody-binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. Ab is an antibody or a binding fragment thereof that specifically binds to CUB domain-containing protein 1 (CDCP1). The linker has the following formula: -R*-L1-L A - having, wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - having, wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is [Chemical formula] or includes this. L1 is, -[CH2] 0-12 -C(O)NH-. The drug moiety is

Chem.

Chem.

Chem.

Chem.

Chem.

[0483] In one embodiment (IIb), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. Ab is an antibody or a binding fragment thereof that specifically binds to CUB domain-containing protein 1 (CDCP1). The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2) 1-5 -C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. Further, R* is optionally a bisulfone or includes this, and optionally, the bisulfone is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0484] In one embodiment (III), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment is (i) (a) The VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) The VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) A heavy chain variable region (VH) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4 and / or comprising a VH complementarity determining region 3 (CDRH3), (ii) (a) A light chain variable region (VL) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6 and / or comprising a VL complementarity determining region 1 (CDRL1), (b) A VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is the linker, L1 is the binding moiety, and R* is the reactive moiety or targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0485] In one embodiment (IV), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D]n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising and / or consisting of a VH complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising and / or consisting of a VL complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting factor. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is of the formula:

Chemical formula

[0486] In one embodiment (V), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment Ab comprises a VH comprising and / or consisting of the amino acid sequence of SEQ ID NO: 1, and / or a VL comprising and / or consisting of the amino acid sequence of SEQ ID NO: 5. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety is of the formula:

Chemical formula

[0487] In one embodiment (VI), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment Ab comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 5. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA -[[]END]] wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is, -[CH2] 0-12 -C(O)NH-. The drug moiety is of the formula:

Chem.

[0488] In one embodiment (VII), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein X AA is a nonpolar dipeptide, p is an integer from 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is, -[CH2] 0-12 -C(O)NH-. The drug moiety is of the formula:

Chem.

[0489] In one embodiment (VIII), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. Ab is an antibody or a binding fragment thereof that specifically binds to CUB domain-containing protein 1 (CDCP1). The linker has the following formula: -R*-L1-L A - having, wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting factor. Linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - having, wherein X AA is a non-polar dipeptide, p is an integer from 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0490] In one embodiment (IX), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein X AAis a non-polar dipeptide, p is an integer of 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula: [ka] exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridinobenzodiazepine (PDD).

[0491] In one embodiment (X), the present disclosure provides an antibody-drug conjugate having formula (I): Ab-[LD] n Formula (I) In formula (I), Ab is an antibody or antibody-binding fragment; L is a linker, D is a drug moiety; n is an integer of 1 to 20. The antibody or binding fragment thereof may be (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12; (b) a VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13; and (c) a heavy chain variable region (VH) comprising a VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14; (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6; (b) a VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7; and It comprises a variable light chain region (VL) comprising and / or consisting of a VL complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or a targeting agent. Linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein X AA is a non-polar dipeptide, and p is an integer from 5 to 10, such as 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0492] In one embodiment (XI), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, and n is an integer from 1 to 20. The antibody or its binding fragment Ab comprises a VH comprising and / or consisting of the amino acid sequence of SEQ ID NO: 1, and / or a VL comprising and / or consisting of the amino acid sequence of SEQ ID NO: 5. The linker has the following formula: -R*-L1-L A - wherein, L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein, X AA is a non-polar dipeptide, p is an integer from 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0493] In one embodiment (XII), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment Ab comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 1 and / or a light chain containing the amino acid sequence of SEQ ID NO: 5. The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a binding moiety, and R* is a reactive moiety or a targeting agent. The linker L A has the formula: -[CH2-CH2-O] p -(CH2)2-C(O)-X AA - wherein X AA is a non-polar dipeptide, p is an integer from 5 to 10, for example, 5, 6, 7, 8, 9, or 10. R* is a reactive moiety selected from succinimide, triazole, amide, and thioether. L1 is -[CH2] 0-12 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0494] In one embodiment (XIII), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, and n is an integer from 1 to 20. The linker has the following formula: -R*-L1-L A - wherein LA is a linker, L1 is a linking moiety, and R* is a reactive moiety or targeting agent. Linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein, Alk represents C2-C4-alkylene, X AA is a dipeptide, and p is an integer from 0 to 50. R* is succinimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety is selected from exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridobenzodiazepine (PDD) having the formula:

Chemical formula

[0495] In one embodiment (XIV), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is a linker, D is a drug moiety, and n is an integer from 1 to 20. Ab is an antibody or a binding fragment thereof that specifically binds to CUB domain-containing protein 1 (CDCP1). The linker has the following formula: -R*-L1-L A - wherein L A is a linker, L1 is a linking moiety, and R* is a reactive moiety or targeting agent. Linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk denotes C2-C4-alkylene, X AA is a dipeptide, p is an integer of 0 to 50. R* is succinimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety has the formula: [ka] exatecan, Dxd, Sn-38, monomethyl auristatin E (MMAE), and pyridinobenzodiazepine (PDD).

