MCL-1 inhibitor antibody-drug conjugates and methods of use

Abstract

Disclosed are antibody-drug conjugates that bind to human oncology targets. The antibody-drug conjugates comprise an Mcl-1 inhibitor drug moiety. The disclosure further relates to methods and compositions for use in treating cancer by administering the antibody-drug conjugates provided herein. Linker-drug conjugates comprising an Mcl-1 inhibitor drug moiety and methods for preparing the same are also disclosed.

Description

[Technical Field]

[0001] Related Applications This application claims benefit of and priority under 35 U.S.C. § 119(e) to the filing date of U.S. Provisional Patent Application No. 62 / 850,098, filed May 20, 2019, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to antibody-drug conjugates (ADCs) comprising an Mcl-1 inhibitor and an antibody or antigen-binding fragment thereof that binds an antigen target, e.g., an antigen expressed on tumor or other cancer cells. The present disclosure further relates to methods and compositions useful in the treatment and / or diagnosis of cancers that express the target antigen and / or that can be applied to treatment by modulating Mcl-1 expression and / or activity, and methods for preparing the compositions. Linker-drug conjugates comprising an Mcl-1 inhibitor drug moiety and methods for preparing the same are also disclosed. [Background technology]

[0003] Apoptosis, or programmed cell death, is a physiological process crucial for embryonic development and the maintenance of tissue homeostasis. Apoptotic cell death is generally accompanied by morphological changes such as nuclear condensation and DNA fragmentation, as well as biochemical changes such as the activation of caspases, which can damage key structural components of the cell. The regulation of apoptosis is complex and typically involves the activation or suppression of several intracellular signaling pathways (Cory et al. (2002) Nature Review Cancer 2:647-656).

[0004] Deregulation of apoptosis is associated with certain pathological conditions. For example, increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, and ischemia. Conversely, defects in apoptosis may play a role in the development of cancer, as well as chemotherapy resistance, autoimmune diseases, inflammatory diseases, and viral infections. Lack of apoptosis is one of the phenotypic characteristics of cancer (Hanahan et al. (2000) Cell 100:57-70). Anti-apoptotic proteins of the Bcl-2 family are associated with many types of cancer, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, and pancreatic cancer.

[0005] Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic Bcl-2 family member, is a regulator of cell survival. Amplification of the Mcl-1 gene and / or overexpression of the Mcl-1 protein has been observed in multiple cancer types and is associated with tumorigenesis (Beroukhim et al. (2010) Nature 463(7283):899-905). Mcl-1 is one of the most frequently amplified genes in human cancers and is also a critical survival factor that has been shown to mediate drug resistance to various anticancer drugs.

[0006] Mcl-1 is thought to promote cell survival by binding to pro-apoptotic proteins such as Bim, Noxa, Bak, and Bax and neutralizing their death-inducing activity. Inhibition of Mcl-1 releases these pro-apoptotic proteins and often induces apoptosis in tumor cells that depend on Mcl-1 for survival. Therefore, therapeutic targeting of Mcl-1 or its upstream and / or downstream proteins in the apoptotic signaling pathway may be a promising strategy for treating various malignancies and overcoming drug resistance in certain human cancers. Summary of the Invention

[0007] In some embodiments, the present disclosure provides, in part, novel antibody-drug conjugate (ADC) compounds that have biological activity against cancer cells. The compounds can slow, inhibit, and / or reverse tumor growth in mammals and / or may be useful in treating human cancer patients. More specifically, the present disclosure, in some embodiments, relates to ADC compounds that can bind and kill cancer cells. In some embodiments, the ADC compounds disclosed herein include a linker that connects the Mcl-1 inhibitor to a full-length antibody or antigen-binding fragment. In some embodiments, the ADC compounds can also be internalized into target cells after binding.

[0008] In some embodiments, the ADC compound has formula (1): Ab-(LD) p (1) (wherein Ab is an antibody or an antigen-binding fragment thereof; D is an Mcl-1 inhibitor, L is a linker covalently linking Ab to D; p is an integer from 1 to 16. In some embodiments, the Ab is an antibody or antigen-binding fragment thereof that targets cancer cells.

[0009] In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0010] In some embodiments, the linker (L) comprises a linking group, at least one spacer group, and at least one cleavable group. In some cases, the cleavable group comprises a pyrophosphate group and / or a self-immolative group. In certain embodiments, L comprises a linking group, at least one bridging spacer group, and at least one cleavable group comprising a pyrophosphate group and / or a self-immolative group.

[0011] In some embodiments, the antibody-drug conjugate has the formula (A):

[0012] [ka] (In the formula, R 1 is a linking group, L is a bridging spacer group, and E is a cleavable group).

[0013] In some embodiments, the cleavable group comprises a pyrophosphate group.

[0014] [ka] Includes.

[0015] In some embodiments, the crosslinking spacer group comprises a polyoxyethylene (PEG) group. In some cases, the PEG group may be selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some embodiments, the crosslinking spacer group may comprise -CO-CH2-CH2-PEG12-. In other embodiments, the crosslinking spacer group comprises a butanoyl, pentanoyl, hexanoyl, heptanoyl, or octanoyl group. In some embodiments, the crosslinking spacer group comprises a hexanoyl group.

[0016] In some embodiments, the linking group is formed from at least one reactive group selected from a maleimide group, a thiol group, a cyclooctyne group, and an azide group. For example, a maleimide group has the structure:

[0017] [ka] may have

[0018] The azide group has the structure: -N=N + =N - may have

[0019] The cyclooctyne group has the structure:

[0020] [ka] where

[0021] [ka] is the binding to the antibody.

[0022] In some cases, the cyclooctyne group has the structure:

[0023] [ka] where

[0024] [ka] is the binding to the antibody.

[0025] In some embodiments, the linking group is

[0026] [ka] and having a formula including:

[0027] [ka] is the binding to the antibody.

[0028] In some embodiments, the antibody

[0029] [ka] and is connected to the linker (L) by a linking group selected from where:

[0030] [ka] is the binding to the antibody, where

[0031] [ka] is the bond to the bridging spacer group.

[0032] In some embodiments, the bridging spacer group is linked to a cleavable group.

[0033] In some embodiments, the bridging spacer group is -CO-CH2-CH2-PEG12-.

[0034] In some embodiments, the cleavable group is -pyrophosphate-CH2-CH2-NH2-.

[0035] In some embodiments, the cleavable group is linked to the Mcl-1 inhibitor (D).

[0036] In some embodiments, the cleavable group is linked to the Mcl-1 inhibitor (D) group via a phenyl-pyrimidinyl group.

[0037] In some embodiments, the linker comprises a linking group, at least one bridging spacer group, a peptide group, and at least one cleavable group.

[0038] In some embodiments, the antibody-drug conjugate has formula (B):

[0039] [ka] (In the formula, R 1is a linking group, L1 is a bridging spacer, Lp is a peptide group comprising 1 to 6 amino acid residues, E is a cleavable group, L2 is a bridging spacer, m is 0 or 1, and D is an Mcl-1 inhibitor. In some cases, m is 1 and the bridging spacer is

[0040] [ka] Includes.

[0041] In some embodiments, at least one crosslinking spacer comprises a PEG group. In some cases, the PEG group is selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some cases, at least one crosslinking spacer is * -C(O)-CH2-CH2-PEG1- ** , * -C(O)-CH2-PEG3- ** , * -C(O)-CH2-CH2-PEG12 ** , * -NH-CH2-CH2-PEG1- ** , polyhydroxyalkyl groups, and * -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)- ** (In the formula, ** indicates the point of direct or indirect attachment of at least one bridge spacer to a linking group; * indicates the point of direct or indirect attachment of at least one cross-linking spacer to the peptide group).

[0042] In some embodiments, L1 is * -C(O)-CH2-CH2-PEG1- ** , * -C(O)-CH2-PEG3- ** , * -C(O)-CH2-CH2-PEG12** , * -NH-CH2-CH2-PEG1- ** and polyhydroxyalkyl groups, ** is R 1 indicates the direct or indirect point of attachment of L1 to * indicates the point of direct or indirect attachment of L1 to Lp).

[0043] In some embodiments, m is 1 and L2 is -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-.

[0044] In some embodiments, the peptide group comprises 1 to 12 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1 to 10 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1 to 8 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1 to 6 amino acid residues. In some embodiments, the peptide group comprises 1 to 4 amino acid residues. In some embodiments, the peptide group comprises 1 to 3 amino acid residues. In some embodiments, the peptide group comprises 1 to 2 amino acid residues. In some cases, the amino acid residue is selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). For example, the peptide group may include Val-Cit, Val-Ala, Val-Lys, and / or sulfo-Ala-Val-Ala. In some embodiments, the peptide group (Lp) is

[0045] [ka] In some embodiments, the peptide group (Lp) comprises one amino acid residue bound to a group:

[0046] [ka] Contains a group.

[0047] In some cases, the peptide group is

[0048] [ka] The group includes a group selected from:

[0049] In some embodiments, the self-immolative group comprises para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0050] In some embodiments, m is 1 and the bridging spacer is

[0051] [ka] Includes.

[0052] In some embodiments, the linker-drug moiety-(LD) is

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka] The compound is formed from a compound selected from:

[0057] In some embodiments, the antibody-drug conjugate comprises:

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka] and where:

[0063] [ka] comprises a linker-drug group-(LD), which is the bond to the antibody.

[0064] In some embodiments, the antibody-drug conjugate has formula (C):

[0065] [ka] (In the formula, R1 is a linking group, L1 is a bridging spacer, and L p is a peptide group containing 1 to 6 amino acids, D is an Mcl-1 inhibitor, G1-L2-A is a self-immolative spacer, L2 is a bond, methylene, neopentylene, or C2-C3 alkenylene, and A is a bond, -OC(=O)- * ,

[0066] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the bonding point with D, L3 is a spacer moiety, and R 2 is a hydrophilic moiety).

[0067] In some embodiments, the antibody-drug conjugate has formula (D):

[0068] [ka] (In the formula, R 1 is a linking group, L1 is a bridging spacer, Lp is a peptide group containing 1 to 6 amino acids, A is a bond, -OC(=O)- * ,

[0069] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-* where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the bonding point with D, L3 is a spacer moiety, and R 2 is a hydrophilic moiety).

[0070] In some embodiments, L1 is

[0071] [ka] or * -CH(OH)CH(OH)CH(OH)CH(OH)- ** wherein each n is an integer from 1 to 12, and wherein L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0072] In some embodiments, L1 is

[0073] [ka] and n is an integer from 1 to 12, where L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0074] In some embodiments, L1 is

[0075] [ka] and n is 1, where L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0076] In some embodiments, L1 is

[0077] [ka] and n is 12, where L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0078] In some embodiments, L1 is

[0079] [ka] and n is an integer from 1 to 12, where L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0080] In some embodiments, L1 is

[0081] [ka] where L1 * indicates the direct or indirect bond point with Lp, and ** is R 1 The point of direct or indirect attachment to the

[0082] In some embodiments, L1 is * -C(=O)(CH2) m O(CH2) m - ** ; * -C(=O)((CH2) m O) t (CH2) n - ** ; *-C(=O)(CH2) m - ** ; * -C(=O)NH((CH2) m O) t (CH2) n - ** ; * -C(=O)O(CH2) m SSC(R 3 )2(CH2) m C(=O)NR 3 (CH2) m NR 3 C(=O)(CH2) m - ** ; * -C(=O)O(CH2) m C(=O)NH(CH2) m - ** ; * -C(=O)(CH2) m NH(CH2) m - ** ; * -C(=O)(CH2) m NH(CH2) n C(=O)- ** ; * -C(=O)(CH2) m X1(CH2) m - ** ; * -C(=O)((CH2) m O) t (CH2) n X1(CH2) n - ** ; * -C(=O)(CH2) m NHC(=O)(CH2) n - ** ; * -C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n - ** ; * -C(=O)(CH2) mNHC(=O)(CH2) n X1(CH2) n - ** ; * -C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n - ** ; * -C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m - ** ; * -C(=O)(CH2) m C(R 3 )2- ** or * -C(=O)(CH2) m C(=O)NH(CH2) m - ** wherein L1 is a bridging spacer comprising * indicates the direct or indirect bond point with Lp, and ** is R 1 where X1 represents a point of direct or indirect attachment to

[0083] [ka] and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.

[0084] In some embodiments, R 2is polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, or 1 to 3

[0085] [ka] In some embodiments, R is a hydrophilic moiety comprising a C2-C6 alkyl substituted with a group. 2 teeth,

[0086] [ka] (wherein n is an integer between 1 and 6),

[0087] [ka] is.

[0088] In some embodiments, the hydrophilic moiety has the formula:

[0089] [ka] (Wherein, R is H, —CH, CHCHNHC(═O)OR a , -CH2CH2NHC(=O)R a or -CH2CH2C(=O)OR a and R' is OH, -OCH3, CH2CH2NHC(=O)OR a , -CH2CH2NHC(=O)R a or -OCH2CH2C(=O)OR a and m and n each are integers between 2 and 25 (eg, between 3 and 25).

[0090] In some embodiments, the hydrophilic moiety is

[0091] [ka] Includes.

[0092] In some embodiments, the hydrophilic moiety is a polysarcosine, e.g., the moiety

[0093] [ka] (wherein n is an integer between 3 and 25, and R is H, —CH 3 , or —CH 2 CH 2 C(═O)OH).

[0094] In some embodiments, L3 has the structure

[0095] [ka] (In the formula, W is -CH2-, -CH2O-, -CH2N(R b )C(=O)O-, -NHC(=O)C(R b )2NHC(=O)O-, -NHC(=O)C(R b )2NH-, -NHC(=O)C(R b )2NHC(=O)-, -CH2N(XR 2 )C(=O)O-, -C(=O)N(XR 2 )-, -CH2N(XR 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH2NR b C(=O)-, -CH2NR b C(=O)NH-, -CH2NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)NH-, -NHS(O)-, -C(=O)-, -C(=O)O- or -NH-, wherein each R b are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; X is a bond, triazolyl, or -CH2-triazolyl- is a spacer moiety having the following structure:

[0096] In some embodiments, L3 has the structure

[0097] [ka] (In the formula, W is -CH2-, -CH2O-, -CH2N(R b )C(=O)O-, -NHC(=O)C(R b )2NHC(=O)O-, -NHC(=O)C(R b )2NH-, -NHC(=O)C(R b )2NHC(=O)-, -CH2N(XR 2 )C(=O)O-, -C(=O)N(XR 2 )-, -CH2N(XR 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH2NR b C(=O)-, -CH2NR b C(=O)NH-, -CH2NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)NH-, -NHS(O)-, -C(=O)-, -C(=O)O- or -NH-, wherein each R b are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0098] X is -CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)NH-, -C 4-6 Cycloalkylene -OC(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-, -(CH2CH2O) n-C(O)NHS(O)2NH-(CH2CH2O) n -or -CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n where each n is independently 1, 2, or 3. is a spacer moiety having the following structure:

[0099] In some embodiments, the linking group is formed by a reaction involving at least one reactive group. In some cases, the linking group is formed by reacting a first reactive group that is attached to a linker with a second reactive group that is attached to an antibody or is an amino acid residue of an antibody.

[0100] In some embodiments, at least one of the reactive groups is thiols, Maleimide, haloacetamides, Azide, Alkynes, cyclooctene, triarylphosphines, oxanorbornadiene, cyclooctyne, diaryltetrazines, monoaryltetrazines, norbornene, aldehyde, hydroxylamine, hydrazine, NH2-NH-C(=O)-, ketones, vinyl sulfone, Aziridine, amino acid residues,

[0101] [ka] , -ONH2, -NH2,

[0102] [ka] , -N3,

[0103] [ka] , -SH, -SR 3 , -SSR 4 , -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NHC(=O)CH2Br, -NHC(=O)CH2I,

[0104] [ka] , -C(O)NHNH2,

[0105] [ka]

[0106] [ka] Including, where: Each R 3 are independently selected from H and C1-C6 alkyl; Each R 4 is 2-pyridyl or 4-pyridyl, Each R 5 are independently selected from H, C1-C6 alkyl, F, Cl, and —OH; Each R 6 are independently selected from H, C1-C6 alkyl, F, Cl, —NH2, —OCH3, —OCH2CH3, —N(CH3)2, —CN, —NO2, and —OH; Each R 7 is H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 C substituted with alkoxy and -C(=O)OH 1~4alkyl.

[0107] In some embodiments, the first reactive group and the second reactive group are thiols and maleimides, thiols and haloacetamides, thiols and vinyl sulfones, thiols and aziridines, Azides and alkynes, azide and cyclooctyne, azide and cyclooctene, azides and triarylphosphines, azides and oxanorbornadienes, diaryltetrazines and cyclooctene, monoaryltetrazines and norbornenes, aldehydes and hydroxylamines, aldehydes and hydrazines, Aldehydes and NH2-NH-C(=O)-, ketones and hydroxylamines, ketones and hydrazines, ketones and NH2-NH-C(=O)-, Hydroxylamine and

[0108] [ka] , amines and

[0109] [ka] ,or CoA or CoA analogue and serine residue Includes.

[0110] In some embodiments, the linking group is

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka] and where: R 32 is H, C 1~4 alkyl, phenyl, pyrimidine or pyridine; R 35 is H, C 1~6 C substituted with alkyl, phenyl, or 1 to 3 -OH groups 1~4 is alkyl, Each R 7 is H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 C substituted with alkoxy and -C(=O)OH 1~4 independently selected from alkyl, R 37 are independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 8 is H or methyl, R 9 is H, —CH3 or phenyl.

[0115] In some embodiments, the peptide group (Lp) comprises 1 to 6 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1 to 4 amino acid residues. In some embodiments, the peptide group comprises 1 to 3 amino acid residues. In some embodiments, the peptide group comprises 1 to 2 amino acid residues. In some embodiments, the amino acid residues are selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). In some embodiments, the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, sulfo-Ala-Val and / or sulfo-Ala-Val-Ala.

[0116] [ka] is selected from.

[0117] In some embodiments, the linker-drug group-(LD) has the formula:

[0118] [ka] (In the formula, R is H, -CH or -CHCHC(=O)OH; A is a bond, -OC(=O)- * ,

[0119] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a)2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0120] In some embodiments, the linker-drug group-(LD) has the formula:

[0121] [ka] (In the formula, R is H, -CH or -CHCHC(=O)OH; A is a bond, -OC(=O)- * ,

[0122] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0123] In some embodiments, the linker-drug group-(LD) has the formula:

[0124] [ka] (In the formula, R is H, -CH or -CHCHC(=O)OH; A is a bond, -OC(=O)- * ,

[0125] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0126] In some embodiments, the linker-drug group-(LD) has the formula:

[0127] [ka] (In the formula, each R is independently selected from H, —CH, and —CHCHC(═O)OH; A is a bond, -OC(=O)- * ,

[0128] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; *indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0129] In some embodiments, the linker-drug group-(LD) has the formula:

[0130] [ka] (In the formula, each R is independently selected from H, —CH, and —CHCHC(═O)OH; A is a bond, -OC(=O)- * ,

[0131] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0132] In some embodiments, the linker-drug group-(LD) has the formula:

[0133] [ka] (In the formula, Xa is -CH2-, -OCH2-, -NHCH2-, or -NRCH2-, and each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)- * ,

[0134] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0135] In some embodiments, the linker-drug group-(LD) has the formula:

[0136] [ka] (In the formula, R is H, -CH or -CHCHC(=O)OH; A is a bond, -OC(=O)- * ,

[0137] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0138] In some embodiments, the linker-drug group-(LD) has the formula:

[0139] [ka] (In the formula, Xb is -CH2-, -OCH2-, -NHCH2-, or -NRCH2-, and each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)- * ,

[0140] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0141] In some embodiments, the linker-drug group-(LD) has the formula:

[0142] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0143] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- *or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0144] In some embodiments, the linker-drug group-(LD) has the formula:

[0145] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0146] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0147] In some embodiments, the linker-drug group-(LD) has the formula:

[0148] [ka] (In the formula, A is a bond, -OC(=O)-* ,

[0149] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0150] In some embodiments, the linker-drug group-(LD) has the formula:

[0151] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0152] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0153] In some embodiments, the linker-drug group-(LD) has the formula:

[0154] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0155] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0156] In some embodiments, the linker-drug group-(LD) has the formula:

[0157] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0158] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R aare independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0159] In some embodiments, the linker-drug group-(LD) has the formula:

[0160] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0161] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * where each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0162] In some embodiments, the linker-drug group-(LD) has the formula:

[0163] [ka] (In the formula, each R is independently H, —CH, or —CHCHC(═O)OH; A is a bond, -OC(=O)- * ,

[0164] [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)- * or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)- * and Here, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; * indicates the point of attachment to D, D is an Mcl-1 inhibitor) The compound comprises or is formed from:

[0165] In some embodiments, A is a bond.

[0166] In some embodiments, R is —CH 3 .

[0167] In some embodiments, the Mcl-1 inhibitor (D) has the formula (I):

[0168] [ka] (In the formula, Ring D0 is a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; Ring E0 is a furyl, thienyl or pyrrolyl ring; X 01 , X 03 , X 04 and X 05 are each independently a carbon atom or a nitrogen atom, X 02 is CR 026 group or a nitrogen atom,

[0169] [ka] means that the ring is aromatic, Y0 is a nitrogen atom or CR 03 It is the basis, Z0 is a nitrogen atom or CR 04 It is the basis, R 01 is a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl group, a hydroxy group, a hydroxy(C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, -Cy 08 , -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ' or -SO2-(C1-C6)alkyl; R 02 , R 03 , R 04 and R 05 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a hydroxy(C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-R 031 , -O-(C1-C6)alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 01 , R 02 ), (R 02 , R 03 ), (R 03 , R 04 ) or (R 04 , R 05 ) together with the carbon atoms to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring may be substituted with halogen, linear or branched (C1-C6) alkyl, (C0-C6) alkyl-NR 011 R 011 ', -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 or oxo, R 06 and R 07are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-R 012 , -C(O)-OR 11 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 11 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ', or -SO2-(C1-C6) alkyl; Or pair (R 06 , R 07 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring can be optionally fused with a linear or branched (C1-C6) alkyl group, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 or optionally substituted with oxo, W0 is a -CH2- group, a -NH- group or an oxygen atom; R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, -CHR 0a R 0b a group, an aryl group, a heteroaryl group, an aryl(C1-C6)alkyl group, or a heteroaryl(C1-C6)alkyl group, R 09 is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 03 , halogen atoms, cyano groups, -C(O)-R 014 or -C(O)-NR 014 R 014 ' and R 010 is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, an aryl (C1-C6) alkyl group, a (C1-C6) cycloalkyl alkyl group, a linear or branched (C1-C6) haloalkyl group, or -(C1-C6) alkyl-O-Cy 04 and Or pair (R 09 , R 010 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N; R 011 and R 011' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the nitrogen may be substituted with one or two groups selected from a hydrogen atom and a linear or branched (C1-C6) alkyl group, wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated; R 012 -Cy 05 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C0-C6) alkyl-Cy 07 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 09 , -Cy 05 -(C0-C6) alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 09 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ', -OR 011 , -NR 011 -C(O)-R011 ', -O-(C1-C6) alkyl-OR 011 , -SO2-R 011 , and -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, R 0a is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 0b is -OC(O)-OR 0c group, -OC(O)-NR 0c R 0c ' group or -OP(O)(OR 0c )2 units, R 0c and R 0c ' are each independently a hydrogen atom, a linear or branched (C1-C8) alkyl group, a cycloalkyl group, a (C1-C6) alkoxy(C1-C6) alkyl group or a (C1-C6) alkoxycarbonyl(C1-C6) alkyl group, Or pair (R 0c , R 0c ') together with the nitrogen atom to which they are attached form a non-aromatic ring consisting of 5 to 7 ring members which, in addition to the nitrogen atom, may contain 1 to 3 heteroatoms selected from oxygen and nitrogen, wherein the nitrogen is optionally substituted with a linear or branched (C1-C6) alkyl group; Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 represent, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth

[0170] [ka] and or Cy 09 is -OP(O)(OR 020 )2;-OP(O)(O - M + )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C1-C6)alkyl;-(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R 021 ', and R 015 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; Linear or branched (C1-C6) alkoxy (C1-C6) alkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group, R 016 represents a hydrogen atom; a hydroxy group; a hydroxy(C1-C6) alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0-V0-OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + )2 groups;-OS(O)2OR 020 Group;-S(O)2OR 020 Group;-(CH2) p0 -O-(CHR018 -CHR 019 -O) q0 -R 020 Group;-(CH2) p0 -OC(O)-NR 022 R 023 group; or -U0-(CH2) q0 -NR 021 R 021 'Based on R 017 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group: -CH2-P(O)(OR 020 ) 2 units, -OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + )2 group; hydroxy group; hydroxy(C1-C6) alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or aldonic acid, M + is a pharmaceutically acceptable monovalent cation, U0 is a bond or an oxygen atom, V0 is -(CH2) s0 - group or -C(O)- group, R 018 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, R 019 is a hydrogen atom or a hydroxy(C1-C6)alkyl group, R 020 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 021 and R 021 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group, or a hydroxy(C1-C6) alkyl group, Or pair (R 021 , R021 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with hydrogen atoms or linear or branched (C1-C6) alkyl groups; R 022 represents a (C1-C6) alkoxy(C1-C6) alkyl group, -(CH2) p0 -NR 024 R 024 ' group or -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 It is the basis, R 023 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, Or pair (R 022 , R 023 ) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 18 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom, a linear or branched (C1-C6) alkyl group or a heterocycloalkyl group; R 024 and R 024 ' are each independently a hydrogen atom or a linear or branched (C1-C6) alkyl group, Or pair (R 024 , R 024 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with hydrogen atoms or linear or branched (C1-C6) alkyl groups; R 025 is a hydrogen atom, a hydroxy group, or a hydroxy(C1-C6)alkyl group, R026 is a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, or a cyano group, R 027 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 028 is -OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 030 ) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -O-SO2-O - Group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-OR 030 Group, -Cy 010 , -(CH2) p0 -SO2-OR 030 group, -OC(O)-R 029 The group -OC(O)-OR 029 group or -OC(O)-NR 029 R 029 'Based on R 029 and R 029 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched amino(C1-C6) alkyl group, R 030 and R 030 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or an aryl (C1-C6) alkyl group, R 031 teeth

[0171] [ka] wherein the ammonium cation optionally exists in zwitterionic form or has a monovalent anionic counterion; n0 is an integer equal to 0 or 1, p0 is an integer equal to 0, 1, 2, or 3; q0 is an integer equal to 1, 2, 3, or 4; r0 and s0 are independently integers equal to 0 or 1; Here, at most, R 03 Group, R 09 group or R 012 One of the groups, if present, is covalently attached to the linker, where the valency of the atom is not exceeded by the one or more substituents attached to it. or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0172] In some embodiments, Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is selected from the group consisting of halo; -(C1-C6)alkoxy; -(C1-C6)haloalkyl; -(C1-C6)haloalkoxy; -(CH2) p0 -O-SO2-OR 030 ; -(CH2) p0 -SO2-OR 030 ;-OP(O)(OR 020 )2;-OP(O)(O - M + )2;-CH2-P(O)(OR 020 )2; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C1-C6)alkyl; -(CH2) r0 -U0-(CH2) s0-heterocycloalkyl; or -U0-(CH2) q0 -NR 021 R 021 Optionally substituted with one or more groups selected from:

[0173] In some embodiments, D is a group represented by formula (II):

[0174] [ka] (In the formula, Z0 is a nitrogen atom or CR 04 It is the basis, R 01 is a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl group, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, -Cy 08 , -NR 011 R 011 ' and R 02 , R 03 and R 04 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R031 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 02 , R 03 ) or (R 03 , R 04 ) together with the carbon atoms to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is selected from linear or branched (C1-C6) alkyl, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 and oxo, R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-R 012, -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ', or -SO2-(C1-C6) alkyl; Or pair (R 06 , R 07 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring can be optionally fused with a linear or branched (C1-C6) alkyl group, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 and oxo, R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, an aryl group, a heteroaryl group, an aryl-(C1-C6) alkyl group or a heteroaryl-(C1-C6) alkyl group, R 09 is a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 03, halogen atoms, cyano groups, -C(O)-R 014 , -C(O)-NR 014 R 014 ' and R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom is optionally substituted with a linear or branched (C1-C6) alkyl group, and wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group is optionally deuterated; R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C0-C6) alkyl-Cy 07 , -Cy 05 -(C0-C6) alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ', -OR 011 , -NR 011 -C(O)-R 011 ', -O-(C1-C6) alkyl-OR 011 , -SO2-R 011 , or -C(O)-OR 011 represents R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group; Cy 01 , Cy 02 , Cy 03 , Cy 05 , Cy 06 , Cy 07 and Cy 08 are, independently of each other, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; Cy 09 teeth

[0175] [ka] and where R 015 , R 016 and R 017 is as defined for formula (I), R 031 teeth

[0176] [ka] where R 027 and R 028 is as defined for formula (I), Here, at most, R 03 Group, R 09 group or R 012 One of the groups, if present, is covalently attached to the linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0177] In some embodiments, D is a group of formula (III):

[0178] [ka] (In the formula, R 01 is a linear or branched (C1-C6) alkyl group, R 03 is -O-(C1-C6) alkyl-NR 011 R 011 'or

[0179] [ka] and where R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted with one or two groups selected from a hydrogen atom or a linear or branched (C1-C6) alkyl group; where R 027 is a hydrogen atom, and R 028 is -(CH2) p0 -O-SO2-O - group or -(CH2) p0 -SO2-OR 030 It is the basis, R 09 is a linear or branched (C2-C6) alkynyl group or -Cy 02 and R 012 -Cy 05 , -Cy 05-(C0-C6) alkyl-Cy 06 or -Cy 05 -(C0-C6) alkyl-Cy 09 and Cy 01 , Cy 02 , Cy 05 and Cy 06 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth

[0180] [ka] and R 015 , R 016 and R 017 is as defined for formula (I), Here, at most, R 03 Group, R 09 group or R 012 One of the groups, if present, is covalently attached to the linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0181] In some embodiments, Cy 01 , Cy 02 , Cy 05 , Cy 06 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is selected from the group consisting of halo; -(C1-C6)alkoxy; -(C1-C6)haloalkyl; -(C1-C6)haloalkoxy; -(CH2) p0 -O-SO2-OR 030 ;-(CH2) p0 -SO2-OR 030 ; -OP(O)(OR 020 )2;-OP(O)(O - M +)2;-CH2-P(O)(OR 020 )2; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C1-C6)alkyl; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; or -U0-(CH2) q0 -NR 021 R 021 Optionally substituted with one or more groups selected from:

[0182] In some embodiments, R 01 is methyl or ethyl.

[0183] In some embodiments, R 03 is -O-CH2-CH2-NR 011 R 011’ (In the formula, R 011 and R 011 ' together with the nitrogen atom that carries them form a piperazinyl group which may be substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group).

[0184] In some embodiments, R 03 is the expression:

[0185] [ka] (In the formula, R 027 is a hydrogen atom, and R 028 Ha-(CH2) p0 -O-SO2-OR 030 group, and p0 is an integer equal to 0, 1, 2, or 3, where R 030 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, or an aryl (C1-C6) alkyl group. Includes.

[0186] In some embodiments, R 03 is the expression:

[0187] [ka] (In the formula,

[0188] [ka] is the bond to the linker) Includes.

[0189] In some embodiments, Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are each independently an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the optional substituents are optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl group, optionally substituted linear or branched (C2-C6) alkynyl group, optionally substituted linear or branched (C1-C6) alkoxy, optionally substituted (C1-C6) alkyl-S-, hydroxyl ... and R is selected from oxy, oxo (or N-oxide, where appropriate), nitro, cyano, —C(O)—OR′, —OC(O)—R′, —C(O)—NR′R′, —NR′R′, —(C═NR′)—OR′, linear or branched (C1-C6) haloalkyl, trifluoromethoxy, or halogen, wherein R′ and R′ are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, and wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group is optionally deuterated.

[0190] In some embodiments, R 09 Cy 02 group, preferably an aryl group, more preferably a phenyl group. 02 is an optionally substituted aryl group.

[0191] In some embodiments, Cy 05 comprises a heteroaryl group selected from pyrazolyl and pyrimidinyl groups.

[0192] In some embodiments, Cy 05 is a pyrimidinyl group.

[0193] In some embodiments, Cy 05 is a pyrimidinyl group, and Cy 06 is a phenyl group.

[0194] In some embodiments, the linker (L) is a linker from L to R of formula (I), (II), or (III). 03 In some embodiments, the linker (L) is connected to D by a covalent bond from L to R of formula (I), (II), or (III). 09 is covalently bonded to D.

[0195] In some embodiments, D is

[0196] [ka]

[0197] [ka] or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0198] In some embodiments, -(LD) is formed from a compound selected from Table A or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or a pharmaceutically acceptable salt thereof. For the compounds in Table A, depending on their electronic charge, these compounds may be substituted with one pharmaceutically acceptable monovalent anionic counterion, M1. - In some embodiments, a monovalent anionic counterion M1 - may be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, or the like. In some embodiments, the monovalent anionic counterion M - is trifluoroacetic acid or formic acid.

[0199] [Table 1-1]

[0200] [Table 1-2]

[0201] [Table 1-3]

[0202] [Table 1-4]

[0203] [Table 1-5]

[0204] [Table 1-6]

[0205] [Table 1-7]

[0206]

Table 1-8

[0207]

Table 1-9

[0208]

Table 1-10

[0209]

Table 1-11

[0210]

Table 1-12

[0211]

Table 1-13

[0212]

Table 1-14

[0213]

Table 1-15

[0214]

Table 1-16

[0215]

Table 1-17

[0216]

Table 1-18

[0217]

Table 1-19

[0218]

Table 1-20

[0219]

Table 1-21

[0220]

Table 1-22

[0221]

Table 1-23

[0222]

Table 1-24

[0223]

Table 1-25

[0224]

Table 1-26

[0225]

Table 1-27

[0226]

Table 1-28

[0227]

Table 1-29

[0228]

Table 1-30

[0229]

Table 1-31

[0230]

Table 1-32

[0231]

Table 1-33

[0232]

Table 1-34

[0233]

Table 1-35

[0234]

Table 1-36

[0235]

Table 1-37

[0236] [Table 1-38]

[0237] [Table 1-39]

[0238] [Table 1-40]

[0239] [Table 1-41]

[0240] [Table 1-42]

[0241] [Table 1-43]

[0242] [Table 1-44]

[0243] [Table 1-45]

[0244] In some embodiments, the antibody-drug conjugate has a formula according to any one of the structures shown in Table 1a.

[0245] [Table 2-1]

[0246] [Table 2-2]

[0247]

Table 2-3

[0248]

Table 2-4

[0249]

Table 2-5

[0250]

Table 2-6

[0251]

Table 2-7

[0252]

Table 2-8

[0253]

Table 2-9

[0254]

Table 2-10

[0255]

Table 2-11

[0256]

Table 2-12

[0257] In some embodiments, the antibody-drug conjugate has a formula according to any one of the structures shown in Table 1b.

[0258] [Table 3-1]

[0259] [Table 3-2]

[0260] [Table 3-3]

[0261] [Table 3-4]

[0262] [Table 3-5]

[0263] [Table 3-6]

[0264] [Table 3-7]

[0265] [Table 3-8]

[0266] [Table 3-9]

[0267] [Table 3-10]

[0268] [Table 3-11]

[0269] [Table 3-12]

[0270] As used herein, "L / P" refers to a linker-payload, linker-drug, or linker-compound disclosed herein, and the terms "L#-P#" and "L#-C#" are used interchangeably to refer to a particular linker-drug disclosed herein, while the codes "P#" and "C#" are used interchangeably to refer to a particular compound unless otherwise specified. For example, "L1-C1" and "L1-P1" both refer to the same linker-payload structure disclosed herein, while "C1" and "P1" both refer to the same compound disclosed herein, including enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0271] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on a cancer cell, hi some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP In some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48.

[0272] In some embodiments, the antibody or antigen-binding fragment is an anti-BCMA antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3), and three light chain complementarity-determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at positions 152 and 375. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at positions 156 and 379. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0273] In some embodiments, the antibody or antigen-binding fragment is an anti-CD33 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:23 (HCDR3), and three light chain complementarity-determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:24 (LCDR1), SEQ ID NO:25 (LCDR2), and SEQ ID NO:26 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a glutamine residue (Q) at position 297. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0274] In some embodiments, the antibody or antigen-binding fragment is an anti-PCAD antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 33 (HCDR1), SEQ ID NO: 34 (HCDR2), and SEQ ID NO: 35 (HCDR3), and three light chain complementarity-determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 36 (LCDR1), SEQ ID NO: 37 (LCDR2), and SEQ ID NO: 38 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0275] In some embodiments, the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 39 (HCDR1), SEQ ID NO: 40 (HCDR2), and SEQ ID NO: 41 (HCDR3), and three light chain complementarity-determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 42 (LCDR1), SEQ ID NO: 43 (LCDR2), and SEQ ID NO: 44 (LCDR3). In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a glutamine residue (Q) at position 297. In some embodiments, the IgG1 heavy chain constant domain comprises a serine residue (S) at position 297. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0276] In some embodiments, the antibody or antigen-binding fragment is an anti-CD38 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-CD46 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-CD48 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-CD79b antibody or antigen-binding fragment.

[0277] Also provided herein, in some embodiments, are compositions comprising multiple copies of an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein). In some embodiments, the average p of the antibody-drug conjugates in the composition is about 2 to about 4.

[0278] Also provided herein, in some embodiments, is a pharmaceutical composition comprising an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein) or composition (e.g., any of the exemplary compositions described herein) and a pharmaceutically acceptable carrier.

[0279] Further provided herein, in some embodiments, are therapeutic uses for the described ADC compounds and compositions, e.g., in the treatment of cancer. In some embodiments, the present disclosure provides methods of treating cancer (e.g., cancers that express an antigen targeted by an antibody or antigen-binding fragment of an ADC, such as BCMA, CD33, PCAD, or HER2). In some embodiments, the present disclosure provides methods of reducing or slowing the expansion of a cancer cell population in a subject. In some embodiments, the present disclosure provides methods of determining whether a subject having or suspected of having cancer will respond to treatment with an ADC compound or composition disclosed herein.

[0280] An exemplary embodiment is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0281] Another exemplary embodiment is a method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the tumor is gastric cancer. In some embodiments, administration of the antibody-drug conjugate, composition or pharmaceutical composition reduces or inhibits tumor growth by 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%, at least about 90%, at least about 95% or at least about 99%.

[0282] Another exemplary embodiment is a method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer cell population expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer cell population is derived from a tumor or a blood cancer. In some embodiments, the cancer cell population is derived from breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer cell population is derived from lymphoma or gastric cancer. In some embodiments, administration of the antibody-drug conjugate, composition or pharmaceutical composition reduces the cancer cell population by 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%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, administration of the antibody-drug conjugate, composition or pharmaceutical composition slows the expansion of the cancer cell population by 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%, at least about 90%, at least about 95%, or at least about 99%.

[0283] Another exemplary embodiment is an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject having or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0284] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in the treatment of a subject having or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0285] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in a method of manufacturing a medicament for treating a subject having or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0286] Another exemplary embodiment is a method of determining whether a subject having or suspected of having cancer will respond to treatment with an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample from the subject; contacting the sample with an antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample. In some embodiments, cancer cells in the sample express the target antigen. In some embodiments, the cancer expresses the target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

[0287] Also disclosed are methods of making the described ADC compounds and compositions. An exemplary embodiment is a method of making an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a cleavable linker linked to an Mcl-1 inhibitor under conditions that allow conjugation. [Brief explanation of the drawings]

[0288] [Figure 1] FIG. 1 shows an exemplary site-specific antibody conjugation using bacterial transglutaminase (BTG). [Figure 2A] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD38-targeted Mcl-1 ADC, and non-targeting isotype ADC on A4-Fuk cells. [Figure 2B] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD38-targeted Mcl-1 ADC, and non-targeting isotype ADC in KMS021 BM cells. [Figure 3A] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD48-targeted Mcl-1 ADC, and non-targeting isotype ADC in NCI-H929 cells. [Figure 3B] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD48-targeted Mcl-1 ADC, and non-targeting isotype ADC on OPM-2 cells. [Figure 3C] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD48-targeted Mcl-1 ADC, and non-targeting isotype ADC in AMO1 cells. [Figure 4] Dose response curves of free Mcl-1 payload (P1), CD79b-targeted Mcl-1 ADC, and non-targeting isotype ADC in RS4, 11 cells are shown. [Figure 5A] FIG. 1 shows dose response curves of free Mcl-1 payload (P1) and HER2-targeted Mcl-1 ADC in HCC1954 cells. [Figure 5B] FIG. 1 shows dose response curves of free Mcl-1 payload (P1) and HER2-targeted Mcl-1 ADC in HCC2218 cells. [Figure 6A] FIG. 1 shows dose response curves of free Mcl-1 payload (P1), CD33-targeted Mcl-1 ADC, and non-targeting isotype ADC on AMO1-CD33 clone D2 cells. [Figure 6B] FIG. 1 shows dose response curves for free Mcl-1 payload (P1), CD33-targeted Mcl-1 ADC, and non-targeting isotype ADC in MOLM-13 cells. [Figure 7] FIG. 1 shows dose response curves for free Mcl-1 payload (P1), BCMA-targeted Mcl-1 ADC, and non-targeting isotype ADC in NCI-H929 cells. [Figure 8A] Results of an MTT cell viability assay are shown. All tested anti-CD33 ADCs and corresponding payloads induced a dose-dependent decrease in the viability of AMO1-CD33 clone D2 cells, while no significant effect was observed with the corresponding naked antibodies. [Figure 8B] Results of an MTT cell viability assay are shown. All tested anti-CD33 ADCs and corresponding payloads induced a dose-dependent decrease in the viability of AMO1-CD33 clone D2 cells, while no significant effect was observed with the corresponding naked antibodies. [Figure 9A] Results of a CTG cell viability assay are shown. All tested anti-HER2 ADCs and corresponding payloads induced a dose-dependent decrease in HCC1954 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 9B] Results of a CTG cell viability assay are shown. All tested anti-HER2 ADCs and corresponding payloads induced a dose-dependent decrease in HCC1954 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 10A] Results of an MTT cell viability assay are shown. All tested anti-BCMA ADCs and corresponding payloads induced a dose-dependent decrease in NCI-H929 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 10B] Results of an MTT cell viability assay are shown. All tested anti-BCMA ADCs and corresponding payloads induced a dose-dependent decrease in NCI-H929 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 10C] Results of an MTT cell viability assay are shown. All tested anti-BCMA ADCs and corresponding payloads induced a dose-dependent decrease in NCI-H929 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 10D] Results of an MTT cell viability assay are shown. All tested anti-BCMA ADCs and corresponding payloads induced a dose-dependent decrease in NCI-H929 cell viability, while no significant effect was observed with the corresponding naked antibodies. [Figure 11]Figure 1 shows tumor volume (mm3) in female SCID mice implanted with NCI-H929 upon treatment with isotype control IgG1-linker-payload Fcsilent, anti-BCMA_CysmAb Fcsilent, or anti-BCMA_CysmAb Fcsilent_L7-P1 (10 and / or 30 mg / kg, IV, single dose, n=6). [Figure 12] Figure 1 shows the percentage (%) of weight loss in NCI-H929 implanted female SCID mice upon treatment with isotype control IgG1-linker-payload Fcsilent, anti-BCMA_CysmAb Fcsilent, or anti-BCMA_CysmAb Fcsilent_L7-P1 (10 and / or 30 mg / kg, IV once, n=6). [Figure 13A] 1 shows the results of a CTG cell viability assay testing anti-CD48 ADCs in NCI-H929 cells. [Figure 13B] 1 shows the results of a CTG cell viability assay testing anti-CD48 ADCs in KHM1B cells. [Figure 13C] 1 shows the results of a CTG cell viability assay testing anti-CD48 ADCs in KMS21BM cells. [Figure 14] Figure 1 shows tumor volume (mm3) in H929 implanted female SCID mice at time (days) after randomization when treated with anti-BCMA_CysmAb Fcsilent or different anti-BCMA_CysmAb Fcsilent ADCs (20 mg / kg, 1 dose IV, n=6). [Figure 15] Figure 1 shows the % weight loss in H929 implanted female SCID mice at time (days) after randomization when treated with anti-BCMA_CysmAb Fcsilent or different anti-BCMA_CysmAb Fcsilent ADCs (20 mg / kg, 1 dose IV, n=6). [Figure 16]Figure 1 shows tumor volume (mm3) in H929-implanted female SCID mice at time (days) after randomization when treated with IgG1-linker-payload Fcsilent, anti-CD48_CysmAb Fcsilent, or anti-CD48_CysmAb Fcsilent_L5-P1 (30 mg / kg, IV once, n=8). [Figure 17] Figure 1 shows the % weight loss in H929-implanted female SCID mice at time (days) after randomization when treated with IgG1-linker-payload Fcsilent, anti-CD48_CysmAb Fcsilent, or anti-CD48_CysmAb Fcsilent_L5-P1 (30 mg / kg, 1 dose IV, n=8). [Figure 18] Results of a CTG cell viability assay are shown. Anti-CD46-Mcl-1 ADC Ab C-L9-C1 and the corresponding payload C1 induced a dose-dependent decrease in KMS21BM cell viability, while no significant effect was observed with the corresponding naked antibody. [Figure 19A] Results of an MTT cell viability assay are shown. All ADCs induced a dose-dependent decrease in the viability of AMO1-CD33 clone D2 cells as single agents. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 19B] Results of an MTT cell viability assay are shown. All ADCs induced a dose-dependent decrease in the viability of AMO1-CD33 clone D2 cells as single agents. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 20A]Results of an MTT cell viability assay are shown. All anti-BCMA-Mcl-1 ADCs induced a dose-dependent decrease in AMO1 cell viability. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 20B] Results of an MTT cell viability assay are shown. All anti-BCMA-Mcl-1 ADCs induced a dose-dependent decrease in AMO1 cell viability. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 21A] Results of an MTT cell viability assay are shown. All anti-BCMA-Mcl-1 ADCs induced a dose-dependent decrease in H929 cell viability. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 21B] Results of an MTT cell viability assay are shown. All anti-BCMA-Mcl-1 ADCs induced a dose-dependent decrease in H929 cell viability. Interestingly, the activity of the ADCs was significantly improved when combined with the BCL2 inhibitor Compound A1, whereas no significant effect was observed after treating these cells with the corresponding naked antibody alone or in combination with 1 μM Compound A1. [Figure 22] Figure 1 shows the inhibitory activity of CD48 MCL-1 antibody drug conjugate CD48-L7-P1, isotype IgG1-L7-P1 ADC, and MCL-1 free payload P1 against KMS-21BM, KMS-20, KMS-27, and NCI-H929. [Figure 23A]Shows the inhibitory activity of CD48 MCL-1 antibody drug conjugate CD48-L7-P1, isotype IgG1-L7-P1 ADC, and MCL-1 free payload P1 in combination with venetoclax against KMS-21BM, KMS-20, KMS-27, and NCI-H929. [Figure 23B] Shows the inhibitory activity of CD48 MCL-1 antibody drug conjugate CD48-L7-P1, isotype IgG1-L7-P1 ADC, and MCL-1 free payload P1 in combination with venetoclax against KMS-21BM, KMS-20, KMS-27, and NCI-H929. DETAILED DESCRIPTION OF THE INVENTION

[0289] The disclosed compositions and methods can be more readily understood by reference to the following detailed description in conjunction with the accompanying drawings, which form a part of this disclosure.