[0496] In one embodiment (XV), the present disclosure provides an antibody-drug conjugate having formula (I): Ab-[LD] n Formula (I) In formula (I), Ab is an antibody or antibody-binding fragment; L is a linker, D is a drug moiety; n is an integer of 1 to 20. The antibody or binding fragment thereof may be (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2; (b) a VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3; and (c) a heavy chain variable region (VH) comprising a VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4; (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6; (b) A VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A light chain variable region (VL) comprising and / or consisting of a VL complementarity-determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is the linker, L1 is the linking moiety, and R* is the reactive moiety or targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is succinimide. L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0497] In one embodiment (XVI), the present disclosure provides an antibody-drug conjugate having the formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or an antibody binding fragment, L is the linker, D is the drug moiety, n is an integer from 1 to 20. The antibody or its binding fragment is (i) (a) A VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) A VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) A heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) A VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) A VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8. The linker has the following formula: -R*-L1-L A - wherein L A is the linker, L1 is the linking moiety, and R* is the reactive moiety or targeting agent. The linker L A has the formula: -[Alk-O] p -(CH2)2-C(O)-X AA - wherein Alk represents C2-C4-alkylene, X AA is a dipeptide, p is an integer from 0 to 50. R* is succinimide, L1 is -[CH2] 1-3 -C(O)NH-. The drug moiety has the formula:

Chemical formula

[0498] In one embodiment (XVII), the present disclosure provides an antibody-drug conjugate having formula (I), Ab-[L-D] n Formula (I) In formula (I), Ab is an antibody or...

Claims

1. An antibody-drug conjugate having formula (I): Ab−[L−D] ｎ Formula (I) In formula (I): Ab comprises an antibody or a binding fragment thereof, and the antibody or the binding fragment thereof specifically binds to cub domain-containing protein-1 (CDCP1); L is a linker of the formula -R ＊ -L １ -L Ａ -, and R ＊ is succinimide, L １ is -[CH ２ １－３ -C(O)NH- and​ L Ａ is -[CH ２ CH ２ O] ｐ -(CH ２ ) １－５ -C(O)-X ＡＡ -, p is an integer from 5 to 10, and X ＡＡ is an amino acid sequence having two amino acid moieties, D is 【Chemical Formula 1-1】 【Chemical Formula 1-2】 【Chemical Formula 1-3】 【Chemical Formula 1-4】 An antibody-drug conjugate selected from

2. L １ is 【Chemical 2】 The antibody-drug conjugate according to claim 1, wherein

3. In the antibody-drug conjugate according to claim 1 or 2, p is 7 or 8.

4. In the antibody-drug conjugate according to any one of claims 1 to 3, p is 8.

5. X ＡＡ The antibody-drug conjugate according to any one of claims 1 to 4, wherein X is selected from Val-Ala, Tyr-Arg, Phe-Arg, Val-Gln, Val-Cit, Tyr-Met, Leu-Gln, Val-Arg, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, Val-Met, Leu-Met, Ala-Asn, D-Val-D-Gln, D-Ala-D-Ala, and Phe-Met.

6. X ＡＡ The antibody-drug conjugate according to any one of claims 1 to 5, wherein X is valine-alanine.

7. L Ａ is -[CH ２ CH ２ O] ｐ -(CH ２ ) １－３ -C(O)-X ＡＡ - and is the antibody-drug conjugate according to any one of claims 1 to 6.

8. L Ａ is -[CH ２ CH ２ O] ｐ -(CH ２ ) ２ -C(O)-X ＡＡ - and is an antibody-drug conjugate according to any one of claims 1 to 7.