[0290] Throughout this text, the description refers to compositions and methods of using the compositions. Where the disclosure describes or claims features or embodiments related to compositions, such features or embodiments are equally applicable to methods of using the compositions. Similarly, where the disclosure describes or claims features or embodiments related to methods of using the compositions, such features or embodiments are equally applicable to the compositions.

[0291] When a range of values ​​is expressed, this includes embodiments using any specific value within the range. Furthermore, reference to values ​​stated in a range includes each and every value within that range. All ranges are inclusive of their endpoints and are combinable. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of "or" is intended to mean "and / or" unless the particular context of its use dictates otherwise. All references cited herein are incorporated by reference for any purpose. In the event of a conflict between a reference and the present specification, the present specification will control.

[0292] Unless otherwise indicated in the context of this specification, when a structure or fragment of a structure is depicted, e.g., without a symbol indicating a particular point of attachment, it can be used by itself or attached to other components of an ADC, in any orientation, e.g., by attaching an antibody to a chemical moiety, e.g., a linker-drug, at any suitable point of attachment. However, when shown, the components of the ADC are attached in the orientation shown in a given formula. For example, if formula (1) is Ab-(LD) p The group "-(LD)" is

[0293] [ka] When explained as, the compact structure of Eq.

[0294] [ka] This is

[0295] [ka] isn't it.

[0296] It will be appreciated that certain features of the disclosed compositions and methods that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0297] As used throughout this application, antibody drug conjugates can be identified using a naming convention of the general form "target antigen / antibody-linker-payload." By way of example only, if an antibody drug conjugate is referred to as "target X-L0-P0," such a conjugate would comprise an antibody that binds to target X, a linker designated L0, and a payload designated P0. Alternatively, if an antibody drug conjugate is referred to as "anti-target X-L0-P0," such a conjugate would comprise an antibody that binds to target X, a linker designated L0, and a payload designated P0. Alternatively, if an antibody drug conjugate is referred to as "AbX-L0-P0," such a conjugate would comprise an antibody designated AbX, a linker designated L0, and a payload designated P0. A control antibody drug conjugate comprising a nonspecific isotype control antibody may be referred to as "isotype control IgG1-L0-P0" or "IgG1-L0-P0."

[0298] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C. 14 C. 15 N, 18 F and36 Cl. Thus, the present disclosure provides, for example, radioisotopes, e.g. 3 H and 14 Compounds incorporating one or more of any of the above-mentioned isotopes, including C, or non-radioactive isotopes therein, e.g. 2 H and 13 It should be understood that this includes compounds in which C is present. Such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substances, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those of skill in the art, e.g., by substituting an appropriate isotopically labeled reagent for a previously employed unlabeled reagent.

[0299] definition Various terms relating to the described embodiments are used throughout the specification and claims. Such terms will be given their ordinary meaning in the art unless otherwise specified. Other specifically defined terms will be interpreted in a manner consistent with the definitions provided herein.

[0300] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context dictates otherwise. The terms "comprising," "having," "being of the formula," "including," and "containing" are to be construed as open terms (i.e., meaning "including, but not limited to") unless otherwise noted. In addition, whenever "comprising" or another open-ended term is used in an embodiment, it is understood that the same embodiment can also be more narrowly claimed using the introductory term "consisting essentially of" or the closed term "consisting of."

[0301] The terms "about" or "approximately," when used in the context of numerical values ​​and ranges, refer to a value or range that is close to or near the recited value or range, such that embodiments can be performed as intended, as would be apparent to one of ordinary skill in the art from the teachings contained herein. In some embodiments, about means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of the quantity. In one embodiment, the term "about" refers to a range of values ​​that is 10% above or below a particular value. In another embodiment, the term "about" refers to a range of values ​​that is 5% above or below a particular value. In another embodiment, the term "about" refers to a range of values ​​that is 1% above or below a particular value.

[0302] The terms "antibody-drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to one or more therapeutic compounds (e.g., Mcl-1 inhibitors) linked to one or more antibodies or antigen-binding fragments. In some embodiments, an ADC has the general formula: Ab-(LD) pADCs are defined by Formula 1, where Ab = antibody or antigen-binding fragment, L = linker moiety, D = drug moiety (e.g., Mcl-1 inhibitor drug moiety), and p = number of drug moieties per antibody or antigen-binding fragment. For ADCs that include Mcl-1 inhibitor drug moieties, "p" refers to the number of Mcl-1 inhibitor compounds linked to the antibody or antigen-binding fragment.

[0303] The term "antibody" in its broadest sense refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the above, through at least one antigen recognition site in the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and can be derived from natural or recombinant sources. "Intact" antibodies are typically glycoproteins comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability termed complementarity-determining regions (CDRs), interspersed with more conserved regions termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of antibodies can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The antibodies can be monoclonal, human, humanized, camelized, or chimeric. The antibody can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. The antibody can be an intact antibody or an antigen-binding fragment thereof.

[0304] The terms "antibody fragment" or "antigen-binding fragment" or "functional antibody fragment," as used herein, refer to a portion of at least one antibody that retains the ability to specifically interact (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) with an epitope of an antigen (e.g., BCMA, CD33, PCAD, or HER2). An antigen-binding fragment may also retain the ability to be internalized into antigen-expressing cells. In some embodiments, an antigen-binding fragment also retains immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, and the like are intended to encompass the use of antibody-derived binding domains in the context of larger macromolecules, e.g., ADCs. Fragments of full-length antibodies have been shown to be capable of performing the antigen-binding function of the full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab'), Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragments consisting of the VH and CH1 domains, linear antibodies, single-domain antibodies such as sdAb (either VL or VH), camelid VHH domains, antibody fragments, such as multispecific antibodies formed from a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bis-scFvs (see, e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):1126-36). Antigen-binding fragments can also be grafted into polypeptide-based scaffolds, such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies).The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment comprising a light chain variable region and at least one antigen-binding fragment comprising a heavy chain variable region, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short, flexible polypeptide linker, and can be expressed as a single-chain polypeptide, wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, an scFv can have the VL and VH variable regions in either order; e.g., relative to the N- and C-termini of the polypeptide, an scFv can comprise VL-linker-VH or VH-linker-VL. Antigen-binding fragments are obtained using conventional techniques known to those skilled in the art, and binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared, for example, by cleavage of the intact protein, e.g., by protease or chemical cleavage.

[0305] The term "complementarity determining region" or "CDR" as used herein refers to the sequence of amino acids in an antibody variable region that confers antigen specificity and binding affinity. For example, there are generally three CDRs (e.g., HCDR1, HCDR2, and HCDR3) in each heavy chain variable region, and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable region. The precise amino acid sequence boundaries of a given CDR can be determined using any one of a number of well-known schemes, or a combination thereof, including those described by Kabat et al. (1991) "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al. (1997) J Mol Biol. 273(4):927-48 ("Chothia" numbering scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77) ("IMGT" numbering scheme). In the combined Kabat and Chothia numbering scheme for a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, the CDRs correspond to the amino acid residues defined as part of the Kabat CDRs along with the amino acid residues defined as part of the Chothia CDRs. As used herein, CDRs defined by the "Chothia" numbering scheme are sometimes referred to as "hypervariable loops."

[0306] In some embodiments, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1) (e.g., insertion after position 35), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) (e.g., insertion after position 27), 50-56 (LCDR2), and 89-97 (LCDR3). In some embodiments, under Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1) (e.g., insertion after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in the VL are numbered 26-32 (LCDR1) (e.g., insertion after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). Combining the CDR definitions of both Kabat and Chothia, in some embodiments, a CDR comprises or consists of, for example, amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in a human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in a human VL. In some embodiments, under IMGT, the CDR amino acid residues in a VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in a VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the CDR regions of an antibody can be determined using the program IMGT / Domain Gap Align.

[0307] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include many antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" refers to the character of the antibody as being obtained from a population of substantially homogeneous antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present disclosure can be made, e.g., by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J Mol Biol. 222:581-97. The term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0308] The monoclonal antibodies described herein can be non-human, human, or humanized. The term specifically includes "chimeric" antibodies in which portions of the heavy and / or light chains are identical to or homologous to sequences in corresponding antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains are identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, and in fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0309] The term "human antibody," as used herein, refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human. This term includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such a human sequence, e.g., a human germline sequence, or a mutated version of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis as described in Knappik et al. ((2000) J Mol Biol. 296(1):57-86). The structure and position of immunoglobulin variable domains, e.g., CDRs, can be defined using well-known numbering schemes, such as the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and / or ImMunoGenTics (IMGT) numbering. The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations induced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or conservative substitutions to facilitate stability or production). However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of other mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0310] The term "recombinant human antibody," as used herein, refers to a human antibody that is prepared, expressed, produced, or isolated by recombinant means, e.g., an antibody isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, an antibody isolated from a host cell, e.g., a transfectoma, that has been transformed to express a human antibody, an antibody isolated from a recombinant combinatorial human antibody library, and an antibody prepared, expressed, produced, or isolated by any other means involving splicing all or part of a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, if animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies, while derived from and related to human germline VH and VL sequences, are sequences that would not naturally occur in the human antibody germline repertoire in vivo.

[0311] The term "chimeric antibody," as used herein, refers to an antibody in which the amino acid sequences of the immunoglobulin molecules are derived from two or more species. In some cases, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species having the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., humans) to minimize immune responses in the latter species.

[0312] As used herein, "humanized antibody" refers to a form of antibody containing sequences from non-human (e.g., murine) and human antibodies. Such antibodies are a type of chimeric antibody, containing minimal sequence derived from non-human immunoglobulin. Generally, a humanized antibody will contain substantially all of at least one, typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody will also optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Humanized antibodies can be further modified by substitution of residues either in the Fv framework regions and / or substituted non-human residues to improve and optimize antibody specificity, affinity, and / or activity.

[0313] The term "Fc region," as used herein, refers to a polypeptide comprising at least a portion of the CH3, CH2, and hinge region of an antibody constant domain. Optionally, the Fc region can include a CH4 domain present in some antibody classes. The Fc region can also include the entire hinge region of an antibody constant domain. In some embodiments, an antibody or antigen-binding fragment comprises the Fc region and CH1 region of an antibody. In some embodiments, an antibody or antigen-binding fragment comprises the Fc region and CH3 region of an antibody. In some embodiments, an antibody or antigen-binding fragment comprises the Fc region, CH1 region, and kappa / lambda regions from the antibody constant domain. In some embodiments, an antibody or antigen-binding fragment comprises a constant region, e.g., a heavy chain constant region and / or a light chain constant region. In some embodiments, such constant regions are modified compared to wild-type constant regions. That is, the polypeptide can include changes or modifications to one or more of the three heavy chain constant domains (CH1, CH2, or CH3) and / or light chain constant region domain (CL). Examples of modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc.

[0314] "Internalization," as used herein in reference to an antibody or antigen-binding fragment, refers to an antibody or antigen-binding fragment that, upon binding to a cell, is capable of passing through the lipid bilayer membrane of the cell and being taken up (i.e., "internalized") into an internal compartment, preferably a degradable compartment within the cell. For example, an anti-HER2 antibody is internalized such that it is capable of being taken up into the cell after binding to HER2 on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen (e.g., BCMA, CD33, PCAD, or HER2) and is an internalizing antibody or internalizing antigen-binding fragment (i.e., the ADC translocates through the cell membrane after antigen binding). In some embodiments, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. An internalizing antibody or internalizing antigen-binding fragment that targets a receptor on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is taken up into the cell via receptor-mediated endocytosis.

[0315] "Non-internalizing," as used herein in reference to an antibody or antigen-binding fragment, refers to an antibody or antigen-binding fragment that remains on the cell surface upon binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., the ADC remains on the cell surface after antigen binding and does not translocate through the cell membrane). In some embodiments, the non-internalizing antibody or antigen-binding fragment binds to a non-internalizing receptor or other cell surface antigen. Representative non-internalizing cell surface antigens include, but are not limited to, CA125 and CEA, and antibodies that bind to non-internalizing antigen targets are also known in the art (see, e.g., Bast et al. (1981) J Clin Invest. 68(5):1331-7; Scholler and Urban (2007) Biomark Med. 1(4):513-23; and Boudousq et al. (2013) PLoS One 8(7):e69613).

[0316] The term "B cell maturation antigen" or "BCMA," as used herein, refers to any naturally occurring form of human BCMA (also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17)). The term encompasses full-length human BCMA (e.g., UniProt Reference Sequence: Q02223; SEQ ID NO: 72) and any form of human BCMA that may result from cellular processing. The term also encompasses functional variants or fragments of human BCMA, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human BCMA (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). BCMA can be isolated from humans or produced recombinantly or by synthetic methods.

[0317] The term "anti-BCMA antibody" or "antibody that binds BCMA," as used herein, refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically binds, to BCMA. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments so long as they bind, e.g., specifically, to BCMA. WO 2012 / 163805 provides representative BCMA-binding sequences, including representative anti-BCMA antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-BCMA antibodies used in the ADCs disclosed herein are internalizing antibodies or internalizing antigen-binding fragments. J6M0 (WO 2012 / 163805) is a representative anti-BCMA antibody.

[0318] The term "myeloid cell surface antigen CD33" or "CD33," as used herein, refers to any native form of human CD33 (also known as sialic acid-binding Ig-like lectin 3 (SIGLEC3)). The term encompasses full-length human CD33 (e.g., UniProt Reference Sequence: P20138; SEQ ID NO: 73) and any form of human CD33 that may result from cellular processing. The term also encompasses functional variants or fragments of human CD33, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD33 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD33 can be isolated from humans or produced recombinantly or by synthetic methods.

[0319] The term "anti-CD33 antibody" or "antibody that binds to CD33," as used herein, refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically, to CD33. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments so long as they bind, e.g., specifically, to CD33. U.S. Patent Application Publication No. 2013 / 0078241 provides representative CD33-binding sequences, including representative anti-CD33 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-CD33 antibodies used in the ADCs disclosed herein are internalizing antibodies or internalizing antigen-binding fragments. MuMy9-6ch (U.S. Patent Application Publication No. 2013 / 0078241) is a representative anti-CD33 antibody.

[0320] The term "P-cadherin" or "PCAD," as used herein, refers to any naturally occurring form of human PCAD (also known as cadherin 3, type 1, or CDH3). The term encompasses full-length human PCAD (e.g., UniProt Reference Sequence: P22223; SEQ ID NO: 74) and any form of human PCAD that may result from cellular processing. The term also encompasses functional variants or fragments of human PCAD, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human PCAD (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). PCAD can be isolated from humans or produced recombinantly or by synthetic methods.

[0321] The term "anti-PCAD antibody" or "antibody that binds to PCAD," as used herein, refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically binds, to PCAD. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments so long as they bind, e.g., specifically, to PCAD. WO 2016 / 203432 provides representative PCAD-binding sequences, including representative anti-PCAD antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-PCAD antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antigen-binding fragment. NOV169N31Q (WO 2016 / 203432) is a representative anti-PCAD antibody.

[0322] The term "human epidermal growth factor receptor 2," "HER2," or "HER2 / NEU" as used herein refers to any naturally occurring form of human HER2. This term encompasses full-length human HER2 (e.g., UniProt Reference Sequence: P04626; SEQ ID NO: 75) and any form of human HER2 that may result from cellular processing. This term also encompasses functional variants or fragments of human HER2, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human HER2 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). HER2 can be isolated from humans or produced recombinantly or by synthetic methods.

[0323] The term "anti-HER2 antibody" or "antibody that binds to HER2," as used herein, refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically, to HER2. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments as long as they bind, e.g., specifically, to HER2. U.S. Pat. Nos. 5,821,337 and 6,870,034 provide representative HER2-binding sequences, including representative anti-HER2 antibody sequences, and are incorporated herein by reference. In some embodiments, the anti-HER2 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antigen-binding fragment. Trastuzumab (U.S. Pat. Nos. 5,821,337 and 6,870,034; see also Molina et al. (2001) Cancer Res. 61(12):4744-9) is a representative anti-HER2 antibody.

[0324] The term "cluster of differentiation 38" or "CD38," as used herein, refers to any native form of human CD38 (also known as ADP-ribosyl cyclase / cyclic ADP-ribose hydrolase). The term encompasses full-length human CD38 (e.g., UniProt Reference Sequence: P28907; SEQ ID NO: 76) and any form of human CD38 that may result from cellular processing. The term also encompasses functional variants or fragments of human CD38, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD38 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD38 can be isolated from humans or produced recombinantly or by synthetic methods.

[0325] The term "cluster of differentiation 48" or "CD48," as used herein, refers to any native form of human CD48 (also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2)). The term encompasses full-length human CD48 (e.g., UniProt Reference Sequence: P09326; SEQ ID NO: 77) and any form of human CD48 that may result from cellular processing. The term also encompasses functional variants or fragments of human CD48, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD48 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD48 can be isolated from humans or produced recombinantly or by synthetic methods.

[0326] The term "cluster of differentiation 79b" or "CD79b," as used herein, refers to any naturally occurring form of human CD79b (also known as B-cell antigen receptor complex-associated protein beta chain). The term encompasses full-length human CD79b (e.g., UniProt Reference Sequence: P40259; SEQ ID NO: 78) and any form of human CD79b that may result from cellular processing. The term also encompasses functional variants or fragments of human CD79b, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD79b (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD79b can be isolated from humans or produced recombinantly or by synthetic methods.

[0327] The term "binding specificity," as used herein, refers to the ability of an individual antibody or antigen-binding fragment to preferentially react with one antigenic determinant over different antigenic determinants. Specificity indicates the degree to which an antibody or fragment preferentially binds to one antigenic determinant over different antigenic determinants. Also, as used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an anti-HER2 antibody) and a target antigen (e.g., HER2) in a heterogeneous population of proteins and other biologics. An antibody can be tested for binding specificity by comparing binding to the appropriate antigen with binding to an unrelated antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to the appropriate antigen with at least 2-fold, 5-fold, 7-fold, 10-fold, or more affinity than an unrelated antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is one that binds only to a target antigen (e.g., BCMA, CD33, PCAD, or HER2) and does not bind (or shows minimal binding to) other antigens. In some embodiments, an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., BCMA, CD33, PCAD, or HER2) is expressed in a concentration of 1x10 -6 Under M, 1x10 -7 Under M, 1x10 -8 Under M, 1x10 -9 Under M, 1x10 -10 Under M, 1x10 -11 Under M, 1x10 -12 M or 1x10 -13 K less than M D In some embodiments, K D In some embodiments, K D is between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[0328] The term "affinity," as used herein, refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Without being bound by theory, within each antigen-binding site, the antibody variable region "arm" interacts with the antigen at numerous sites through weak non-covalent forces, and the more interactions there are, the stronger the affinity typically is. The binding affinity of an antibody is the sum of the attractive and repulsive forces acting between an antigenic determinant and the antibody binding site.

[0329] "k on " or "k a The term "on-rate constant" refers to the on-rate constant for the association of an antibody to an antigen to form an antibody / antigen complex. This rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0330] "k off " or "k d The term "off-rate constant" refers to the off-rate constant for dissociation of an antibody from the antibody / antigen complex. This rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0331] "K D The term K refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. D is k a / k d This rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0332] The term "epitope" refers to that portion of an antigen capable of being recognized and specifically bound by an antibody (or antigen-binding fragment). Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. When the antigen is a polypeptide, epitopes can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of the polypeptide. Epitopes can be "linear" or "conformational." Conformational epitopes are distinguished from linear epitopes in that the binding to the former but not the latter is lost in the presence of denaturing solvents. The epitope bound by an antibody (or antigen-binding fragment) can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, and monitoring binding of the antibody to fragments or mutated versions of the antigen, or monitoring the solvent accessibility of different portions of the antibody and antigen. Exemplary strategies for mapping antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) BioDrugs 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev Proteomics 2:745-56).

[0333] Competitive binding and epitope binning can also be used to determine antibodies that share the same or overlapping epitopes. Competitive binding can be assessed using a cross-blocking assay, such as that described in "Antibodies, A Laboratory Manual," Cold Spring Harbor Laboratory, Harlow and Lane (1st edition 1988, 2nd edition 2014). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces the binding of a reference antibody or binding protein (e.g., a binding protein comprising a CDR and / or variable domain selected from those identified in Tables 3-5) to a target antigen, such as BCMA, CD33, PCAD, or HER2, by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or more, or any percentage therebetween) in a cross-blocking assay, and / or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., particularly overlapping) epitopes, or due to steric hindrance of antibodies or binding proteins binding to nearby epitopes (see, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66)). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes. For example, binding proteins that compete for binding can be "binned" into a group of binding proteins with overlapping or nearby epitopes, while those that do not compete are placed into a separate group of binding proteins that do not have overlapping or nearby epitopes.

[0334] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to a polymer of amino acid residues. The term encompasses amino acid polymers containing two or more amino acids connected together by peptide bonds, amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, and naturally occurring and non-naturally occurring amino acid polymers. The term specifically encompasses, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. The term also encompasses natural peptides, recombinant peptides, synthetic peptides, or combinations thereof. Unless otherwise specified, a particular polypeptide sequence implicitly encompasses conservatively modified variants thereof.

[0335] A "recombinant" protein refers to a protein (eg, an antibody) made using recombinant techniques, eg, through the expression of a recombinant nucleic acid.

[0336] An "isolated" protein refers to a protein that is free from at least some of the materials that normally accompany it in its natural state. For example, a naturally occurring polynucleotide or polypeptide present in a living organism is not isolated, but the same polynucleotide or polypeptide separated from some or all of the coexisting materials in a living organism is isolated. This definition includes the production of antibodies in a wide variety of organisms and / or host cells known in the art.

[0337] An "isolated antibody," as used herein, is an antibody that has been identified and separated from one or more (e.g., multiple) components of its source environment, such as components of a hybridoma cell culture or a different cell culture used to produce it. In some embodiments, separation is performed to sufficiently remove components that may otherwise interfere with the suitability of the antibody for a desired use (e.g., therapeutic use). Methods for preparing isolated antibodies are known in the art and include, without limitation, protein A chromatography, anion exchange chromatography, cation exchange chromatography, virus retentive filtration, and ultrafiltration.

[0338] As used herein, the term "variant" refers to a nucleic acid sequence or amino acid sequence that differs from a reference nucleic acid sequence or amino acid sequence, respectively, but retains one or more biological properties of the reference sequence. A variant can contain one or more amino acid substitutions, deletions, and / or insertions (or corresponding codon substitutions, deletions, and / or insertions) relative to the reference sequence. Changes in a nucleic acid variant may not change the amino acid sequence of a peptide encoded by the reference nucleic acid sequence, or may result in amino acid substitutions, additions, deletions, fusions, and / or truncations. In some embodiments, the nucleic acid variants disclosed herein encode an amino acid sequence identical to that encoded by the unmodified nucleic acid, or encode a modified amino acid sequence that retains one or more functional properties of the unmodified amino acid sequence. Changes in the sequence of a peptide variant are typically limited or conservative, so that the sequences of the unmodified peptide and the variant are closely similar overall and, in many regions, identical. In some embodiments, a peptide variant retains one or more functional properties of the unmodified peptide sequence. A variant may differ in amino acid sequence from the unmodified peptide by one or more substitutions, additions, deletions in any combination.

[0339] Nucleic acid or peptide variants can be naturally occurring variants or variants that are not known to occur naturally.Nucleic acid and peptide variants can be produced by mutagenesis techniques, by direct synthesis, or by other techniques known in the art.Variant does not necessarily require physical manipulation of the reference sequence.As long as a sequence contains different nucleic acids or amino acids compared to the reference sequence, it is considered a "variant" regardless of how much it is synthesized.In some embodiments, variants have high sequence identity (i.e., 60% or more identity of nucleic acid or amino acid sequence) compared to the reference sequence. In some embodiments, peptide variants include polypeptides with amino acid substitutions, deletions, and / or insertions, so long as the polypeptide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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% amino acid sequence identity with a reference sequence or a corresponding segment (e.g., functional fragment) of a reference sequence, e.g., a variant that also retains one or more functions of the reference sequence. In some embodiments, nucleic acid variants include polynucleotides with amino acid substitutions, deletions, and / or insertions, so long as the polynucleotide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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% nucleic acid sequence identity to a reference sequence or a corresponding segment (e.g., a functional fragment) of a reference sequence.

[0340] The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. For nucleic acid sequences, conservatively modified variants refer to nucleic acids that encode identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Thus, at every position where alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are a type of conservatively modified variation. Every nucleic acid sequence herein that encodes a polypeptide also describes all possible silent variations of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except AUG, the only codon for conventional methionine, and TGG, the only codon for conventional tryptophan) can be modified to obtain a functionally identical molecule. Thus, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence. For polypeptide sequences, conservatively modified variants include individual substitutions, deletions, or additions to the polypeptide sequence that result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art.

[0341] The term "conservative sequence modification" as used herein refers to an amino acid modification that does not significantly affect or alter the binding properties of, for example, an antibody or antigen-binding fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into antibodies or antigen-binding fragments by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, in some embodiments, one or more amino acid residues in an antibody can be substituted with other amino acid residues from the same side chain family, and the altered antibodies can be tested using the functional assays described herein.

[0342] The term "homologous" or "identity," as used herein, refers to the sequence identity of subunits between two polymer molecules, e.g., between two nucleic acid molecules, e.g., two DNA molecules or two RNA molecules, or between two polypeptide molecules. If a subunit position in both of the two molecules is occupied by the same monomer subunit, e.g., if each position in two DNA molecules is occupied by adenine, they are homologous or identical at that position. The homology between two sequences is a linear function of the number of matching or homologous positions. For example, if half of the positions in two sequences (e.g., five positions in a polymer 10 subunits long) are matched or homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 out of 10) are matched or homologous, the two sequences are 90% homologous.

[0343] The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where the amino acid sequence fragment in the comparison window can contain additions or deletions (e.g., gaps or overhangs) compared to the reference sequence (which contains no additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions where identical amino acid residues occur in both sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity. The output is the percent identity of the subject sequence to the query sequence. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap. Generally, the amino acid identity or homology between the proteins disclosed herein and variants thereof, including variants of target antigens (e.g., BCMA, CD33, PCAD or HER2) and variants of antibody variable domains (including individual variant CDRs), is at least 80% of the sequences set forth herein, such as at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, near 100% or 100% identity or homology.

[0344] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a numerical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J Mol Biol. 48:444-53) algorithm incorporated into the GAP program in the GCG software package, using either a Blossum62 matrix or a PAM250 matrix, a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna.CMP matrix, a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. A representative set of parameters is a Blossum62 score matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences may also be determined using the algorithm of Meyers and Miller ((1989) CABIOS 4:11-17) as incorporated into the ALIGN program (version 2.0), using the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0345] The term "drug" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination of two or more thereof. The term "therapeutic agent" or "drug" refers to an agent capable of modulating biological processes and / or biological activity. Mcl-1 inhibitors as described herein and ADCs containing them are representative therapeutic agents.

[0346] The term "chemotherapeutic agent" or "anti-cancer agent" is used herein to refer to all agents effective in treating cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is often a property of chemotherapeutic agents. Chemotherapeutic agents include antibodies, biological molecules, and small molecules, including Mcl-1 inhibitors as described herein and ADCs containing them. Chemotherapeutic agents may be cytotoxic or cytostatic agents. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or cell proliferation. The term "cytotoxic agent" refers to a substance that causes cell death primarily by interfering with cellular expression activity and / or function.

[0347] The term "myeloid cell leukemia 1" or "Mcl-1," as used herein, refers to any naturally occurring form of human Mcl-1, an anti-apoptotic member of the Bcl-2 protein family. This term encompasses full-length human Mcl-1 (e.g., UniProt Reference Sequence: Q07820; SEQ ID NO: 71) and any form of human Mcl-1 that may result from cellular processing. This term also encompasses functional variants or fragments of human Mcl-1, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Mcl-1 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). Mcl-1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0348] The term "inhibit" or "inhibition" or "inhibiting," as used herein, means to reduce a biological activity or process by a measurable amount, but may include, but does not require, complete prevention or inhibition. In some embodiments, "inhibition" refers to reducing the expression and / or activity of Mcl-1 and / or one or more of its upstream regulators or downstream targets.

[0349] The term "Mcl-1 inhibitor," as used herein, refers to an agent capable of reducing the expression and / or activity of Mcl-1 and / or one or more of its upstream regulators or downstream targets. Representative Mcl-1 regulators (including representative inhibitors of Mcl-1) are described in WO 2015 / 097123; WO 2016 / 207216; WO 2016 / 207217; WO 2016 / 207225; WO 2016 / 207226; WO 2017 / 125224; WO 2019 / 035899; WO 2019 / 035911; WO 2019 / 035914.

[0004] The present invention relates to a method for the preparation of Mcl-1 modulators, such as those described in FRET, WO 2019 / 035927, U.S. Patent Application Publication No. 2019 / 0055264, WO 2016 / 033486, WO 2017 / 147410, WO 2018 / 183418, and WO 2017 / 182625, each of which is incorporated by reference herein as representative Mcl-1 modulators, including representative Mcl-1 inhibitors that can be included as drug moieties in the disclosed ADCs. For example, a representative Mcl-1 inhibitor that can be included as a drug moiety in the disclosed ADCs has the formula:

[0350] [ka] wherein each variable is defined as in WO 2019 / 035911; WO 2019 / 035899; WO 2019 / 035914; or WO 2019 / 035927. Specific examples include, for example:

[0351] [ka] wherein each compound as a drug payload can be conjugated to an antibody or a linker via the N-methyl nitrogen atom in the piperazinyl functional group of the compound. As used herein, the terms "derivative" and "analog," when referring to Mcl-1 inhibitors and the like, refer to any such compound that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound, but has an altered chemical or biological structure.

[0352] As used herein, "Mcl-1 inhibitor drug moiety," "Mcl-1 inhibitor," and the like refer to a component of an ADC or composition that provides a compound structure modified for attachment to an ADC that retains essentially the same, similar, or enhanced biological function or activity compared to the Mcl-1 inhibitor compound or the parent compound. In some embodiments, the Mcl-1 inhibitor drug moiety is component (D) in an ADC of Formula (1).

[0353] The term "cancer," as used herein, refers to the presence of cells with characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological characteristics. While cancer cells often take the form of a tumor or mass, such cells may exist alone in a subject or circulate in the bloodstream as individual cells, e.g., leukemia or lymphoma cells. The term "cancer" includes all types of cancer and cancer metastasis, including blood cancers, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Blood cancers can include B-cell malignancies, cancers of the blood (leukemia), cancers of plasma cells (myeloma, e.g., multiple myeloma), or cancers of the lymph nodes (lymphoma). Representative B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. Lymphomas include Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc. Other blood cancers include myelodysplastic syndromes (MDS). Solid tumors include carcinomas, such as adenocarcinomas, e.g., breast cancer, pancreatic cancer, prostate cancer, colon or colorectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, etc. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0354] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, whether benign or malignant, including precancerous lesions. In some embodiments, the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the tumor is gastric cancer.

[0355] The terms "tumor cell" and "cancer cell" can be used interchangeably herein and refer to an individual cell or the entire population of cells derived from a tumor or cancer, including both non-tumorigenic cells and cancer stem cells. When referring only to cells that have lost the ability to reproduce and differentiate, the terms "tumor cell" and "cancer cell" will be modified by the term "non-tumorigenic" to distinguish these cells from cancer stem cells.

[0356] The terms "target negative," "target antigen negative," or "antigen negative," as used herein, refer to the absence of target antigen expression by a cell or tissue. The terms "target positive," "target antigen positive," or "antigen positive" refer to the presence of target antigen expression. For example, a cell or cell line that does not express a target antigen can be described as target negative, while a cell or cell line that expresses a target antigen can be described as target positive.

[0357] The terms "subject" and "patient" are used interchangeably herein and refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[0358] The term "subject in need of treatment," as used herein, refers to a subject who would benefit biologically, medically, or in quality of life from treatment (e.g., treatment with any one or more of the representative ADC compounds described herein).

[0359] As used herein, the terms "treat," "treating," or "treatment" refer to any improvement in any outcome of a disease, disorder, or condition, e.g., extending survival, reducing morbidity, and / or reducing side effects resulting from alternative therapies. In some embodiments, treatment includes delaying or reversing the disease, disorder, or condition (i.e., delaying, halting, or reducing the onset of the disease or at least one of its clinical symptoms). In some embodiments, treatment includes delaying, alleviating, or reversing at least one physical parameter of the disease, disorder, or condition, including those that may not be discernible by the patient. In some embodiments, treatment includes modulating the disease, disorder, or condition either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In some embodiments, treatment includes administering a described ADC compound or composition to a subject, e.g., a patient, to obtain the treatment benefits enumerated herein. Treatment can be to cure, ameliorate, alleviate, delay, prevent, relieve, alter, counteract, ameliorate, ameliorate, or affect a disease, disorder, or condition (e.g., cancer), a symptom of a disease, disorder, or condition (e.g., cancer), or the propensity for a disease, disorder, or condition (e.g., cancer). In some embodiments, in addition to treating a subject with a disease, disorder, or condition, the compositions disclosed herein can also be provided prophylactically to prevent or reduce the likelihood of developing the disease, disorder, or condition.

[0360] As used herein, the terms "prevent," "preventing," or "prevention" of a disease, disorder, or condition refers to prophylactic treatment of a disease, disorder, or condition, or delaying the onset or progression of a disease, disorder, or condition.

[0361] As used herein, a "pharmaceutical composition" refers to a composition, e.g., a formulation of an ADC compound or composition, in addition to at least one other component (and optionally more than one other component), e.g., a pharmaceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient, that is suitable for administration to a subject. The pharmaceutical compositions provided herein are in a form that allows for administration and subsequently provides the intended biological activity of the active ingredient and / or achieves a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that are unacceptably toxic to the subject to whom the formulation will be administered.

[0362] As used herein, the terms "pharmaceutically acceptable carrier" and "physiologically acceptable carrier" can be used interchangeably and refer to a carrier or diluent that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered ADC compound or composition and / or any additional therapeutic agents in the composition. Pharmaceutically acceptable carriers can enhance or stabilize a composition or can be used to facilitate preparation of the composition. Pharmaceutically acceptable carriers can include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.Carrier can be selected to minimize adverse side effects in subject and / or minimize the deterioration of active ingredient.Adjuvants can also be included in any of these formulations.

[0363] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of active ingredients.Formulations for parenteral administration can contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils or hydrogenated naphthalene.Other representative excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, including, for example, polysorbate 20.

[0364] The term "pharmaceutically acceptable salts" as used herein refers to salts that do not abrogate the biological activity and properties of the compounds of the present invention and do not cause significant irritation to the subject to which they are administered. Examples of such salts include, but are not limited to: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.; and (b) salts formed from elemental anions, such as chlorine, bromine, and iodine. See, for example, Haynes et al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database," J. Pharmaceutical Sciences, vol. 94, no. 10 (2005), and Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, vol. 66, no. 1 (1977), which are incorporated by reference herein.

[0365] In some embodiments, the antibody-drug conjugates (ADCs), linkers, payloads, and linker-payloads described herein may be coupled to a monovalent anionic counterion M1 depending on their charge. - Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharmaceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M1 - can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, etc. In some embodiments, the monovalent anionic counterion M - is a trifluoroacetate or formate.

[0366] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of a compound described herein, e.g., an ADC compound or composition described herein, to produce a desired therapeutic result (i.e., reduction or inhibition of enzyme or protein activity, amelioration of symptoms, alleviation of a symptom or condition, delay in disease progression, reduction in tumor size, inhibition of tumor growth, prevention of metastasis). In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount induces and causes only those side effects that are tolerable by the treating physician in light of the patient's condition. In some embodiments, a therapeutically effective amount is effective to detectably kill, reduce, and / or inhibit the growth or spread of cancer cells, tumor size or number, and / or other measures of the level, stage, progression, and / or severity of cancer. The term also applies to a dose that will induce a specific response in target cells, e.g., reduction, delay, or inhibition of cell proliferation. A therapeutically effective amount can be determined by administering a low dose initially, then gradually increasing the dose until the desired effect is achieved. A therapeutically effective amount can vary depending on the intended use (in vitro or in vivo) or the subject and disease state being treated, e.g., the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. Specific amounts can vary depending, for example, on the particular pharmaceutical composition, the subject and their age and pre-existing health condition or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered. In the case of cancer, a therapeutically effective amount of an ADC can reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0367] As used herein, the term "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a compound disclosed herein, e.g., an ADC compound or composition described herein, effective at the dosage and for the period of time necessary to achieve the desired prophylactic result. Typically, a prophylactic dose is used in a subject prior to or at an early stage of disease, and therefore the prophylactically effective amount will be less than the therapeutically effective amount. In some embodiments, the prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with cancer.

[0368] The term "p" or "drug loading" or "drug:antibody ratio" or "drug-to-antibody ratio" or "DAR" refers to the number of drug moieties per antibody or antigen-binding fragment, i.e., drug loading, or the number of -LD moieties per antibody or antigen-binding fragment (Ab) in an ADC of Formula (1). In an ADC containing an Mcl-1 inhibitor drug moiety, "p" refers to the number of Mcl-1 inhibitor compounds linked to the antibody or antigen-binding fragment. For example, if two Mcl-1 inhibitor compounds are linked to the antibody or antigen-binding fragment, p = 2. In a composition comprising multiple copies of an ADC of Formula (1), "average p" refers to the average number of -LD moieties per antibody or antigen-binding fragment, also referred to as "average drug loading."

[0369] Antibody-drug conjugates Antibody-drug conjugate (ADC) compounds of the present disclosure include those with anti-cancer activity. In particular, ADC compounds comprise an antibody or antigen-binding fragment conjugated (i.e., covalently attached via a linker) to a drug moiety (e.g., an Mcl-1 inhibitor), where the drug moiety has a cytotoxic or cytostatic effect when not conjugated to the antibody or antigen-binding fragment. In some embodiments, the drug moiety, when not conjugated to the antibody or antigen-binding fragment, is capable of reducing the expression and / or activity of Mcl-1 and / or one or more of its upstream regulators or downstream targets. Without being bound by theory, by targeting Mcl-1 expression and / or activity, in some embodiments, the ADCs disclosed herein can provide potent anti-cancer agents. Also, without being bound by theory, by conjugating the drug moiety to an antibody that binds to an antigen associated with tumor cell or cancer expression, the ADC can provide improved activity, better cytotoxic specificity, and / or reduced off-target killing compared to the drug moiety when administered alone.

[0370] In some embodiments, the components of the ADC are therefore selected to (i) retain one or more therapeutic properties exhibited by the isolated antibody and drug moiety, (ii) maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) optimize drug loading and drug-to-antibody ratio; (iv) enable delivery of the drug moiety, e.g., intracellular delivery, via stable attachment to the antibody or antigen-binding fragment; (v) maintain stability of the ADC as an intact conjugate until translocation or delivery to the target site; (vi) minimize aggregation of the ADC before and after administration; (vii) enable the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage or other release mechanism in the cellular environment; (viii) demonstrate in vivo anti-cancer treatment efficacy comparable to or superior to that of the isolated antibody and drug moiety; (ix) minimize off-target killing by the drug moiety; and / or (x) exhibit desirable pharmacokinetic and pharmacodynamic properties, formulatability, and toxicological / immunological profile. Each of these properties can provide improved ADCs for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0371] The disclosed ADC compounds can selectively deliver an effective amount of a cytotoxic or cytostatic agent to cancer cells or tumor tissues. In some embodiments, the cytotoxic and / or cytostatic activity of the ADC depends on the expression of the target antigen in the cells. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells that express the target antigen while minimizing off-target killing. In some embodiments, the disclosed ADCs do not exhibit cytotoxic and / or cytostatic effects against cancer cells that do not express the target antigen.

[0372] Representative BCMA-expressing cancers include, but are not limited to, multiple myeloma (Cho et al. (2018) Front Immunol. 9:1821).

[0373] Representative CD33-expressing cancers include, but are not limited to, colorectal cancer, pancreatic cancer, lymphoma, and leukemia (e.g., acute myeloid leukemia) (Human Protein Atlas; Walter (2014) Expert Opin Ther Targets 18(7):715-8).

[0374] Representative PCAD-expressing cancers include, but are not limited to, breast cancer, gastric cancer, endometrial cancer, ovarian cancer, pancreatic cancer, bladder cancer, prostate cancer, and melanoma (Vieira and Paredes (2015) Mol Cancer 14:178).

[0375] Representative HER2-expressing cancers include, but are not limited to, breast cancer, gastric cancer, bladder cancer, urothelial cell carcinoma, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial carcinoma), salivary duct cancer, cervical cancer, endometrial cancer, and ovarian cancer (English et al. (2013) Mol Diagn Ther. 17:85-99).

[0376] In certain aspects, provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab), an Mcl-1 inhibitor drug moiety (D), and a linker moiety (L) covalently linking the Ab to D. In some embodiments, provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab) that targets cancer cells, an Mcl-1 inhibitor drug moiety (D), and a linker moiety (L) covalently linking the Ab to D. In some embodiments, the antibody or antigen-binding fragment is capable of binding to a tumor-associated antigen (e.g., BCMA, CD33, PCAD, or HER2), e.g., with high specificity and high affinity. In some embodiments, the antibody or antigen-binding fragment is internalized into the target cell upon binding, e.g., into a degradable compartment within the cell. In some embodiments, the ADC is internalized upon binding to the target cell and undergoes degradation, releasing the Mcl-1 inhibitor drug moiety and killing the cancer cell. The Mcl-1 inhibitor drug moiety can be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0377] A typical ADC is represented by the formula (1): Ab-(LD) p (1) where Ab = antibody or antigen-binding fragment, L = linker moiety, D = Mcl-1 inhibitor drug moiety, and p = number of Mcl-1 inhibitor drug moieties per antibody or antigen-binding fragment. It has.

[0378] antibody The antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cell. In some embodiments, the antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. The antibody or antigen-binding fragment may have a dissociation constant (K) of ≦1 mM, ≦100 nM, or ≦10 nM, or any amount therebetween, as measured, for example, by BIAcore® analysis. D) and can bind to the target antigen. In some embodiments, K D In some embodiments, K D is between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[0379] In some embodiments, the antibody or antigen-binding fragment is a four-chain antibody (also referred to as an immunoglobulin or a full-length or intact antibody), having two heavy chains and two light chains. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin that retains the ability to bind to a target cancer antigen and / or provides at least one function of an immunoglobulin.

[0380] In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof binds to a target cancer antigen expressed on the surface of a cell and enters the cell upon binding. In some embodiments, the Mcl-1 inhibitor drug moiety of the ADC is released from the antibody or antigen-binding fragment of the ADC after the ADC enters and resides in a cell expressing the target cancer antigen (i.e., after the ADC is internalized), e.g., by cleavage, degradation of the antibody or antigen-binding fragment, or any other suitable release mechanism.

[0381] In some embodiments, the antibody contains mutations that reduce or completely mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, these mutations are known as Fc silencing, Fc silent, or Fc silent mutations. In some embodiments, amino acid residues L234 and L235 in the IgG1 constant region are substituted with A234 and A235 (also known as "LALA"). In some embodiments, amino acid residue N297 in the IgG1 constant region is substituted with A297 (also known as "N297A"). In some embodiments, amino acid residues D265 and P329 in the IgG1 constant region are substituted with A265 and A329 (also known as "DAPA"). Other antibody Fc silencing mutations can also be used. In some embodiments, Fc silencing mutations are used in combination, for example, D265A, N297A, and P329A (also known as "DANAPA").

[0382] The amino acid sequences of representative antibodies of the present disclosure, along with representative antigen targets, are listed in Tables 2-6.

[0383] [Table 4]

[0384] [Table 5-1]

[0385] [Table 5-2]

[0386] [Table 5-3]

[0387] [Table 6-1]

[0388]

Table 6-2

[0389]

Table 7-1

[0390]

Table 7-2

[0391]

Table 7-3

[0392]

Table 7-4

[0393]

Table 7-5

[0394]

Table 7-6

[0395]

Table 7-7

[0396]

Table 7-8

[0397]

Table 8-1

[0398] [Table 8-2]

[0399] [Table 8-3]

[0400] [Table 8-4]

[0401] In some embodiments, the antibodies or antigen-binding fragments of the ADCs disclosed herein can comprise any set of heavy and light chain variable domains listed in the table above, or a set of six CDRs from any set of heavy and light chain variable domains listed in the table above. ... -8 K less than M D The ADCs may contain conservatively modified and / or homologous amino acid sequences to those listed in the table above, so long as they retain the ability to bind to the antigen (e.g., at 1000 .ANG.) and retain one or more functional properties of the ADCs disclosed herein (e.g., the ability to be internalized, to bind to an antigen target, e.g., an antigen expressed on a tumor or other cancer cell, etc.).

[0402] In some embodiments, the antibodies or antigen-binding fragments of the ADCs disclosed herein further comprise human heavy and light chain constant domains or fragments thereof. For example, the antibodies or antigen-binding fragments of the disclosed ADCs can comprise a human IgG heavy chain constant domain (e.g., IgG1) and a human kappa or lambda light chain constant domain. In some embodiments, the antibodies or antigen-binding fragments of the disclosed ADCs comprise a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain together with a human Ig kappa light chain constant domain.

[0403] In some embodiments, the target cancer antigen for the ADC is BCMA.

[0404] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 15, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 16, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 17; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 18, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 19, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 20.

[0405] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 1, and a light chain variable region amino acid sequence of SEQ ID NO: 2, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0406] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-BCMA antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in a wild-type (unmodified) IgG1 heavy chain constant domain, as numbered according to the EU numbering system. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 156 and 379 in a wild-type (unmodified) IgG1 heavy chain constant domain. In some embodiments, the anti-BCMA antibody comprises a human Ig kappa light chain constant domain or a modified Ig kappa light chain constant domain.

[0407] In some embodiments, the anti-BCMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57, or a sequence at least 95% identical to SEQ ID NO: 57, and a light chain amino acid sequence of SEQ ID NO: 58, or a sequence at least 95% identical to SEQ ID NO: 58. In some embodiments, the anti-BCMA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 57, and a light chain amino acid sequence of SEQ ID NO: 58, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-BCMA antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 57, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 58. In some embodiments, the anti-BCMA antibody is J6M0 (WO 2012 / 163805) or an antigen-binding fragment thereof.

[0408] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of J6M0, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 15), HCDR2 (SEQ ID NO: 16), HCDR3 (SEQ ID NO: 17); LCDR1 (SEQ ID NO: 18), LCDR2 (SEQ ID NO: 19) and LCDR3 (SEQ ID NO: 20).

[0409] In some embodiments, the target cancer antigen for the ADC is CD33.

[0410] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 21, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 22, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 23; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 24, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 26.

[0411] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 3, and the light chain variable region amino acid sequence of SEQ ID NO: 4, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 3, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 4.

[0412] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD33 antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a glutamine residue (Q) at the amino acid position corresponding to 297 in the wild-type (unmodified) IgG1 heavy chain constant domain. In some embodiments, the anti-CD33 antibody comprises a human Ig kappa light chain constant domain or a modified Ig kappa light chain constant domain.

[0413] In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59, or a sequence at least 95% identical to SEQ ID NO: 59, and a light chain amino acid sequence of SEQ ID NO: 60, or a sequence at least 95% identical to SEQ ID NO: 60. In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 60, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-CD33 antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 59, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 60. In some embodiments, the anti-CD33 antibody is MuMy9-6ch (U.S. Patent Application Publication No. 2013 / 0078241) or an antigen-binding fragment thereof.

[0414] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of MuMy9-6ch, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 21), HCDR2 (SEQ ID NO: 22), HCDR3 (SEQ ID NO: 23); LCDR1 (SEQ ID NO: 24), LCDR2 (SEQ ID NO: 25) and LCDR3 (SEQ ID NO: 26).