9. The linker L has the formula: 【Chemical Formula 3】 The antibody-drug conjugate according to any one of claims 1 to 8, having

10. D is 【Chemical Formula 4】 The antibody-drug conjugate according to any one of claims 1 to 9, having

11. L-D has the formula: 【Chemical Formula 5】 The antibody-drug conjugate according to any one of claims 1 to 10, having

12. In the antibody-drug conjugate according to any one of claims 1 to 11, n is an integer from 4 to 8.

13. In the antibody-drug conjugate according to claim 12, n is 4.

14. In the antibody-drug conjugate according to claim 12, n is 8.

15. The antibody or the binding fragment thereof has (i) (a)A VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b)A VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c)A VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and a heavy chain variable region (VH), and (ii) (a)A VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b)A VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c)A VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, and a light chain variable region (VL). The antibody-drug conjugate according to any one of claims 1 to 14, comprising

16. The antibody or the binding fragment thereof has (i) (a)A VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising a VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementarity-determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity-determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, the antibody-drug conjugate according to any one of claims 1 to 14. **Claim 17** The antibody-drug conjugate according to any one of claims 1 to 16, wherein the antibody or a binding fragment thereof comprises a VH having an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, and / or a VL having an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

5. **Claim 18** The antibody-drug conjugate according to claim 17, wherein the antibody or a binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and / or a VL comprising the amino acid sequence of SEQ ID NO:

5. **Claim 19** The antibody-drug conjugate according to any one of claims 1 to 18, wherein the antibody or its binding fragment comprises a heavy chain having an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, and / or a light chain having an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

5.

20. The antibody-drug conjugate according to claim 19, wherein the antibody or its binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and / or a light chain comprising the amino acid sequence of SEQ ID NO:

5.

21. The antibody-drug conjugate according to any one of claims 1 to 20, wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) in the range of about 1 to about 10, optionally, the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally, the DAR is about 4, optionally, the DAR is about 8.

22. A pharmaceutical composition comprising the antibody-drug conjugate according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier.

23. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody-drug conjugate according to any one of claims 1 to 21 or the pharmaceutical composition according to claim 22.

24. The method according to claim 23, wherein less than about 50% of the antibody-drug conjugate is converted to a metabolite about 24 hours after administering the therapeutically effective amount of the antibody-drug conjugate to the subject.

25. The method according to claim 23 or 24, wherein about 50% of the antibody-drug conjugate is converted to a metabolite about 96 hours after administering the therapeutically effective amount of the antibody-drug conjugate to the subject.

26. The antibody-drug conjugate is of formula 300: 【Chemical Formula 6】 The method according to any one of claims 23 to 25, wherein the antibody-drug conjugate is converted to a metabolite of formula 300.

27. The antibody-drug conjugate is of formula 301: 【Chemical Formula 7】 The method according to any one of claims 23 to 26, wherein the antibody-drug conjugate is converted to a metabolite of formula 301.

28. The antibody-drug conjugate is converted into a metabolite of formula 302: 【Chemical Formula 8】 The method according to any one of claims 23 to 27, wherein the antibody-drug conjugate is converted into a metabolite. **Claim 29** The method according to any one of claims 23 to 28, wherein the antibody-drug conjugate is converted into a metabolite in vivo. **Claim 30** The method according to any one of claims 23 to 28, wherein the antibody-drug conjugate is converted into a metabolite in vitro. **Claim 31** The cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain tumor, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck tumor, breast tumor, ovarian tumor, lung tumor, small cell lung tumor, Wilms tumor, cervical tumor, testicular tumor, bladder tumor, pancreatic tumor, stomach tumor, colon tumor, prostate tumor, genitourinary tumor, thyroid tumor, esophageal tumor, myeloma, multiple myeloma, adrenal tumor, renal cell tumor, endometrial tumor, adrenal cortical tumor, malignant pancreatic insulinoma, malignant carcinoid tumor, choriocarcinoma, fungating polypoid tumor, malignant hypercalcemia, cervical hypertrophy, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, or retinoblastoma, etc., and the method according to any one of claims 23 to 30. In other embodiments, the cancer is acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, triple negative breast cancer (TNBC), bronchogenic lung carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, epithelioma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary thyroid carcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung carcinoma, pharyngeal cancer, uterine cancer, Wilms tumor, blood cancer, acute erythroleukemia, acute lymphoblastic B cell leukemia, acute lymphoblastic T cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

32. The method according to any one of claims 23 to 31, wherein the cancer is triple negative breast cancer (TNBC).

33. An antibody-drug conjugate having formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), D comprises a drug moiety, n is an integer from 1 to 20, L has the formula: 【Chemical Formula 9】 An antibody-drug conjugate.