[0415] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 27, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 28, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 29; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 30, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 31, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 32.

[0416] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 5 and the light chain variable region amino acid sequence of SEQ ID NO: 6, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 5 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 6.

[0417] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD33 antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain according to the EU numbering system.

[0418] In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 61, or a sequence at least 95% identical to SEQ ID NO: 61, and a light chain amino acid sequence of SEQ ID NO: 62, or a sequence at least 95% identical to SEQ ID NO: 62. In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 61 and a light chain amino acid sequence of SEQ ID NO: 62, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-CD33 antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 61, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 62. In some embodiments, the anti-CD33 antibody is gemtuzumab or an antigen-binding fragment thereof.

[0419] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of gemtuzumab, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 27), HCDR2 (SEQ ID NO: 28), HCDR3 (SEQ ID NO: 29); LCDR1 (SEQ ID NO: 30), LCDR2 (SEQ ID NO: 31) and LCDR3 (SEQ ID NO: 32).

[0420] In some embodiments, the target cancer antigen for the ADC is PCAD.

[0421] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 33, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 34, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 36, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 37, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 38.

[0422] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 7 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 8.

[0423] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-PCAD antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain according to the EU numbering system.

[0424] In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 63, or a sequence at least 95% identical to SEQ ID NO: 63, and a light chain amino acid sequence of SEQ ID NO: 64, or a sequence at least 95% identical to SEQ ID NO: 64. In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 63 and a light chain amino acid sequence of SEQ ID NO: 64, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-PCAD antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 63, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 64. In some embodiments, the anti-PCAD antibody is NOV169N31Q (WO 2016 / 203432) or an antigen-binding fragment thereof.

[0425] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of NOV169N31Q, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35); LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37) and LCDR3 (SEQ ID NO: 38).

[0426] In some embodiments, the target cancer antigen for the ADC is HER2.

[0427] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 39, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 41; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 42, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44.

[0428] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 9, and the light chain variable region amino acid sequence of SEQ ID NO: 10, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 9, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 10.

[0429] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-HER2 antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a glutamine residue (Q) at the amino acid position corresponding to 297 in the wild-type (unmodified) IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a serine residue (S) at the amino acid position corresponding to 297 in the wild-type (unmodified) IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain as numbered according to the EU numbering system. In some embodiments, the anti-HER2 antibody comprises a human Ig kappa light chain constant domain or a modified Ig kappa light chain constant domain.

[0430] In some embodiments, the anti-HER2 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 65, or a sequence at least 95% identical to SEQ ID NO: 65, and a light chain amino acid sequence of SEQ ID NO: 66, or a sequence at least 95% identical to SEQ ID NO: 66. In some embodiments, the anti-HER2 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 65, and a light chain amino acid sequence of SEQ ID NO: 66, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-HER2 antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 65, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 66. In some embodiments, the anti-HER2 antibody is trastuzumab (see also U.S. Patent Nos. 5,821,337 and 6,870,034; Molina et al. (2001) Cancer Res. 61(12):4744-9) or an antigen-binding fragment thereof.

[0431] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of trastuzumab, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 39), HCDR2 (SEQ ID NO: 40), HCDR3 (SEQ ID NO: 41); LCDR1 (SEQ ID NO: 42), LCDR2 (SEQ ID NO: 43) and LCDR3 (SEQ ID NO: 44).

[0432] In some embodiments, the target cancer antigen for the ADC is CD38.

[0433] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 45, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 46, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 47; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 48, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 49, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 50.

[0434] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 11, and the light chain variable region amino acid sequence of SEQ ID NO: 12, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 11, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 12.

[0435] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD38 antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain according to the EU numbering system.

[0436] In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 67, or a sequence at least 95% identical to SEQ ID NO: 67, and a light chain amino acid sequence of SEQ ID NO: 68, or a sequence at least 95% identical to SEQ ID NO: 68. In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 67 and a light chain amino acid sequence of SEQ ID NO: 68, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-CD38 antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 67, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 68. In some embodiments, the anti-CD38 antibody is daratumumab or an antigen-binding fragment thereof.

[0437] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of gemtuzumab, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 45), HCDR2 (SEQ ID NO: 46), HCDR3 (SEQ ID NO: 47); LCDR1 (SEQ ID NO: 48), LCDR2 (SEQ ID NO: 49) and LCDR3 (SEQ ID NO: 50).

[0438] In some embodiments, the target cancer antigen for the ADC is CD46.

[0439] In some embodiments, the anti-CD46 antibody or antigen-binding fragment is one described in WO 2018 / 089807, which is incorporated herein by reference. In some embodiments, the anti-CD46 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-CD46 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 90 and the light chain variable region amino acid sequence of SEQ ID NO: 91, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD46 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 90 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 91.

[0440] In some embodiments, the target cancer antigen for the ADC is CD48.

[0441] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 51, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 52, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 53; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 54, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 55, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 56.

[0442] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 13, and the light chain variable region amino acid sequence of SEQ ID NO: 14, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 13, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 14.

[0443] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD48 antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain according to the EU numbering system.

[0444] In some embodiments, the anti-CD48 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 69, or a sequence at least 95% identical to SEQ ID NO: 69, and a light chain amino acid sequence of SEQ ID NO: 70, or a sequence at least 95% identical to SEQ ID NO: 70. In some embodiments, the anti-CD48 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 69 and a light chain amino acid sequence of SEQ ID NO: 70, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-CD48 antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 69, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 70. In some embodiments, the anti-CD48 antibody is SGN-48A or an antigen-binding fragment thereof.

[0445] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of gemtuzumab, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 51), HCDR2 (SEQ ID NO: 52), HCDR3 (SEQ ID NO: 53); LCDR1 (SEQ ID NO: 54), LCDR2 (SEQ ID NO: 55) and LCDR3 (SEQ ID NO: 56).

[0446] In some embodiments, the target cancer antigen for the ADC is CD79B.

[0447] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 82, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 83, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 84; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 85, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 86, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 87.

[0448] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 81. In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 80, and the light chain variable region amino acid sequence of SEQ ID NO: 81, or a sequence at least 95% identical to a disclosed sequence. In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 80, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 81.

[0449] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-CD79B antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain according to the EU numbering system.

[0450] In some embodiments, the anti-CD79B antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 88, or a sequence at least 95% identical to SEQ ID NO: 88, and a light chain amino acid sequence of SEQ ID NO: 89, or a sequence at least 95% identical to SEQ ID NO: 89. In some embodiments, the anti-CD33 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 88 and a light chain amino acid sequence of SEQ ID NO: 89, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-CD79B antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 88, and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 89. In some embodiments, the anti-CD79B antibody is polatizumab or an antigen-binding fragment thereof.

[0451] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs and three light chain CDRs of gemtuzumab, wherein the CDRs comprise no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions in HCDR1 (SEQ ID NO: 82), HCDR2 (SEQ ID NO: 83), HCDR3 (SEQ ID NO: 84); LCDR1 (SEQ ID NO: 85), LCDR2 (SEQ ID NO: 86) and LCDR3 (SEQ ID NO: 87).

[0452] Residues in two or more polypeptides are said to "correspond" if they occupy similar positions in the polypeptide structure. Similar positions in two or more polypeptides can be determined by aligning the polypeptide sequences based on the similarity of amino acid sequence or structure. Those skilled in the art will understand that it may be necessary to introduce gaps into either sequence to produce a good alignment.

[0453] In some embodiments, amino acid substitutions are of a single residue. Insertions typically occur between about 1 and about 20 amino acid residues, although significantly larger insertions may be tolerated as long as biological function (e.g., binding to a target antigen) is maintained. Deletions typically range from about 1 to about 20 amino acid residues, although in some cases deletions may be much larger. Substitutions, deletions, insertions, or any combination thereof, can be used to arrive at a final derivative or variant. Generally, these changes are made on a small number of amino acids to minimize alterations in the immunogenicity and specificity of the molecule, particularly antigen-binding proteins. However, larger changes may be tolerated in certain circumstances. Conservative substitutions can be made according to the following chart, shown as Table 7:

[0454] [Table 9]

[0455] In some embodiments, in which variant antibody sequences are used in ADCs, the variants typically exhibit the same quality of biological activity and induce the same immune response, but the variants can also be selected to modify the properties of the antigen-binding protein as needed. Alternatively, the variants can be designed to alter the biological activity of the antigen-binding protein. For example, glycosylation sites can be altered or removed.

[0456] Various antibodies can be used in the ADCs used herein to target cancer cells. As shown below, the linker-payloads in the ADCs disclosed herein are highly effective with different tumor antigen-targeting antibodies. Suitable antigens expressed in cancer cells but not in healthy cells, or expressed at higher levels in cancer cells than in healthy cells, are known in the art for antibodies to target them. Additional antibodies against these antigen targets can be prepared by those skilled in the art. These antibodies can be used with the linkers and Mcl-1 inhibitor payloads disclosed herein. In some embodiments, the antibody or antigen-binding fragment targets BCMA, and the BCMA-targeting antibody or antigen-binding fragment is J6M0. In some embodiments, the antibody or antigen-binding fragment targets CD33, and in some embodiments, the CD33-targeting antibody or antigen-binding fragment is MuMy9-6ch. In some embodiments, the antibody or antigen-binding fragment targets PCAD, and in some embodiments, the PCAD-targeting antibody or antigen-binding fragment is NOV169N31Q. In some embodiments, the antibody or antigen-binding fragment targets HER2, and in some embodiments, the HER2-targeting antibody or antigen-binding fragment is trastuzumab. In some embodiments, the disclosed linkers and Mcl-1 inhibitor payloads are highly effective with several different tumor-targeting antibodies, while BCMA-targeting antibodies, e.g., J6M0, CD33-targeting antibodies, e.g., MuMy9-6ch, PCAD-targeting antibodies, e.g., NOV169N31Q, and HER2-targeting antibodies, e.g., trastuzumab, provided particularly improved drug:antibody ratios, aggregation levels, stability (i.e., in vitro and in vivo stability), tumor targeting (i.e., cytotoxicity, efficacy), minimized off-target killing, and / or treatment efficacy. Improved treatment efficacy can be measured in vitro or in vivo and can include reduced tumor growth rate and / or reduced tumor volume.

[0457] In some embodiments, an alternative antibody against the same target or an antibody against a different antigen target is used, providing at least some of the advantageous functional properties described above (e.g., improved stability, improved tumor targeting, improved treatment efficacy, etc.). In some embodiments, some or all of these advantageous functional properties are observed when the disclosed linkers and Mcl-1 inhibitor payloads are conjugated to alternative BCMA-, CD33-, CD46-, CD48-, PCAD-, or HER2-targeting antibodies or antigen-binding fragments. In some other embodiments, some or all of these advantageous functional properties are observed when the disclosed linkers and Mcl-1 inhibitor payloads are conjugated to a BCMA-targeting antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets BCMA. In some embodiments, the BCMA-targeting antibody or antigen-binding fragment is J6M0. In other embodiments, some or all of these advantageous functional properties are observed when the disclosed linkers and Mcl-1 inhibitor payloads are conjugated to a CD33-targeting antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets CD33. In some embodiments, the CD33-targeting antibody or antigen-binding fragment is MuMy9-6ch. In other embodiments, some or all of these favorable functional properties are observed when the disclosed linkers and Mcl-1 inhibitor payloads are conjugated to a PCAD-targeting antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets PCAD. In some embodiments, the PCAD-targeting antibody or antigen-binding fragment is NOV169N31Q. In other embodiments, some or all of these favorable functional properties are observed when the disclosed linkers and Mcl-1 inhibitor payloads are conjugated to a HER2-targeting antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets HER2. In some embodiments, the HER2-targeting antibody or antigen-binding fragment is trastuzumab.

[0458] Linker In some embodiments, the linker in the ADC is sufficiently extracellularly stable to be therapeutically effective. In some embodiments, the linker is extracellularly stable such that the ADC remains intact when present in extracellular conditions (e.g., before transport or delivery to a cell). The term "intact" as used in the context of an ADC means that the antibody or antigen-binding fragment remains attached to the drug moiety (e.g., an Mcl-1 inhibitor).

[0459] As used herein, "stable" in the context of a linker, or an ADC comprising a linker, means that when the ADC is present in extracellular conditions, no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 3%, or no more than about 1% (or any percentage therebetween) of the linkers in a sample of the ADC are cleaved (or the entire ADC is not otherwise intact). In some embodiments, the linkers and / or ADCs disclosed herein are more stable than ADCs with alternative linkers and / or alternative linkers and / or Mcl-1 inhibitor payloads. In some embodiments, the ADCs disclosed herein may remain intact for more than about 48 hours, more than 60 hours, more than about 72 hours, more than about 84 hours, or more than about 96 hours.

[0460] Whether a linker is stable extracellularly can be determined, for example, by placing the ADC in plasma for a predetermined period of time (e.g., 2, 4, 6, 8, 16, 24, 48, or 72 hours) and then quantifying the amount of free drug moiety present in the plasma. Stability may allow the ADC time to localize to target cancer cells and prevent premature release of the drug moiety, which could reduce the therapeutic index of the ADC by indiscriminately damaging both normal and cancer tissues. In some embodiments, the linker is stable outside the target cell and releases the drug moiety from the ADC once inside the cell, allowing the drug to bind to its target. Thus, an effective linker: (i) maintains the specific binding properties of the antibody or antigen-binding fragment; (ii) enables delivery of the drug moiety, e.g., intracellular delivery, via stable binding to the antibody or antigen-binding fragment; (iii) remains stable and intact until the ADC is transported or delivered to its target site; and (iv) enables the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage or an alternative release mechanism.

[0461] Linkers can affect the physicochemical properties of ADCs. Because many cytotoxic agents are hydrophobic in nature, linking them to antibodies with additional hydrophobic moieties can result in aggregation. ADC aggregates are often insoluble and limit the achievable drug loading on the antibody, which can negatively impact the efficacy of the ADC. Protein aggregation of biologics is also commonly associated with increased immunogenicity. As shown below, the linkers disclosed herein result in ADCs with low aggregation levels and desirable drug loading levels.

[0462] Linkers can be "cleavable" or "non-cleavable" (Ducry and Stump (2010) Bioconjugate Chem. 21:5-13). Cleavable linkers are designed to release the drug moiety (e.g., an Mcl-1 inhibitor) when subjected to certain environmental factors, such as when internalized within target cells, whereas non-cleavable linkers generally rely on degradation of the antibody or antigen-binding fragment itself.

[0463] The term "alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. The term "C1-C6 alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. Non-limiting examples of "C1-C6 alkyl" groups include methyl (C1 alkyl), ethyl (C2 alkyl), 1-methylethyl (C3 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), n-butyl (C4 alkyl), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), n-pentyl (C5 alkyl), isopentyl (C5 alkyl), neopentyl (C5 alkyl), and hexyl (C6 alkyl).

[0464] The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and containing at least one double bond. The term "C2-C6 alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 6 carbon atoms and attached to the rest of the molecule by a single bond. Non-limiting examples of "C2-C6 alkenyl" groups include ethenyl (C2 alkenyl), prop-1-enyl (C3 alkenyl), but-1-enyl (C4 alkenyl), pent-1-enyl (C5 alkenyl), pent-4-enyl (C5 alkenyl), penta-1,4-dienyl (C5 alkenyl), hex-1-enyl (C6 alkenyl), hex-2-enyl (C6 alkenyl), hex-3-enyl (C6 alkenyl), hexa-1,4-dienyl (C6 alkenyl), hexa-1,5-dienyl (C6 alkenyl), and hexa-2,4-dienyl (C6 alkenyl). The term "C2-C3 alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having 2 to 3 carbon atoms, and attached to the rest of the molecule by a single bond. Non-limiting examples of "C2-C3 alkenyl" groups include ethenyl (C2 alkenyl) and prop-1-enyl (C3 alkenyl).

[0465] The term "alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms and containing no unsaturation. The term "C1-C6 alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 6 carbon atoms. Non-limiting examples of "C1-C6 alkylene" groups include methylene (C1 alkylene), ethylene (C2 alkylene), 1-methylethylene (C3 alkylene), n-propylene (C3 alkylene), isopropylene (C3 alkylene), n-butylene (C4 alkylene), isobutylene (C4 alkylene), sec-butylene (C4 alkylene), tert-butylene (C4 alkylene), n-pentylene (C5 alkylene), isopentylene (C5 alkylene), neopentylene (C5 alkylene), and hexylene (C6 alkylene).

[0466] The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond. The term "C2-C6 alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 6 carbon atoms. Non-limiting examples of "C2-C6 alkenylene" groups include ethenylene (C2 alkenylene), prop-1-enylene (C3 alkenylene), but-1-enylene (C4 alkenylene), pent-1-enylene (C5 alkenylene), pent-4-enylene (C5 alkenylene), penta-1,4-dienylene (C5 alkenylene), hex-1-enylene (C6 alkenylene), hex-2-enylene (C6 alkenylene), hex-3-enylene (C6 alkenylene), hexa-1-,4-dienylene (C6 alkenylene), hexa-1-,5-dienylene (C6 alkenylene), and hexa-2-,4-dienylene (C6 alkenylene). The term "C2-C6 alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 3 carbon atoms. Non-limiting examples of "C2-C3 alkenylene" groups include ethenylene (C2 alkenylene) and prop-1-enylene (C3 alkenylene).

[0467] The term "cycloalkyl" or "C3-C8 cycloalkyl," as used herein, refers to a saturated, monocyclic, fused bicyclic, fused tricyclic, or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and adamantanyl. Non-limiting examples of monocyclic C3-C8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0468] The term "haloalkyl" as used herein refers to a linear or branched alkyl chain in which one or more halogen groups are substituted for hydrogen along the hydrocarbon chain. Examples of halogen groups suitable for substitution in haloalkyl groups include fluorine, bromine, chlorine, and iodine. A haloalkyl group may contain multiple halogen groups substituted for hydrogen in the alkyl chain, where the halogen groups can be bonded to the same carbon or different carbons in the alkyl chain.

[0469] As used herein, alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups include optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl groups, optionally substituted linear or branched (C2-C6) alkynyl groups, optionally substituted linear or branched (C1-C6) alkoxy, optionally substituted (C1-C6) alkyl-S-, hydroxy, oxo (or N-oxide, as appropriate), nitrite, ... and optionally substituted with 1 to 4 groups selected from phenyl, cyano, —C(O)—OR′, —OC(O)—R′, —C(O)—NR′R′, —NR′R′, —(C═NR′)—OR′, linear or branched (C1-C6) haloalkyl, trifluoromethoxy, or halogen, wherein R′ and R′ are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, and wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated.

[0470] The terms "polyoxyethylene," "polyethylene glycol," or "PEG," as used herein, refer to a linear, branched, or star-shaped construct composed of (OCHCH) groups. In certain embodiments, the polyethylene or PEG group is -(OCHCH) t * - (wherein t is 1 to 40 or 4 to 40, where "-" indicates the end directed toward the self-immolative spacer, * The "-" indicates the point of attachment to the terminal group R', where R' is OH, OCH, or OCHCHC(=O)OH. In other embodiments, the polyethylene or PEG group is -(CHCHO). t * - (wherein t is 1 to 40 or 4 to 40, where "-" indicates the end directed toward the self-immolative spacer, *The "-" indicates the point of attachment to the terminal group R", where R" is H, CH, or CHCHC(=O)OH. For example, the term "PEG12", as used herein, means that t is 12.

[0471] The term "polyalkylene glycol" as used herein means (O(CH) m ) n In certain embodiments, a polyethylene or PEG group refers to a linear, branched, or star-shaped configuration composed of —O(CH) groups. m ) t * - (wherein m is 1 to 10, and t is 1 to 40 or 4 to 40, where "-" indicates the end directed toward the self-immolative spacer, * The "-" indicates the point of attachment to the terminal group R', where R' is OH, OCH, or OCHCHC(=O)OH. In other embodiments, the polyethylene or PEG group is -((CH) m O) t * - (wherein m is 1 to 10, and t is 1 to 40 or 4 to 40, where "-" indicates the end directed toward the self-immolative spacer, * The "-" indicates the point of attachment to the terminal group R", where R" is H, CH3, or CH2CH2C(=O)OH.

[0472] The term "reactive group," as used herein, is a functional group that can form a covalent bond with a functional group of an antibody, antibody fragment, or another reactive group attached to an antibody or antibody fragment. Non-limiting examples of such functional groups include the reactive groups in Table 8 provided herein.

[0473] The term "attachment group" or "coupling group," as used herein, refers to a bivalent moiety that links a bridging spacer and an antibody or fragment thereof. The bond or linking group is a bivalent moiety formed by the reaction between a reactive group and a functional group on an antibody or fragment thereof. Non-limiting examples of such bivalent moieties include the bivalent chemical moieties set forth in Tables 8 and 9 provided herein.

[0474] The term "bridge spacer," as used herein, refers to one or more linker components that are covalently linked together to form a bivalent moiety that connects a bivalent peptide spacer to a reactive group, a bivalent peptide spacer to a linking group, or a linking group to at least one cleavable group. In certain embodiments, a "bridge spacer" comprises a carboxyl group that is attached to the N-terminus of the bivalent peptide spacer via an amide bond.

[0475] The term "spacer moiety," as used herein, refers to one or more linker components that are covalently bonded together to form the moiety that connects the self-immolative spacer and the hydrophilic moiety.

[0476] The term "bivalent peptide spacer," as used herein, refers to a bivalent linker that includes one or more amino acid residues that are covalently linked together to form the moiety that connects the bridging spacer and the self-immolative spacer. The one or more amino acid residues may be residues of an amino acid selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine.

[0477] In certain embodiments, a "bivalent peptide spacer" is a peptide spacer in which each residue is selected from the group consisting of alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (A a combination of 2 to 4 amino acid residues independently selected from amino acid residues selected from amino acid residues selected from: -Val, -Ser, -Thr, -Val, -Valg, -Trp, -Tyr, -Cit, -Nva, -Norleucine (Nle), -Selenocysteine ​​(Sec), -Pyrrolysine (Pyl), -Homoserine, -Homocysteine, and -Desmethylpyrrolysine, for example, -ValCit * ;-CitVal * ;-AlaAla * ;-AlaCit * ;-CitAla * ;-AsnCit *;-CitAsn * ;-CitCit * ;-ValGlu * ;-GluVal * ;-SerCit * ;-CitSer * ;-LysCit * ;-CitLys * ;-AspCit * ;-CitAsp * ;-AlaVal * ;-ValAla * ;-PheAla * ;-AlaPhe * ;-PheLys * ;-LysPhe * ;-ValLys * ;-LysVal * ;-AlaLys * ;-LysAla * ;-PheCit * ;-CitPhe * ;-LeuCit * ;-CitLeu * ;-IleCit * ;-CitIle * ;-PheArg * ;-ArgPhe * ;-CitTrp * ;-TrpCit * ;-PhePheLys * ;-LysPhePhe * ;-DPhePheLys * ;-DLysPhePhe * ;-GlyPheLys * ;-LysPheGly * -GlyPheLeuGly-[SEQ ID NO: 160]; -GlyLeuPheGly-[SEQ ID NO: 161]; -AlaLeuAlaLeu-[SEQ ID NO: 162], -GlyGlyGly * -GlyGlyGlyGly-[SEQ ID NO: 163]; -GlyPheValGly-[SEQ ID NO: 164]; and -GlyValPheGly-[SEQ ID NO: 165], where "-" indicates the point of attachment to the bridging spacer. *" indicates the point of attachment to the self-immolative spacer.

[0478] The term "linker moiety," as used herein, refers to a chemical moiety that is part of a linker. Examples of linker moieties include: alkylene groups: -(CH), which can be either linear or branched. n - (where n is 1 to 18); alkenylene group; alkynylene group; alkenyl group; alkynyl group; ethylene glycol unit: -OCH2CH2- or -CH2CH2O-; polyethylene glycol unit: (-CH2CH2O-) x (wherein x is 2 to 20); -O-; -S-; carbonyl: -C(=O); ester: C(=O)-O or OC(=O); carbonate: -OC(=O)O-; amine: -NH-; tertiary amine; amide: -C(=O)-NH-, -NH-C(=O)- or -C(=O)N(C 1~6 alkyl); carbamate: -OC(=O)NH- or -NHC(=O)O; urea: -NHC(=O)NH; sulfonamide: -S(O)NH- or -NHS(O)2; ether: -CHO- or -OCH2-; alkylene substituted with one or more groups independently selected from carboxy, sulfonic acid, hydroxyl, amine, amino acid, sugar, phosphoric acid, and phosphonic acid; alkenylene substituted with one or more groups independently selected from carboxy, sulfonic acid, hydroxyl, amine, amino acid, sugar, phosphoric acid, and phosphonic acid; alkynylene substituted with one or more groups independently selected from carboxy, sulfonic acid, hydroxyl, amine, amino acid, sugar, phosphoric acid, and phosphonic acid; C1-C in which one or more methylene groups are replaced with one or more -S-, -NH-, or -O- moieties. 10alkylene; a bivalent ring selected from ring systems having two available points of attachment, such as phenyl (including 1,2-, 1,3-, and 1,4-disubstituted phenyl), C5-C6 heteroaryl, C3-C8 cycloalkyl (including 1,1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and 1,4-disubstituted cyclohexyl), and C4-C8 heterocycloalkyl; alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Ly), residues of amino acids selected from the group consisting of alanine (Ala), cysteine ​​(Cla), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine; Cys, aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle ... Combinations of two or more amino acid residues independently selected from amino acid residues selected from Sec, pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine, e.g., Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; Val-Ala;Phe-Lys; Lys-Phe; Val-Lys; Lys-Val; Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu-Cit; Cit-Leu; Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; Cit-Trp; and Trp-Cit; and self-immolative spacers comprising one or more protecting (trigger) groups that are susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage.

[0479] Non-limiting examples of such self-immolative spacers include:

[0480] [ka] (In the formula, PG is a protecting (trigger) group, X a is O, NH or S, X b is O, NH, NCH3 or S, X c is O or NH, Y a is CH2, CH2O or CH2NH, Y b is CH2, O or NH, Y c is a bond, CH, O, or NH, LG is a leaving group, such as the drug moiety (D) of a linker-drug group of the invention. Examples include: Additional non-limiting examples of such self-immolative spacers are described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0481] Additionally, a linker component can be a chemical moiety that is readily formed by a reaction between two reactive groups. Non-limiting examples of such chemical moieties are shown in Table 8.

[0482] [Table 10-1]

[0483] [Table 10-2]

[0484] [Table 10-3]

[0485] [Table 10-4]

[0486] [Table 10-5]

[0487] [Table 10-6] Here, R in Table 8 32 is H, C 1~4 alkyl, phenyl, pyrimidine or pyridine, and R in Table 8 35 is H, C 1~6 C substituted with alkyl, phenyl, or 1 to 3 -OH groups 1~4 alkyl, and each R in Table 8 7 is H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 Alkoxy and C substituted with -C(=O)OH 1~4 alkyl; 37are independently selected from H, phenyl and pyridine, q in Table 8 is 0, 1, 2 or 3, and R in Table 8 8 and R 13 is H or methyl, and R in Table 8 9 and R 14 is H, —CH or phenyl, R in Table 8 is H or any suitable substituent, R in Table 8 50 is H.

[0488] In addition, the linker moiety can be a group listed in Table 9 below.

[0489] [Table 11-1]

[0490] [Table 11-2]

[0491] [Table 11-3]

[0492] [Table 11-4]

[0493] As used herein, when a substructure of a compound is illustrated, it is indicated by a wavy line (

[0494] [ka] ) indicates the point of attachment of the substructure to the rest of the molecule.

[0495] The terms "self-immolative spacer" and "self-immolative group," as used herein, refer to a moiety containing one or more trigger groups (TG) that are activated by acid-, peptidase-, esterase-, glycosidase-, phosphodiesterase-, phosphatase-, protease-, lipase-, or disulfide bond cleavage, whereupon the protecting groups are removed, resulting in a cascade of decomposition reactions that lead to the time-sequential release of leaving groups. Such a cascade of reactions can be, but is not limited to, 1,4-, 1,6-, or 1,8-elimination reactions.

[0496] Non-limiting examples of self-immolative spacers or groups include:

[0497] [ka] wherein such groups may be optionally substituted, During the ceremony, TG is a trigger group, X a is O, NH or S, X b is O, NH, NCH3 or S, X c is O or NH, Y a is CH2, CH2O or CH2NH, Y b is CH2, O or NH, Y c is a bond, CH, O, or NH, LG is a leaving group, such as the drug moiety (D) of a linker-drug group of the invention. Examples include: Additional non-limiting examples of self-immolative spacers are described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0498] In certain embodiments, the self-immolative spacer has the structure

[0499] [ka] where Lp is an enzyme-cleavable bivalent peptide spacer, and A, D, L3 and R 2 are as defined herein) It is a part having the following.

[0500] In a preferred embodiment, the self-immolative spacer has the structure

[0501] [ka] where Lp is an enzyme-cleavable bivalent peptide spacer, and D, L3 and R 2 are as defined herein) In some embodiments, D is a quaternized tertiary amine containing MCl1 inhibitor.

[0502] In another preferred embodiment, the self-immolative spacer has the structure

[0503] [ka] where Lp is an enzyme-cleavable bivalent peptide spacer, and D, L3 and R 2 are as defined herein) It is a part having the following.

[0504] The term "hydrophilic moiety," as used herein, refers to a moiety that has hydrophilic properties that increase the water solubility of the drug moiety (D) when the drug moiety (D) is attached to a linker group of the present invention. Examples of such hydrophilic groups include, but are not limited to, polyethylene glycol, polyalkylene glycol, saccharides, oligosaccharides, polypeptides, 1-3 alkyl groups, and the like.

[0505] [ka] Examples include C2 to C6 alkyl substituted with a group.

[0506] Drug portion In some embodiments, an intermediate that is a precursor to the linker moiety is reacted with a drug moiety (e.g., an Mcl-1 inhibitor) under appropriate conditions. In some embodiments, a reactive group is used on the drug and / or intermediate or linker. The product of the reaction between the drug and intermediate, or the derivatized drug (drug plus linker), is then reacted with an antibody or antigen-binding fragment under conditions that facilitate conjugation of the drug and intermediate or derivatized drug to the antibody or antigen-binding fragment. Alternatively, the intermediate or linker may be first reacted with an antibody or antigen-binding fragment, or a derivatized antibody or antigen-binding fragment, and then reacted with the drug or derivatized drug.

[0507] Several different reactions are available for covalently linking drug moieties and / or linker moieties to antibodies or antigen-binding fragments. This is often achieved by reacting one or more amino acid residues of antibodies or antigen-binding fragments, including the amine groups of lysine, the free carboxylic acid groups of glutamic acid and aspartic acid, the sulfhydryl groups of cysteine, and various aromatic amino acid residues. For example, nonspecific covalent linkages can be performed using a carbodiimide reaction to link a carboxy (or amino) group on the drug moiety with an amino (or carboxy) group on the antibody or antigen-binding fragment. In addition, bifunctional agents such as dialdehydes or imidoesters may also be used to link amino groups on the drug moiety with amino groups on the antibody or antigen-binding fragment. The Schiff base reaction can also be used to link drugs (e.g., Mcl-1 inhibitors) with binders. This method involves periodate oxidation of drugs containing glycol or hydroxy groups to form aldehydes, which are then reacted with binders. The binding occurs via the formation of a Schiff base with the amino group of the binding agent. Isothiocyanates can also be used as coupling agents to covalently bind drugs to binding agents. Other techniques are known to those skilled in the art and are within the scope of the present disclosure. Examples of drug moieties that can be generated and linked to antibodies or antigen-binding fragments using various chemistries known in the art include Mcl-1 inhibitors, such as the Mcl-1 inhibitors described and exemplified herein.

[0508] Suitable drug moieties may include compounds of Formula (I), (II), (III), or their enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable acid or base addition salts. In addition, the drug moiety may include any of the Mcl-1 inhibitors (D) described herein.

[0509] As used herein, an "atropisomer" is a stereoisomer that arises due to restricted rotation about a single bond when the energy difference due to steric strain or other contributors creates a barrier to rotation high enough to allow isolation of individual conformers (Bringmann et al. Angew. Chem. Int. Ed. 2005, 44, 5384-5427). For example, for a compound of formula (II) according to the present invention, the atropisomers may be:

[0510] [ka]

[0511] For example, the preferred atropisomer is (5aS), also referred to as (5S a ) can be.

[0512] The drug moieties of the present disclosure may be any of the compounds disclosed in International Patent Application Publication Nos. WO2015 / 097123; WO2016 / 207216; WO2016 / 207217; WO2016 / 207225; WO2016 / 207226; WO2017 / 125224; WO2019 / 035899; WO2019 / 035911; WO2019 / 035914; WO and WO2017 / 182625, and U.S. Patent Application Publication No. 2019 / 0055264 (each of which is incorporated herein by reference in its entirety).

[0513] In some embodiments, the drug moiety of the present disclosure has formula (I):

[0514] [ka] (In the formula, Ring D0 is a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; Ring E0 is a furyl, thienyl or pyrrolyl ring; X 01 , X 03 , X 04 and X 05 are each independently a carbon atom or a nitrogen atom, X 02 is CR 026 group or a nitrogen atom,

[0515] [ka] means that the ring is aromatic, Y0 is a nitrogen atom or CR 03 It is the basis, Z0 is a nitrogen atom or CR 04 It is the basis, R 01 is a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl group, a hydroxy group, a hydroxy(C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, -Cy 08 , -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR011 R 011 ' or -SO2-(C1-C6)alkyl; R 02 , R 03 , R 04 and R 05 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a hydroxy(C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-R 031 , -O-(C1-C6)alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 01 , R 02 ), (R 02 , R 03 ), (R 03 , R 04) or (R 04 , R 05 ) together with the carbon atoms to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring may be substituted with halogen, linear or branched (C1-C6) alkyl, (C0-C6) alkyl-NR 011 R 011 ', -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 or oxo, R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR011 R 011 ', or -SO2-(C1-C6) alkyl; Or pair (R 06 , R 07 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring can be optionally fused with a linear or branched (C1-C6) alkyl group, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 or optionally substituted with oxo, W0 is a -CH2- group, a -NH- group or an oxygen atom; R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, -CHR 0a R 0b a group, an aryl group, a heteroaryl group, an aryl(C1-C6)alkyl group, or a heteroaryl(C1-C6)alkyl group, R 09 is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 03 , halogen atoms, cyano groups, -C(O)-R 014 or -C(O)-NR 014 R 014 ' and R 010is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, an aryl (C1-C6) alkyl group, a (C1-C6) cycloalkyl alkyl group, a linear or branched (C1-C6) haloalkyl group, or -(C1-C6) alkyl-O-Cy 04 and Or pair (R 09 , R 010 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N; R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom is optionally substituted with one or two groups selected from linear or branched (C1-C6) alkyl groups, wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated; R 012 -Cy 05 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C0-C6) alkyl-Cy07 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 09 , -Cy 05 -(C0-C6) alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 09 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ', -OR 011 , -NR 011 -C(O)-R 011 ', -O-(C1-C6) alkyl-OR 011 , -SO2-R 011 , -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group; R 0a is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 0b is -OC(O)-OR 0c group, -OC(O)-NR 0c R 0c ' group or -OP(O)(OR 0c )2 units, R 0c and R 0c ' are each independently a hydrogen atom, a linear or branched (C1-C8) alkyl group, a cycloalkyl group, a (C1-C6) alkoxy(C1-C6) alkyl group or a (C1-C6) alkoxycarbonyl(C1-C6) alkyl group, Or pair (R 0c , R 0c') together with the nitrogen atom to which they are attached form a non-aromatic ring consisting of 5 to 7 ring members which, in addition to the nitrogen atom, may contain 1 to 3 heteroatoms selected from oxygen and nitrogen, wherein the nitrogen is optionally substituted with a linear or branched (C1-C6) alkyl group; Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are, independently of each other, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; Cy 09 teeth

[0516] [ka] and or Cy 09 is -OP(O)(OR 020 )2;-OP(O)(O - M + )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C1-C6)alkyl;-(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R 021 ', and R 015 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020Group; Linear or branched (C1-C6) alkoxy (C1-C6) alkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group, R 016 represents a hydrogen atom; a hydroxy group; a hydroxy(C1-C6) alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0-V0-OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + )2 groups;-OS(O)2OR 020 Group;-S(O)2OR 020 Group;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group;-(CH2) p0 -OC(O)-NR 022 R 023 group; or -U0-(CH2) q0 -NR 021 R 021 'Based on R 017 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group: -CH2-P(O)(OR 020 ) 2 units, -OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + )2 group; hydroxy group; hydroxy(C1-C6) alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or aldonic acid, M +is a pharmaceutically acceptable monovalent cation, U0 is a bond or an oxygen atom, V0 is -(CH2) s0 - group or -C(O)- group, R 018 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, R 019 is a hydrogen atom or a hydroxy(C1-C6)alkyl group, R 020 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 021 and R 021 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group, or a hydroxy(C1-C6) alkyl group, Or pair (R 021 , R 021 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with hydrogen atoms or linear or branched (C1-C6) alkyl groups; R 022 represents a (C1-C6) alkoxy(C1-C6) alkyl group, -(CH2) p0 -NR 024 R 024 ' group or -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 It is the basis, R 023 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, Or pair (R 022 , R 023) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 18 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom, a linear or branched (C1-C6) alkyl group or a heterocycloalkyl group; R 024 and R 024 ' are each independently a hydrogen atom or a linear or branched (C1-C6) alkyl group, Or pair (R 024 , R 024 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with hydrogen atoms or linear or branched (C1-C6) alkyl groups; R 025 is a hydrogen atom, a hydroxy group, or a hydroxy(C1-C6)alkyl group, R 026 is a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, or a cyano group, R 027 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 028 is -OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 030 ) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -O-SO2- group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-OR 030 Group, -Cy 010 , -(CH2) p0 -SO2-OR 030 group, -OC(O)-R 029The group -OC(O)-OR 029 group or -OC(O)-NR 029 R 029 'Based on R 029 and R 029 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched amino(C1-C6) alkyl group, R 030 and R 030 ' are each independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or an aryl (C1-C6) alkyl group, R 031 teeth

[0517] [ka] wherein the ammonium ion is optionally present in zwitterionic form or has a monovalent anionic counterion; n0 is an integer equal to 0 or 1, p0 is an integer equal to 0, 1, 2, or 3; q0 is an integer equal to 1, 2, 3, or 4; r0 and s0 are independently integers equal to 0 or 1; Here, at most, R 03 Group, R 09 group or R 012 one of the groups, if present, is covalently attached to the linker; where the valency of the atom is not exceeded by one or more substituents attached to it. or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0518] In some embodiments, the drug moiety of the present disclosure has formula (II):

[0519] [ka] (In the formula, Z0 is a nitrogen atom or CR 04 It is the basis, R 01 is a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl group, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, -Cy 08 , -NR 011 R 011 ' and R 02 , R 03 and R 04 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 031 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 02 , R 03 ) or (R 03 , R 04 ) together with the carbon atoms to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is selected from linear or branched (C1-C6) alkyl, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 and oxo, R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a linear or branched (C1-C6) haloalkyl, a hydroxy group, a linear or branched (C1-C6) alkoxy group, an -S-(C1-C6) alkyl group, a cyano group, a nitro group, or a -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 , -O-(C1-C6) alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R011 ', or -SO2-(C1-C6) alkyl; Or pair (R 06 , R 07 ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring can be optionally fused with a linear or branched (C1-C6) alkyl group, -NR 013 R 013 ', -(C0-C6) alkyl-Cy 01 and oxo, R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, an aryl group, a heteroaryl group, an aryl-(C1-C6) alkyl group or a heteroaryl-(C1-C6) alkyl group, R 09 is a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 03 , halogen atoms, cyano groups, -C(O)-R 014 , -C(O)-NR 014 R 014 ' and R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom is optionally substituted with a linear or branched (C1-C6) alkyl group, and wherein one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group is optionally deuterated; R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 , -Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy 06 , -Cy 05 -(C0-C6) alkyl-NR 011 -(C0-C6) alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C0-C6) alkyl-Cy 07 , -Cy 05 -(C0-C6) alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ', -OR 011 , -NR 011 -C(O)-R 011 ', -O-(C1-C6) alkyl-OR 011 , -SO2-R 011 , or -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group; Cy 01 , Cy 02 , Cy 03 , Cy 05, Cy 06 , Cy 07 and Cy 08 are, independently of each other, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; Cy 09 teeth

[0520] [ka] and where R 015 , R 016 and R 017 is as defined for formula (I), R 031 teeth

[0521] [ka] where R 027 and R 028 is as defined for formula (I), Here, at most, R 03 Group, R 09 group or R 012 One of the groups, if present, is covalently attached to the linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0522] In some embodiments, the drug moiety of the present disclosure has formula (III):

[0523] [ka] (In the formula, R 01 is a linear or branched (C1-C6) alkyl group, R 03 is -O-(C1-C6) alkyl-NR 011 R011 'or

[0524] [ka] and where R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group, or -(C0-C6) alkyl-Cy 01 and Or pair (R 011 , R 011 ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted with one or two groups selected from a hydrogen atom or a linear or branched (C1-C6) alkyl group; where R 027 is a hydrogen atom, and R 028 is -(CH2) p0 -O-SO2-O - group or -(CH2) p0 -SO2-OR 030 It is the basis, R 09 is a linear or branched (C2-C6) alkynyl group or -Cy 02 and R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 or -Cy 05 -(C0-C6) alkyl-Cy 09 and Cy 01 , Cy 02 , Cy 05 and Cy 06 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth,

[0525] [ka] and p0, R 015 , R 016 and R 017 is as defined for formula (I), Here, at most, R 03 Group, R 09 group or R 012 One of the groups, if present, is covalently attached to the linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0526] In some embodiments, Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010are each independently an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the optional substituents are optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl group, optionally substituted linear or branched (C2-C6) alkynyl group, optionally substituted linear or branched (C1-C6) alkoxy, optionally substituted (C1-C6) alkyl-S-, hydro and R is selected from oxy, oxo (or N-oxide, where appropriate), nitro, cyano, —C(O)—OR′, —OC(O)—R′, —C(O)—NR′R′, —NR′R′, —(C═NR′)—OR′, linear or branched (C1-C6) haloalkyl, trifluoromethoxy, or halogen, where R′ and R′ are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, and where one or more of the carbon atoms of the linear or branched (C1-C6) alkyl group is optionally deuterated.

[0527] In some embodiments, the drug moiety (D) is

[0528] [ka]

[0529] [ka] or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing.

[0530] Additionally, the drug moiety of the present disclosure may be:

[0531] [ka]

[0532] [ka] It may include any one of the following:

[0533] In some embodiments, the linker-drug (or "linker-payload") moiety -(LD) can comprise a compound in Table A or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or a pharmaceutically acceptable salt of any of the foregoing.

[0534] Drug Load The drug load is represented by p and is also referred to herein as the drug-to-antibody ratio (DAR). The drug load may range from 1 to 16 per drug moiety antibody or antigen-binding fragment. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p is an integer from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 2. In some embodiments, p is 4.

[0535] Drug loading may be limited by the number of binding sites on the antibody or antigen-binding fragment. In some embodiments, the linker moiety (L) of the ADC is attached to the antibody or antigen-binding fragment via a chemically active group on one or more amino acid residues on the antibody or antigen-binding fragment. For example, the linker may be attached to the antibody or antigen-binding fragment via a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., to the N- or C-terminus, to the epsilon-amino group of one or more lysine residues, to the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteine ​​residues). The linker attachment site may be a natural residue in the amino acid sequence of the antibody or antigen-binding fragment, or may be introduced into the antibody or antigen-binding fragment by, for example, recombinant DNA techniques (e.g., by introducing a cysteine ​​residue into the amino acid sequence) or protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis).

[0536] In some embodiments, the number of drug moieties that can be conjugated to an antibody or antigen-binding fragment is limited by the number of free cysteine ​​residues. For example, if the bond is a cysteine ​​thiol group, the antibody may have only one or a few cysteine ​​thiol groups, or only one or a few sufficiently reactive thiol groups to which a linker can be attached. Generally, antibodies do not contain many free and reactive cysteine ​​thiol groups that can be linked to a drug moiety. In fact, most cysteine ​​thiol residues in antibodies are involved in either inter- or intra-chain disulfide bonds. As a result, in some embodiments, conjugation to cysteines may require at least partial reduction of the antibody. Excessive conjugation of linker-toxins to an antibody may compromise antibody stability by reducing the number of cysteine ​​residues available for disulfide bond formation. Consequently, an optimal drug:antibody ratio should increase the potency of the ADC (by increasing the number of drug moieties conjugated per antibody) without compromising the stability of the antibody or antigen-binding fragment. In some embodiments, the optimal ratio may be 2, 4, 6, or 8. In some embodiments, the optimal ratio may be 2 or 4.

[0537] In some embodiments, the antibody or antigen-binding fragment is exposed to reducing conditions prior to conjugation to generate one or more free cysteine ​​residues. In some embodiments, the antibody may be reduced under partial or total reducing conditions using a reducing agent, such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP), to generate reactive cysteine ​​thiol groups. Unpaired cysteines may be generated through partial reduction using a limited molar equivalent of TCEP, which reduces the interchain disulfide bonds connecting the light and heavy chains (one pair per HL pair) and the two heavy chains in the hinge region (two pairs per HH pair in the case of human IgG1), while leaving the intrachain disulfide bonds intact (Stefano et al. (2013) Methods Mol Biol. 1045:145-71). In embodiments, disulfide bonds within the antibody are electrochemically reduced, for example, by using a working electrode that alternately applies a reducing and oxidizing voltage. This approach can allow online coupling of disulfide bond reduction to an analytical device (e.g., an electrochemical detection device, an NMR spectrometer, or a mass spectrometer) or a chemical separation device (e.g., a liquid chromatography (e.g., HPLC) or an electrophoresis device (see, e.g., U.S. Patent Application Publication No. 2014 / 0069822)). In some embodiments, the antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups on amino acid residues, e.g., cysteines.

[0538] Drug loading of ADCs may be controlled in different ways, for example: (i) by limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody; (ii) by limiting the conjugation reaction time or temperature; (iii) by partial or limited reducing conditions for cysteine ​​thiol modifications; and / or (iv) by recombinantly engineering the amino acid sequence of the antibody to modify the number and position of cysteine ​​residues to control the number and / or position of linker-drug bonds.

[0539] In some embodiments, a free cysteine ​​residue is introduced into the amino acid sequence of an antibody or antigen-binding fragment. For example, a cysteine-engineered antibody may be prepared in which one or more amino acids of a parent antibody are replaced with a cysteine ​​amino acid. Both forms of antibodies may be engineered, i.e., mutated, in this manner. For example, a parent Fab antibody fragment may be engineered to form a cysteine-engineered Fab, referred to as a "ThioFab." Similarly, a parent monoclonal antibody may be engineered to form a "ThioMab." A single-site mutation results in a single engineered cysteine ​​residue in a ThioFab, while a single-site mutation results in two engineered cysteine ​​residues in a ThioMab due to the dimeric nature of IgG antibodies. DNA encoding amino acid sequence variants of a parent polypeptide can be prepared by various methods known in the art (see, for example, the methods described in WO 2006 / 034488). These methods include, but are not limited to, site-directed (or oligonucleotide-mediated) mutagenesis, PCR mutagenesis, and cassette mutagenesis of initially prepared DNA encoding the polypeptide. Recombinant antibody variants may also be constructed by restriction fragment engineering or overlap extension PCR using synthetic oligonucleotides. ADCs of formula (1) include, but are not limited to, antibodies with one, two, three, or four engineered cysteine ​​amino acids (Lyon et al. (2012) Methods Enzymol. 502:123-38). In some embodiments, one or more free cysteine ​​residues are already present in an unengineered antibody or antigen-binding fragment, in which case the existing free cysteine ​​residues may be used to conjugate the antibody or antigen-binding fragment to a drug moiety.