34. The antibody or its binding fragment is (i) (a) A VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a VH complementary determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising a VH complementary determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a) a VL complementary determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementary determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementary determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, the antibody-drug conjugate according to claim 33. [

35. ] The antibody or a binding fragment thereof is (i) (a) a VH complementary determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementary determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising a VH complementary determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementary determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementary determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementary determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, the antibody-drug conjugate according to claim 33. [

36. ] The drug moiety is 【Chemical Formula 10-1】 【Chemical Formula 10-2】 【Chemical Formula 10-3】 【Chemical Formula 10-4】 The antibody-drug conjugate according to any one of claims 34 to 36, selected from [

37. ] The drug moiety is 【Chemical formula 11】 The antibody-drug conjugate according to any one of claims 33 to 36, selected from [

38. ] The antibody-drug conjugate has a drug-to-antibody ratio (DAR) in the range of about 1 to about 10, optionally, the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally, the DAR is about 4, optionally, the DAR is about 8, the antibody-drug conjugate according to any one of claims 33 to 37. [

39. ] An antibody-drug conjugate having formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is an integer from 1 to 20, L-D has the formula: 【Chemical 12】 An antibody-drug conjugate.

40. The antibody or its binding fragment is (i) (a)VH complementarity-determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b)VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c)A heavy chain variable region (VH) comprising VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a)VL complementarity-determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b)VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c)A light chain variable region (VL) comprising VL complementarity-determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, The antibody-drug conjugate according to claim 39.

41. The antibody or its binding fragment is (i) (a)VH complementarity-determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b)VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c)A heavy chain variable region (VH) comprising VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a)VL complementarity-determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b)VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c)A light chain variable region (VL) comprising VL complementarity-determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, The antibody-drug conjugate according to claim 40.

42. The antibody-drug conjugate has a drug-to-antibody ratio (DAR) in the range of about 1 to about 10, optionally, the DAR is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, optionally, the DAR is about 4, optionally, the DAR is about 8, the antibody-drug conjugate according to any one of claims 39 to 42.

43. n is an integer of 1 to 10, 2 to 8, or 4 to 8, optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, optionally, n is 4 or 8, optionally, n is 4, optionally, n is 8, the antibody-drug conjugate according to any one of claims 39 to 42.

44. An antibody-drug conjugate having any one of Formulas 1030 to 1064 or 1100 to 1118, wherein Ab comprises an antibody or an antibody-binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1).

45. The antibody-drug conjugate of any one of embodiments (I) to (XVII).

46. An antibody-drug conjugate having Formula (I), wherein Ab - [L - D] ｎ Formula (I) In Formula (I), Ab comprises an antibody or an antibody-binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 1, L-D has the formula: 【Chemical 13】 having, the antibody or its binding fragment is (i) (a) A VH complementarity-determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) A VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) A heavy chain variable region (VH) comprising a VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, (ii) (a) A VL complementarity-determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) A VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) A light chain variable region (VL) comprising a VL complementarity-determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, the antibody-drug conjugate comprising.

47. An antibody-drug conjugate having Formula (I), wherein Ab−[L−D] ｎ Formula (I) In Formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 4, L-D has the formula: 【Chemical 14】 having, the antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, an antibody-drug conjugate.

48. An antibody-drug conjugate having the formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 8, L-D has the formula: 【Chemical Formula 15】 having, the antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 2, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 3, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 4, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, an antibody-drug conjugate.

49. An antibody-drug conjugate having the formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 1, L-D has the formula: 【Chemical 16】 having, the antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, and an antibody-drug conjugate.

50. An antibody-drug conjugate having the formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 4, L-D has the formula: 【Chemical 17】 having, the antibody or its binding fragment is (i) (a) a VH complementarity determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a heavy chain variable region (VH) comprising a VH complementarity determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and (ii) (a) a VL complementarity determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a light chain variable region (VL) comprising a VL complementarity determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, and an antibody-drug conjugate.

51. An antibody-drug conjugate having the formula (I), Ab−[L−D] ｎ Formula (I) In formula (I), Ab comprises an antibody or an antibody binding fragment, and the antibody or its binding fragment specifically binds to CUB domain-containing protein-1 (CDCP1), n is 8, L-D has the formula: 【Chemical 18】 having,[[]] the antibody or its binding fragment is,[[]] (i)[[]] (a) a VH complementarity-determining region 1 (CDRH1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 12, (b) a VH complementarity-determining region 2 (CDRH2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 13, and (c) a VH complementarity-determining region 3 (CDRH3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 14, and a heavy chain variable region (VH), (ii)[[]] (a) a VL complementarity-determining region 1 (CDRL1) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 6, (b) a VL complementarity-determining region 2 (CDRL2) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 7, and (c) a VL complementarity-determining region 3 (CDRL3) comprising and / or consisting of the amino acid sequence of SEQ ID NO: 8, and a light chain variable region (VL), and an antibody-drug conjugate.[[]] [

52. ][[]] A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody-drug conjugate according to any one of claims 33 to 51.[[]]

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