[0540] When more than one nucleophilic group reacts with a drug-linker intermediate or with a linker moiety reagent followed by a drug moiety reagent in a reaction mixture containing multiple copies of an antibody or antigen-binding fragment and a linker moiety, the resulting product can be a mixture of ADC compounds with a distribution of one or more drug moieties attached to each copy of the antibody or antigen-binding fragment in the mixture. In some embodiments, the drug load in the mixture of ADCs resulting from the conjugation reaction ranges from 1 to 16 attached drug moieties per antibody or antigen-binding fragment. The average number of drug moieties per antibody or antigen-binding fragment (i.e., average drug load, or average p) can be calculated by any conventional method known in the art, for example, by mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC-MS)) and / or high-performance liquid chromatography (e.g., HIC-HPLC). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is determined by liquid chromatography-mass spectrometry (LC-MS). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 1.5 to about 3.5, about 2.5 to about 4.5, about 3.5 to about 5.5, about 4.5 to about 6.5, about 5.5 to about 7.5, about 6.5 to about 8.5, or about 7.5 to about 9.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 2 to about 4, about 3 to about 5, about 4 to about 6, about 5 to about 7, about 6 to about 8, about 7 to about 9, about 2 to about 8, or about 4 to about 8.

[0541] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 2. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 2.

[0542] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 4. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 4.

[0543] In some embodiments, the term "about," when used in reference to the average number of drug moieties per antibody or antigen-binding fragment, means plus or minus 20%, 15%, 10%, 5%, or 1%. In one embodiment, the term "about" refers to a range of values ​​that are 10% greater or less than a particular value. In another embodiment, the term "about" refers to a range of values ​​that are 5% greater or less than a particular value. In another embodiment, the term "about" refers to a range of values ​​that are 1% greater or less than a particular value.

[0544] Individual ADC compounds or "species" may be identified in the mixture by mass spectroscopy and separated, for example, by UPLC or HPLC, such as hydrophobic interaction chromatography (HIC-HPLC). In some embodiments, a homogeneous or near-homogeneous ADC product having a single loading value may be isolated from the conjugation mixture, for example, by electrophoresis or chromatography.

[0545] In some embodiments, high drug loads (e.g., p>16) may result in aggregation, insolubility, toxicity, or loss of cell permeability of certain antibody-drug conjugates. High drug loads may also negatively impact the pharmacokinetics (e.g., clearance) of certain ADCs. In some embodiments, low drug loads (e.g., p<2) may reduce the potency of certain ADCs against target-expressing cells. In some embodiments, the drug load for an ADC of the present disclosure ranges from about 2 to about 16, about 2 to about 10, about 2 to about 8; about 2 to about 6; about 2 to about 5; about 3 to about 5; about 2 to about 4; or about 4 to about 8.

[0546] In some embodiments, a drug load and / or average drug load of about 2 is achieved, for example, using partial reduction of intrachain disulfides in the antibody or antigen-binding fragment, providing beneficial properties. In some embodiments, a drug load and / or average drug load of about 4, about 6, or about 8 is achieved, for example, using partial reduction of intrachain disulfides in the antibody or antigen-binding fragment, providing beneficial properties. In some embodiments, a drug load and / or average drug load of less than about 2 results in an unacceptably high level of unconjugated antibody species, which may compete with the ADC for binding to the target antigen and / or may reduce the efficacy of treatment. In some embodiments, a drug load and / or average drug load greater than about 16 may result in an unacceptably high level of product heterogeneity and / or ADC aggregation. A drug load and / or average drug load greater than about 16 may also affect the stability of the ADC, due to loss of one or more chemical bonds required to stabilize the antibody or antigen-binding fragment.

[0547] The present disclosure includes methods for producing the described ADCs. Briefly, an ADC comprises an antibody or antigen-binding fragment that remains as an antibody or antigen-binding fragment, a drug moiety (e.g., an Mcl-1 inhibitor), and a linker connecting the drug moiety and the antibody or antigen-binding fragment. In some embodiments, an ADC may be prepared using a linker with a reactive functional group for covalently attaching the drug moiety to the antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is functionalized to prepare a functional group that is reactive with a linker or drug-linker intermediate. For example, in some embodiments, a cysteine ​​thiol of the antibody or antigen-binding fragment can form a bond with a reactive functional group of a linker or drug-linker intermediate to produce an ADC. In some embodiments, antibodies or antigen-binding fragments are prepared using bacterial transglutaminase (BTG), a reactive glutamine specifically functionalized with an amine-containing cyclooctyne BCN (N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethyloxycarbonyl]-1,8-diamino-3,6-dioxaoctane) moiety. In some embodiments, site-specific conjugation of a linker or drug-linker intermediate to the BCN moiety of the antibody or antigen-binding fragment is performed, for example, as described and exemplified herein. Generation of ADCs can be achieved by techniques known to those skilled in the art.

[0548] In some embodiments, ADCs are produced by contacting an antibody or antigen-binding fragment with a linker and a drug moiety (e.g., an Mcl-1 inhibitor) in a sequential manner, such that the antibody or antigen-binding fragment is first covalently linked to the linker and then a preformed antibody-linker intermediate is reacted with the drug moiety. The antibody-linker intermediate may or may not undergo a purification step before contacting the drug moiety. In other embodiments, ADCs are produced by contacting an antibody or antigen-binding fragment with a linker-drug compound that is preformed by reacting the linker with the drug moiety. The preformed linker-drug compound may or may not undergo a purification step before contacting the antibody or antigen-binding fragment. In other embodiments, the antibody or antigen-binding fragment is contacted with the linker and drug moiety in a single reaction mixture, allowing for simultaneous formation of covalent bonds between the antibody or antigen-binding fragment and the linker and between the linker and the drug moiety. This method of producing an ADC may involve contacting an antibody or antigen-binding fragment with an antibody or antigen-binding fragment and then adding a linker to the reaction mixture, or vice versa. In some embodiments, the ADC is produced by reacting an antibody or antigen-binding fragment with a linker linked to a drug moiety, e.g., an Mcl-1 inhibitor, under conditions that allow conjugation.

[0549] The ADC prepared according to the above-mentioned method may be subjected to a purification step. The purification step may involve any biochemical method known in the art for purifying proteins, or any combination of these methods. These include, but are not limited to, tangential flow filtration (TFF), affinity chromatography, ion exchange chromatography, any charge- or isoelectric-based chromatography, mixed-mode chromatography, such as CHT (ceramic hydroxyapatite), hydrophobic interaction chromatography, size exclusion chromatography, dialysis, filtration, selective precipitation, or any combination thereof.

[0550] Therapeutic Uses and Compositions Disclosed herein are methods for using compositions described herein, for example, the disclosed ADC compounds and compositions, in the treatment of subjects with disorders, for example, cancer.Compositions, for example, ADCs, can be administered alone or in combination with at least one additional inactive agent and / or active agent, for example, at least one additional therapeutic agent, and can be administered in any pharmaceutically acceptable formulation, dosage, and dosing regimen.The effectiveness of treatment can be evaluated based on toxicity and efficacy indicators and adjusted accordingly.Measures of effectiveness include, but are not limited to, cytostatic and / or cytotoxic effects observed in vitro or in vivo, reduction in tumor volume, tumor growth inhibition, and / or prolonged survival.

[0551] Methods for determining whether an ADC exerts a cytostatic and / or cytotoxic effect on cells are known. For example, the cytotoxicity or cytostatic activity of an ADC can be measured by, for example, exposing mammalian cells expressing the target antigen of the ADC in cell culture medium; culturing the cells for a period of about 6 hours to about 6 days; and measuring cell viability (for example, using CellTiter-Glo® (CTG) or MTT cell viability assay). Cell-based in vitro assays can also be used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) of the ADC.

[0552] To assess cytotoxicity, necrosis or apoptosis (programmed cell death) may be measured. Necrosis is typically accompanied by increased plasma membrane permeability, cell swelling, and plasma membrane rupture. Apoptosis can be quantified, for example, by measuring DNA fragmentation. Commercially available photometric methods for quantitatively assessing DNA fragmentation in vitro are available. Examples of such assays include TUNEL (detecting the incorporation of labeled nucleotides into fragmented DNA) and ELISA-based assays, which are described in Biochemica (1999) 2:34-7 (Roche Molecular Biochemicals).

[0553] Apoptosis may also be determined by measuring morphological changes in cells. For example, loss of plasma membrane integrity, similar to necrosis, may be determined by measuring the uptake of certain dyes (e.g., fluorescent dyes such as acridine orange or ethidium bromide). Methods for measuring the number of apoptotic cells are described by Duke and Cohen in Current Protocols in Immunology (Coligan et al., eds. (1992) pp. 3.17.1-3.17.16). Cells may also be labeled with DNA dyes (e.g., acridine orange, ethidium bromide, or propidium iodide) and observed for chromatin condensation and margination along the inner side of the nuclear membrane. Apoptosis may also be determined, in some embodiments, by screening for caspase activity. In some embodiments, the Caspase-Glo® assay may be used to measure the activity of caspase-3 and caspase-7. In some embodiments, the assay provides a luminescent caspase-3 / 7 substrate in a reagent optimized for caspase activity, luciferase activity, and cell lysis. In some embodiments, addition of the Caspase-Glo® 3 / 7 Reagent in an "add-mix-measure" format can result in cell lysis, followed by caspase cleavage of the substrate and the generation of a "glow-type" luminescent signal generated by luciferase. In some embodiments, luminescence can be proportional to the amount of caspase activity present and can serve as an indicator of apoptosis. Other morphological changes that can be measured to determine apoptosis include, for example, cytoplasmic condensation, increased membrane blebbing, and cell shrinkage. Determining any of these effects on cancer cells indicates that the ADC is useful in treating cancer.

[0554] Cell viability may be measured, for example, by determining cellular uptake of a dye, such as neutral red, trypan blue, crystal violet, or ALAMAR™ blue (see, e.g., Page et al. (1993) Intl J Oncology 3:473-6). In such assays, cells are incubated in medium containing the dye, washed, and the remaining dye, which reflects cellular uptake of the dye, is measured spectrophotometrically.

[0555] Cell viability may also be measured, for example, by quantifying ATP, an indicator of metabolically active cells. In some embodiments, the in vitro potency and / or cell viability of the prepared ADC or Mcl-1 inhibitor compound may be assessed using the CellTiter-Glo® (CTG) cell viability assay, as described in the examples provided herein. In this assay, in some embodiments, a single reagent (CellTiter-Glo® Reagent) is added directly to cells cultured in serum-supplemented medium. Addition of the reagent results in cell lysis and the generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture.

[0556] Cell viability may also be measured, for example, by measuring the reduction of tetrazolium salts. In some embodiments, the in vitro efficacy and / or cell viability of the prepared ADC or Mcl-1 inhibitor compound may be evaluated using an MTT cell viability assay, as described in the examples provided herein. In this assay, in some embodiments, the yellow tetrazolium MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) is reduced by metabolically active cells, in part by the action of dehydrogenase enzymes, to generate reducing equivalents, such as NADH and NADPH. The resulting intracellular purple formazan may then be solubilized and quantified by spectrophotometric means.

[0557] In certain aspects, the present disclosure features methods for killing cancer cells or tissues and inhibiting or modulating their growth by disrupting the expression and / or activity of Mcl-1 and / or one or more upstream modulators or downstream targets thereof. The methods may be used in any subject for whom disruption of Mcl-1 expression and / or activity provides a therapeutic benefit. Subjects that may benefit from disrupting Mcl-1 expression and / or activity include, but are not limited to, those with or at risk of having cancer, such as tumors or blood cancers. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0558] In some embodiments, the disclosed ADCs may be administered to any cell or tissue that expresses BCMA, such as a BCMA-expressing cancer cell or tissue. Exemplary embodiments include methods of killing BCMA-expressing cancer cells or tissues. The methods may be used on any cell or tissue that expresses BCMA, such as cancerous cells or metastatic lesions. A non-limiting example of a BCMA-expressing cancer is multiple myeloma (Cho et al. (2018) Front Immunol. 9:1821). Non-limiting examples of BCMA-expressing cells include NCI-H929 multiple myeloma cells and cells containing a recombinant nucleic acid encoding BCMA, or a portion thereof.

[0559] In some embodiments, the disclosed ADCs may be administered to any cell or tissue that expresses CD33, such as a CD33-expressing cancer cell or tissue. Exemplary embodiments include methods for killing CD33-expressing cancer cells or tissues. The methods may be used on any cell or tissue that expresses CD33, such as cancerous cells or metastatic lesions. Non-limiting examples of CD33-expressing cancers include colorectal cancer, pancreatic cancer, lymphoma, and leukemia (e.g., acute myeloid leukemia) (Human Protein Atlas; Walter (2014) Expert Opin Ther Targets 18(7):715-8). Non-limiting examples of CD33-expressing cells include MOLM-13 leukemia cells and cells containing a recombinant nucleic acid encoding CD33 or a portion thereof.

[0560] In some embodiments, the disclosed ADCs may be administered to any cell or tissue that expresses PCAD, such as a PCAD-expressing cancer cell or tissue. Exemplary embodiments include methods for killing PCAD-expressing cancer cells or tissues. The methods may be used in any cell or tissue that expresses PCAD, such as cancerous cells or metastatic lesions. Non-limiting examples of PCAD-expressing cancers include breast cancer, gastric cancer, endometrial cancer, ovarian cancer, pancreatic cancer, bladder cancer, prostate cancer, and melanoma (Vieira and Paredes (2015) Mol Cancer 14:178).

[0561] In some embodiments, the disclosed ADCs may be administered to any cell or tissue that expresses HER2, such as a HER2-expressing cancer cell or tissue. Exemplary embodiments include methods of killing HER2-expressing cancer cells or tissues. The methods may be used in any cell or tissue that expresses HER2, such as cancerous cells or metastatic lesions. Non-limiting examples of HER2-expressing cancers include breast cancer, gastric cancer, bladder cancer, urothelial cell carcinoma, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial carcinoma), salivary duct carcinoma, cervical cancer, endometrial cancer, and ovarian cancer (English et al. (2013) Mol Diagn Ther. 17:85-99). Non-limiting examples of HER2-expressing cells include HCC1954 and HCC2218 breast cancer cells, and cells containing a recombinant nucleic acid encoding HER2, or a portion thereof.

[0562] An exemplary method includes contacting cells with an ADC, as described herein, in an effective amount, i.e., an amount sufficient to kill the cells. The method may be used on cells in culture, e.g., in vitro, in vivo, ex vivo, or in situ. For example, HER2-expressing cells (e.g., cells collected by biopsy of a tumor or metastatic lesion; cells from an established cancer cell line; or recombinant cells) may be cultured in vitro in culture medium, and the contacting step may be affected by adding an ADC to the culture medium. The method will result in the killing of HER2-expressing cells, including specifically HER2-expressing cancer cells. Alternatively, the ADC may be administered to a subject by any suitable administration route (e.g., intravenously, subcutaneously, or by direct contact with tumor tissue) to have an in vivo effect. This approach may also be used with antibodies targeting other cell surface antigens (e.g., BCMA, CD33, PCAD).

[0563] The in vivo efficacy of the disclosed ADC therapeutic compositions may be evaluated in a suitable animal model. For example, a xenogeneic cancer model may be used, in which cancer explants or serial xenografts are introduced into immunodeficient animals, such as nude or SCID mice (Klein et al. (1997) Nature Med. 3:402-8). Efficacy may be predicted using assays that measure tumor formation, tumor regression, or inhibition of metastasis, etc.

[0564] In vivo assays that evaluate the mechanism of tumor killing promotion, such as apoptosis, may also be used. In some embodiments, xenografts from tumor-bearing mice treated with therapeutic compositions may be examined for the presence of apoptotic foci and compared with untreated control xenograft-bearing mice. The degree of apoptotic foci observed in the tumors of treated mice provides an indication of the therapeutic effectiveness of the composition.

[0565] Further provided herein is a method for treating disorders, for example, cancer.The compositions described herein, for example, the ADCs disclosed herein, can be administered to non-human mammals or human subjects for therapeutic purposes.The therapeutic method includes administering a therapeutically effective amount of a composition comprising an Mcl-1 inhibitor, for example, an ADC, to a subject who has or is suspected of having cancer, wherein the inhibitor is linked to a targeting antibody that binds to an antigen, and the antigen (1) is expressed on cancer cells, (2) is accessible for binding, and / or (3) is located or primarily expressed on the surface of cancer cells compared to non-cancer cells.

[0566] An exemplary embodiment is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a composition, e.g., an ADC, composition, or pharmaceutical composition disclosed herein (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44v 6, CD51, CD52, CD70, CD72 (Lyb-2, B-cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor metastasis-associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAPI, STEAP2, PCANAPI, STAMPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b. In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T cell or B cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or spleen cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0567] Another exemplary embodiment is a method of delivering an Mcl-1 inhibitor to a cell expressing BCMA, comprising conjugating the Mcl-1 inhibitor to an antibody that immunospecifically binds to a BCMA epitope and exposing the cell to the ADC. Exemplary BCMA-expressing cancer cells for which the ADCs of the present disclosure are applicable include multiple myeloma cells.

[0568] Another exemplary embodiment is a method of delivering an Mcl-1 inhibitor to a cell expressing CD33, comprising conjugating the Mcl-1 inhibitor to an antibody that immunospecifically binds to the CD33 epitope and exposing the cell to the ADC. Exemplary cancer cells expressing CD33 for which the ADCs of the present disclosure are applicable include leukemia cells.

[0569] Another exemplary embodiment is a method of delivering an Mcl-1 inhibitor to a cell expressing PCAD, comprising conjugating the Mcl-1 inhibitor to an antibody that immunospecifically binds to a PCAD epitope and exposing the cell to the ADC. Exemplary cancer cells expressing PCAD to which the ADCs of the present disclosure are applicable include breast cancer and gastric cancer cells.

[0570] Another exemplary embodiment is a method of delivering an Mcl-1 inhibitor to a cell expressing HER2, comprising conjugating the Mcl-1 inhibitor to an antibody that immunospecifically binds to a HER2 epitope and exposing the cell to the ADC. Exemplary cancer cells expressing HER2 for which the ADCs of the present disclosure are applicable include breast cancer cells.

[0571] In certain aspects, the present disclosure further provides methods of reducing or inhibiting the growth of a tumor (e.g., a BCMA-expressing tumor, a CD33-expressing tumor, a PCAD-expressing tumor, a HER2-expressing tumor), comprising administering a therapeutically effective amount of an ADC or a composition comprising the ADC. In some embodiments, the treatment is sufficient to reduce or inhibit tumor growth, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, prolong survival, and / or maintain or improve quality of life in a patient. In some embodiments, the tumor is resistant or refractory to treatment with an antibody or antigen-binding fragment of the ADC (e.g., an anti-BCMA antibody, an anti-CD33 antibody, an anti-PCAD antibody, an anti-HER2 antibody) when administered alone, and / or the tumor is resistant or refractory to treatment with an Mcl-1 inhibitor drug moiety when administered alone.

[0572] An exemplary embodiment is a method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB. In some embodiments, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44v 6, CD51, CD52, CD70, CD72 (Lyb-2, B-cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor metastasis-associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMPIn some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, ...

Claims

1. Formula (1): A-(L-D) ｐ (1) wherein Ab is an antibody or an antigen-binding fragment thereof; D is an Mcl-1 inhibitor; L is a linker covalently linking Ab to D; p is an integer from 1 to 16; D is a compound of formula (II): 【Chemical 1】 (In the formula, Z ０ is a nitrogen atom or C—R ０４ It is the basis, R ０１ is a halogen atom, a linear or branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) haloalkyl group, hydroxy group, linear or branched (C １ ~C ６ ) alkoxy group, —S—(C １ ~C ６ ) alkyl group, cyano group, -Cy ０８ , or -NR ０１１ R ０１１ ' and R ０２ , R ０３ and R ０４ are each independently a hydrogen atom, a halogen atom, a linear or branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) haloalkyl, hydroxy group, linear or branched (C １ ~C ６ ) alkoxy group, —S—(C １ ~C ６ ) alkyl group, cyano group, nitro group, -(C ０ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -O-Cy ０１ , -(C ０ ~C ６ ) Alkyl-Cy ０１ , -(C ２ ~C ６ ) Alkenyl-Cy ０１ , -(C ２ ~C ６ ) Alkynyl-Cy ０１ , —O—(C １ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -O-(C １ ~C ６ ) alkyl-R ０３１ , —C(O)—OR ０１１ , -O-C(O)-R ０１１ , —C(O)—NR ０１１ R ０１１ ', -NR ０１１ -C(O)-R ０１１ ', -NR ０１１ -C(O)-OR ０１１ ', -(C １ ~C ６ ) alkyl-NR ０１１ -C(O)-R ０１１ ', -SO ２ -NR ０１１ R ０１１ ', or -SO ２ -(C １ ~C ６ ) alkyl, Or pair (R ０２ , R ０３ ) or (R ０３ , R ０４ ) together with the carbon atoms to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members; R ０６ and R ０７ are each independently a hydrogen atom, a halogen atom, a linear or branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) haloalkyl, hydroxy group, linear or branched (C １ ~C ６ ) alkoxy group, —S—(C １ ~C ６ ) alkyl group, cyano group, nitro group, -(C ０ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -O-Cy ０１ , -(C ０ ~C ６ ) Alkyl-Cy ０１ , -(C ２ ~C ６ ) Alkenyl-Cy ０１ , -(C ２ ~C ６ ) Alkynyl-Cy ０１ , —O—(C １ ~C ６ ) alkyl-R ０１２ , —C(O)—OR ０１１ , -O-C(O)-R ０１１ , —C(O)—NR ０１１ R ０１１ ', -NR ０１１ -C(O)-R ０１１ ', -NR ０１１ —C(O)—OR ０１１ ', -(C １ ~C ６ ) alkyl-NR ０１１ -C(O)-R ０１１ ', -SO ２ -NR ０１１ R ０１１ ', or -SO ２ -(C １ ~C ６ ) alkyl, Or pair (R ０６ , R ０７ ), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members; R ０８ is a hydrogen atom, a linear or branched (C １ ~C ８ ) alkyl group, aryl group, heteroaryl group, aryl-(C １ ~C ６ ) alkyl group or heteroaryl (C １ ~C ６ ) alkyl group, R ０９ is linear or branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) an alkynyl group, -Cy ０２ , -(C １ ~C ６ ) Alkyl-Cy ０２ , -(C ２ ~C ６ ) Alkenyl-Cy ０２ , -(C ２ ~C ６ ) Alkynyl-Cy ０２ , -Cy ０２ -Cy ０３ , -(C ２ ~C ６ ) Alkynyl-O-Cy ０２ , -Cy ０２ -(C ０ ~C ６ ) alkyl-O—(C ０ ~C ６ ) Alkyl-Cy ０３ , a halogen atom, a cyano group, —C(O)—R ０１４ or —C(O)—NR ０１４ R ０１４ ' and R ０１１ and R ０１１ ' are independently a hydrogen atom, an unsubstituted or substituted linear or branched (C １ ~C ６ ) alkyl group, or -(C ０ ~C ６ ) Alkyl-Cy ０１ or the pair (R ０１１ , R ０１１ ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members; R ０１２ is -Cy ０５ , -Cy ０５ -(C ０ ~C ６ ) Alkyl-Cy ０６ , -Cy ０５ -(C ０ ~C ６ ) alkyl-O—(C ０ ~C ６ ) Alkyl-Cy ０６ , -Cy ０５ -(C ０ ~C ６ ) alkyl-NR ０１１ -(C ０ ~C ６ ) Alkyl-Cy ０６ , -Cy ０５ -Cy ０６ -O-(C ０ ~C ６ ) Alkyl-Cy ０７ , -Cy ０５ -(C ０ ~C ６ ) Alkyl-Cy ０９ , -NH-C(O)-NH-R ０１１ , —C(O)—NR ０１１ R ０１１ ', -NR ０１１ R ０１１ ', -OR ０１１ , -NR ０１１ -C(O)-R ０１１ ', -O-(C １ ~C ６ ) alkyl-OR ０１１ , -SO ２ -R ０１１ or —C(O)—OR ０１１ and R ０１４ and R ０１４ ' are each independently a hydrogen atom or an unsubstituted or substituted linear or branched (C １ ~C ６ ) alkyl group, Ｃｙ０１ , Cy ０２ , Cy ０３ , Cy ０５ , Cy ０６ , Cy ０７ , Cy ０８ and Cy 010 are each independently a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is unsubstituted or substituted; Cy ０９ teeth 【Chemistry 2】 and R ０１５ represents a hydrogen atom; -(CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ０２０ group; linear or branched (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl group; -U ０ - (CH ２ ) ｑ０ -NR ０２１ R ０２１ ' group; or -(CH ２ ) ｒ０ -U ０ - (CH ２ ) ｓ０ -heterocycloalkyl group, R ０１６ represents a hydrogen atom; a hydroxy group; a hydroxy (C １ ~C ６ ) alkyl group; ２ ) ｒ０ -U ０ - (CH ２ ) ｓ０ -heterocycloalkyl group; (CH ２ ) ｒ０ -U ０ -V ０ -O-P(O)(OR ０２０ ) ２ Group: —O—P(O)(O － M ＋ ) ２ Group: —O—S(O) ２ OR ０２０ Group;-S(O) ２ OR ０２０ Group;-(CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ０２０ Group;-(CH ２ ) ｐ０ -O-C(O)-NR ０２２ R ０２３ group; or -U ０ - (CH ２ ) ｑ０ -NR ０２１ R ０２１ 'Based on R ０１７ represents a hydrogen atom; -(CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ０２０ Group; -CH ２ -P(O)(OR ０２０ ) ２ group, -OP(O)(OR ０２０ ) ２ Group: —O—P(O)(O － M ＋ ) ２ group; hydroxy group; hydroxy (C １ ~C ６ ) alkyl group; ２ ) ｒ０ -U ０ - (CH ２ ) ｓ０ -heterocycloalkyl group; -U ０ - (CH ２ ) ｑ０ -NR ０２１ R ０２１ or an aldonic acid, M ＋ is a pharmaceutically acceptable monovalent cation, U ０ is a bond or an oxygen atom, V ０ is -(CH ２ ) ｓ０ - group or -C(O)- group, R ０１８ is a hydrogen atom or (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl group, R ０１９ is a hydrogen atom or a hydroxyl (C １ ~C ６ ) alkyl group, R ０２０ is a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, R ０２１ and R ０２１ ' are independently a hydrogen atom, a linear or branched (C １ ~C ６ ) alkyl group, or hydroxy (C １ ~C ６ ) alkyl group, Or pair (R ０２１ , R ０２１ ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members; R 022 is a (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group, a —(CH 2 ) p0 —NR 024 R 024 ′ group or a —(CH 2 ) p0 —O—(CHR 018 —CHR 019 —O) q0 —R 20 group; R 023 is a hydrogen atom or a (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group; or the pair (R 022 , R 023 ) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 18 ring members, which optionally contains, in addition to said nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, wherein said resulting ring is optionally substituted with hydrogen atoms, linear or branched (C 1 -C 6 ) alkyl groups or heterocycloalkyl groups; R 024 and R 024 ′ are each independently a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group; or the pair (R 024 , R 024 ′) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring of 5 to 7 ring members which, in addition to said nitrogen atom, may contain 1 to 3 heteroatoms selected from O, S and N, wherein said resulting ring is optionally substituted with hydrogen atoms or linear or branched (C 1 -C 6 ) alkyl groups; R ０３１ teeth 【Chemistry 3】 and R 027 is a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group; R 028 represents a —O—P(O)(O − )(O − ) group, a —O—P(O)(O − )(OR 030 ) group, a —O—P(O)(OR 030 )(OR 030 ′) group, a —(CH 2 ) p0 —O—SO 2 —O — group, a —(CH 2 ) p0 —SO 2 —O — group, a —(CH 2 ) p0 —O—SO 2 —OR 030 group, —Cy 010 , a —(CH 2 ) p0 —SO 2 —OR 030 group, a —O—C(O)—R 029 group, a —O—C(O)—OR 029 group or a —O—C(O)—NR 029 R 029 'Based on R 029 and R 029 ′ are each independently a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group or a linear or branched amino(C 1 -C 6 ) alkyl group; R 030 and R 030 ′ are each independently a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group or an aryl (C 1 -C 6 ) alkyl group; p0 is an integer equal to 0, 1, 2 or 3; q0 is an integer equal to 1, 2, 3, or 4; r0 and s0 are independently integers equal to 0 or 1; R 03, R ０９ and one of R012 is covalently attached to said linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing) Antibody-drug conjugates of

2. The pair (R ０２ , R ０３ ), (R ０３ , R ０４ ) or (R ０６ , R ０７ ) containing 5 to 7 ring members, the aromatic or non-aromatic ring formed by the １ ~C ６ ) alkyl, —NR ０１３ R ０１３ ', -(C ０ ~C ６ ) Alkyl-Cy ０１ and oxo; The pair (R ０１１ , R ０１１ The aromatic or non-aromatic ring containing 5 to 7 ring members formed by the nitrogen atom (C ′) contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, and the N atom is linear or branched (C １ ~C ６ ) alkyl group, and the linear or branched (C １ ~C ６ ) one or more of the carbon atoms of the alkyl group are deuterated, or vs. (R ０２１ , R ０２１ The aromatic or non-aromatic ring containing 5 to 7 ring members formed by the nitrogen atom (C ′) contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, and the resulting ring is unsubstituted or contains hydrogen atoms or linear or branched (C １ ~C ６ ) substituted with an alkyl group; R ０１３ and R ０１３ ' are each independently a hydrogen atom or an unsubstituted or substituted linear or branched (C １ ~C ６ 2. The antibody-drug conjugate of claim 1, wherein the aryl group is an alkyl group.

3. -(LD) is a compound of formula (A): 【Chemistry 4】 (In the formula, R １ is a linking group, L １ is a bridging spacer group, E is a cleavable group. The antibody-drug conjugate of claim 1 or 2,

4. (1) The cleavable group comprises a pyrophosphate group, or the cleavable group is 【Chemistry 5】 Including, (2) The bridging spacer group is (i) a polyoxyethylene (PEG) group; (ii) a PEG group selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15; (iii)-CO-CH ２ -CH ２ -PEG12-based; (iv) a butanoyl, pentanoyl, hexanoyl, heptanoyl, or octanoyl group; or (v) hexanoyl group Including, (3) (i) the binding group is formed from at least one reactive group selected from a maleimide group, a thiol group, a cyclooctyne group, and an azide group; (ii) The binding group is formed from at least one reactive group selected from the following a) to d): a) a compound having the following structure: 【Chemistry 6】 a maleimide group having b) Structure: -N=N ＋ = N － an azido group having c) a compound having the following structure: 【Chemistry 7】 a cyclooctyne group having the formula: 【Chemistry 8】 is the binding to the antibody, d) a compound having the following structure: 【Chemistry 9】 a cyclooctyne group having the formula where: 【Chemistry 10】 is the binding to the antibody, or (iii) the linking group is 【Chemistry 11】 and having a formula comprising where: 【Chemistry 12】 is the binding to the antibody, (4) The antibody or antigen-binding fragment thereof 【Chemistry 13】 and is connected to the linker (L) by a linking group selected from where: 【Chemistry 14】 is the binding of said antibody or antigen-binding fragment, wherein: 【Chemistry 15】 is the bond to the bridging spacer group, (5) The crosslinking spacer group is —CO—CH ２ -CH ２ -PEG12-, (6) the bridging spacer group is linked to a cleavable group; (7) The cleavable group is -pyrophosphate-CH ２ -CH ２ -NH ２ and / or (8) The cleavable group is linked to the Mcl-1 inhibitor (D), or the cleavable group is linked to the Mcl-1 inhibitor (D) via a phenyl-pyrimidinyl group. The antibody-drug conjugate according to any one of claims 1 to 3.

5. The linker is a linking group; at least one bridging spacer group; a peptide group; at least one cleavable group; The antibody-drug conjugate of claim 1, comprising:

6. -(LD) is a compound of formula (B): 【Chemistry 16】 (In the formula, R １ is a linking group, L １ is a bridging spacer, Lp is a peptide group containing 1 to 6 amino acid residues, or Lp is 【Chemistry 17】 group, E is a cleavable group; L ２ is a bridging spacer, m is 0 or 1; D is an Mcl-1 inhibitor) The antibody-drug conjugate of claim 5,

7. (1) (i) the linking group is formed from at least one reactive group including a maleimide group, a thiol group, a cyclooctyne group, and / or an azide group; (ii) the binding group is formed from at least one reactive group selected from the following a) to d): a) a compound having the following structure: 【Chemistry 18】 a maleimide group having b) Structure: -N=N ＋ = N － an azido group having c) a compound having the following structure: 【Chemistry 19】 a cyclooctyne group having the formula: 【Chemistry 20】 is the binding to the antibody, d) a compound having the following structure: 【Chemical 21】 a cyclooctyne group having the formula where: 【Chemical 22】 is the binding to the antibody, or (iii) the linking group is 【Chemical 23】 and having a formula comprising where: 【Chemistry 24】 is the binding to the antibody, (2) (i) at least one crosslinking spacer comprises a PEG group, and the PEG group is selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15; or (ii) at least one bridging spacer is ＊ —C(O)—CH ２ -CH ２ -PEG1- ＊＊ , ＊ —C(O)—CH ２ -PEG3- ＊＊ , ＊ —C(O)—CH ２ -CH ２ -PEG12 ＊＊ , ＊ -NH-CH ２ -CH ２ -PEG1- ＊＊ , polyhydroxyalkyl groups, and ＊ -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ )-C(O)- ＊＊ (In the formula, ＊＊ indicates the point of direct or indirect attachment of said at least one bridge spacer to said linking group; ＊ indicates the point of direct or indirect attachment of said at least one cross-linking spacer to said peptide group. Selected from: (3) L １ but, ＊ —C(O)—CH ２ -CH ２ -PEG1- ＊＊ , ＊ —C(O)—CH ２ -PEG3- ＊＊ , ＊ —C(O)—CH ２ -CH ２ -PEG12 ＊＊ , ＊ -NH-CH ２ -CH ２ -PEG1- ＊＊ and polyhydroxyalkyl groups, ＊＊ is R １ With L １ indicates the direct or indirect point of attachment of ＊ is Lp and L １ indicating a direct or indirect point of attachment of (4) m is 1 and L ２ -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ )-C(O)-; (5) (i) the peptide group comprises 1 to 6, 1 to 4, 1 to 3, or 1 to 2 amino acid residues; (ii) the peptide group comprises 1 to 6, 1 to 4, 1 to 3, or 1 to 2 amino acid residues selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr); (iii) the peptide group comprises Val-Cit, Val-Ala, Val-Lys and / or Sulfo-Ala-Val-Ala; (iv) the peptide group is 【Chemistry 25】 Selected from: (6) (i) the cleavable group comprises a pyrophosphate group and / or a self-immolative group, (ii) the cleavable group comprises a self-immolative group, or (iii) the cleavable group comprises a self-immolative group comprising para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium, and / or (7) m is 0 or 1, or m is 1, and the bridging spacer is 【Chemical 26】 Including, The antibody-drug conjugate according to claim 5 or 6.

8. (1)-(L-D) is 【Chemical 27】 【change】 【change】 or (2)-(L-D) is 【Chemical formula 28】 【change】 【change】 【change】 【change】 and where: 【Chemical 29】 is the binding to the antibody, The antibody-drug conjugate according to claim 6 or 7.

9. (1)-(LD) is a compound of formula (C): 【Chemistry 30】 (In the formula, R １ is a linking group, L １ is a bridging spacer, L ｐ is a peptide group containing 1 to 6 amino acids, D is an Mcl-1 inhibitor; G １ -L ２ -A is a self-immolative spacer, L ２ is a bond, methylene, neopentylene or C ２ ~C ３ is alkenylene, A is a bond, —OC(═O)— ＊ , 【Chemical 31】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, L ３ is the spacer moiety, R ２ is the hydrophilic moiety) or (2)-(LD) is a compound of formula (D): 【Chemical Formula 32】 (In the formula, R １ is a linking group, L １ is a bridging spacer, Lp is a peptide group containing 1 to 6 amino acids; A is a bond, —OC(═O)— ＊ , 【Chemical Formula 33】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, L ３ is the spacer moiety, R ２ is the hydrophilic moiety) It is of The antibody-drug conjugate of claim 1.

10. (1) L １ but, 【Chemical 34】 or ＊ -CH(OH)CH(OH)CH(OH)CH(OH)- ＊＊ Including, where each n is an integer from 1 to 12, and where L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (2) L １ but, 【Chemical Formula 35】 and n is an integer from 1 to 12, or n is 1, or n is 12, wherein L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (3) L １ but, 【Chemical 36】 and n is an integer from 1 to 12, where L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (4) L １ but, 【Chemical 37】 where L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (5)L １ が、 ＊ -C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)O(CH ２ ) ｍ SSC(R ３ ) ２ (CH ２ ) ｍ C(=O)NR ３ (CH ２ ) ｍ NR ３ C(=O)(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)O(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ NH(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ NH(CH ２ ) ｎ C(=O)- ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ X １ (CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ NHC(=O)(CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ NHC(=O)(CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ NHC(=O)(CH ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ NHC(=O)(CH ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ C(=O)NH(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ C(R ３ ) ２ - ＊＊ または ＊ -C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - ＊＊ where L is a bridging spacer comprising １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to X １ teeth, 【Chemical Formula 38】 and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; Each R ３ is H and C １ ~C ６ The antibody-drug conjugate of claim 9 , wherein the aryl, ...

11. (1) R ２ is polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, or 1 to 3 【Chemical 39】 C substituted with a group ２ ~C ６ an alkyl-containing hydrophilic moiety, (2) R ２ but, 【Chemistry 40】 wherein n is an integer between 1 and 6. 【Chemistry 41】 or (3) The hydrophilic portion is (i) Polysarcosine, for example, the following moiety: 【Chemistry 42】 (wherein n is an integer between 3 and 25, and R is H, —CH ３ or -CH ２ CH ２ C(═O)OH), or (ii) Formula: 【Chemistry 43】 Polyethylene glycol: (Wherein, R is H, —CH ３ , C.H. ２ CH ２ NHC(=O)OR ａ , -CH ２ CH ２ NHC(=O)R ａ or -CH ２ CH ２ C(=O)OR ａ and R' is OH, —OCH ３ , -CH ２ CH ２ NHC(=O)OR ａ , -CH ２ CH ２ NHC(=O)R ａ or -OCH ２ CH ２ C(=O)OR ａ where R ａ is H, unsubstituted C １～４ Alkyl, or OH or C １～４ C substituted with any of alkoxyl １～４ alkyl, and each of m and n is independently an integer between 2 and 25. Including, The antibody-drug conjugate of claim 9 or 10.

12. (i) L ３ But the structure 【Chemical 44】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(=O)C(R ｂ ) ２ NHC(=O)O-、 -NHC(=O)C(R ｂ ) ２ NH-、-NHC(=O)C(R ｂ ) ２ NHC(=O)-、-CH ２ N(X-R ２ )C(=O)O-、-C(=O)N(X-R ２ )-、-CH ２ N(X-R ２ )C(=O)-、-C(=O)NR ｂ -、-C(=O)NH-、-CH ２ NR ｂ C(=O)-、-CH ２ NR ｂ C(=O)NH-、-CH ２ NR ｂ C(=O)NR ｂ -、-NHC(=O)-、-NHC(=O)O-、-NHC(=O)NH-、-OC(=O)NH-、 -S(O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; X is a bond, triazolyl or —CH ２ -triazolyl-) or a spacer moiety having (ii) L ３ But the structure 【Chemistry 45】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(=O)C(R ｂ ) ２ NHC(=O)O-、 -NHC(=O)C(R ｂ ) ２ NH-、-NHC(=O)C(R ｂ ) ２ NHC(=O)-、-CH ２ N(X-R ２ )C(=O)O-、-C(=O)N(X-R ２ )-、 -CH ２ N(X-R ２ )C(=O)-、-C(=O)NR ｂ -、-C(=O)NH-、-CH ２ NR ｂ C(=O)-、-CH ２ NR ｂ C(=O)NH-、 -CH ２ NR ｂ C(=O)NR ｂ -、-NHC(=O)-、-NHC(=O)O-、-NHC(=O)NH-、-OC(=O)NH-、 -S(O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; X is -CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-, -C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-, -(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-, -(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ - or -CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -, where each n is independently 1, 2, or 3. The antibody-drug conjugate of any one of claims 9 to 11, wherein the spacer moiety has the formula:

13. (1) the linking group is formed by a reaction involving at least one reactive group; (2) The bonding group is a first reactive group attached to the linker; a second reactive group that is attached to the antibody or antigen-binding fragment or is an amino acid residue of the antibody or antigen-binding fragment; wherein: (i) at least one of the reactive groups is thiols, Maleimide, haloacetamides, Azide, Alkynes, cyclooctene, triarylphosphines, oxanorbornadiene, cyclooctyne, diaryltetrazines, monoaryltetrazines, norbornene, aldehyde, hydroxylamine, hydrazine, NH ２ -NH-C(=O)-、 ketones, vinyl sulfone, Aziridine, amino acid residues, 【Chemistry 46】 、-ONH ２ 、-NH ２ 、 【Chemistry 47】 、-N ３ 、 【Chemistry 48】 、-SH、-SR ３ 、-SSR ４ 、-S(=O) ２ (CH=CH ２ )、-(CH ２ ) ２ S(=O) ２ (CH=CH ２ )、-NHS(=O) ２ (CH=CH ２ )、-NHC(=O)CH ２ Br、-NHC(=O)CH ２ I、 【Chemistry 49】 、-C(O)NHNH ２ 、 【Chemistry 50】 【change】 Including, where: Each R ３ is H and C １ ~C ６ independently selected from alkyl, Each R ４ is 2-pyridyl or 4-pyridyl, Each R ５ is H, C １ ~C ６ independently selected from alkyl, F, Cl, and —OH; Each R ６ is H, C １ ~C ６ Alkyl, F, Cl, —NH ２ , -OCH ３ , -OCH ２ CH ３ , -N(CH ３ ) ２ , -CN, -NO ２ and —OH, Each R ７ is H, C １～６ Alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C(═O) substituted with —C(═O)OH １～４ C substituted with alkoxy and —C(═O)OH １～４ alkyl; and / or (ii) the first reactive group and the second reactive group are thiols and maleimides, thiols and haloacetamides, thiols and vinyl sulfones, thiols and aziridines, Azides and alkynes, azide and cyclooctyne, azide and cyclooctene, azides and triarylphosphines, azides and oxanorbornadienes, diaryltetrazines and cyclooctene, monoaryltetrazines and norbornenes, aldehydes and hydroxylamines, aldehydes and hydrazines, Aldehydes and NH ２ -NH-C(=O)-, ketones and hydroxylamines, ketones and hydrazines, Ketones and NH ２ -NH-C(=O)-, Hydroxylamine and 【Chemistry 51】 、 amines and 【Chemistry 52】 ,or CoA and serine residues or (3) The bonding group is 【Chemistry 53】 【change】 【change】 【change】 and where: R ３２ is H, C １～４ alkyl, phenyl, pyrimidine or pyridine; R ３５ is H, C １～６ C substituted with alkyl, phenyl, or 1 to 3 —OH groups １～４ is alkyl, Each R ７ is H, C １～６ Alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C(═O) substituted with —C(═O)OH １～４ C substituted with alkoxy and —C(═O)OH １～４ independently selected from alkyl, R ３７ is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R ８ is H or methyl, R ９ is H, -CH ３ or phenyl; The antibody-drug conjugate of any one of claims 5 to 12.

14. (1) The peptide group contains 1 to 4, 1 to 3, or 1 or 2 amino acid residues; (2) The peptide group comprises 1 to 4, 1 to 3, or 1 or 2 amino acid residues, and the amino acid residues are selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). (3) the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Sulfo-Ala-Val and / or Sulfo-Ala-Val-Ala, or (4) Lp is 【Chemical 54】 Selected from: The antibody-drug conjugate of any one of claims 9 to 13.

15. -(LD) is a compound of the formula: （１） 【Chemistry 55】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemical 56】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （２） 【Chemical 57】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 58】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （３） 【Chemical Formula 59】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 60】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （４） 【Hua 61】 (In the formula, Each R is H, —CH ３ and -CH ２ CH ２ C(═O)OH; A is a bond, —OC(═O)— ＊ , 【Hua 62】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （５） 【Chemistry 63】 (In the formula, Each R is H, —CH ３ and -CH ２ CH ２ C(═O)OH; A is a bond, —OC(═O)— ＊ , 【Hua 64】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （６） 【Chemistry 65】 (In the formula, Xa is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ -, and each R is independently H, -CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Hua 66】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （７） 【Hua 67】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 68】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （８） 【Chemical Formula 69】 (In the formula, Xb is —CH ２ -, -OCH ２ --NHCH ２ -or-NRCH ２ -, and each R is independently H, -CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 70】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （９） 【Chemical Formula 71】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemical Formula 72】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１０） 【Chemical 73】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemical 74】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１１） 【Chemistry 75】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemical 76】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１２） 【Chemical 77】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemical 78】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１３） 【Chemical 79】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 80】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１４） 【Chemistry 81】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 82】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１５） 【Chemistry 83】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 84】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor), or （１６） 【Chemistry 85】 (In the formula, Each R is independently H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 86】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ or -OC(=O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ ) C(=O)- ＊ and Here, each R ａ is H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) 2. The antibody-drug conjugate of claim 1, comprising or formed from a compound of formula:

16. A is a bond and / or R is —CH ３ The antibody-drug conjugate of claim 15,

17. D is of formula (III): 【Hua 87】 (In the formula, R ０１ is linear or branched (C １ ~C ６ ) alkyl group, R ０３ is -O-(C １ ~C ６ ) alkyl-NR ０１１ R ０１１ 'or 【Hua 88】 and Here, R ０１１ and R ０１１ ' are independently a hydrogen atom, an unsubstituted or substituted linear or branched (C １ ~C ６ ) alkyl group, or -(C ０ ~C ６ ) Alkyl-Cy ０１ and Or pair (R ０１１ , R ０１１ ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which contains, in addition to said nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein said N atom is a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl groups, Here, R ０２７ is a hydrogen atom, and R ０２８ is -(CH ２ ) ｐ０ -O-SO ２ -O － group or -(CH ２ ) ｐ０ -SO ２ -OR ０３０ It is the basis, p ０ is an integer equal to 0, 1, 2, or 3, R ０９ is linear or branched (C ２ ~C ６ ) an alkynyl group or -Cy ０２ and R ０１２ is -Cy ０５ , -Cy ０５ -(C ０ ~C ６ ) Alkyl-Cy ０６ or -Cy ０５ -(C ０ ~C ６ ) Alkyl-Cy ０９ and Cy ０１ , Cy ０２ , Cy ０５ and Cy ０６ are each independently a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is unsubstituted or substituted; Cy ０９ teeth 【Chemistry 89】 and R ０１５ , R ０１６ and R ０１７ is as defined for formula (II), Here, R 03 , R ０９ and one of R012 is covalently attached to said linker or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing, The antibody-drug conjugate of any one of claims 1 to 16.

18. (1) R ０１ is methyl or ethyl; (2) R ０３ -O-CH ２ -CH ２ -NR ０１１ R ０１１ '(in the formula, R ０１１ and R ０１１ ' are hydrogen atoms and linear or branched (C １ ~C ６ ) alkyl groups), forming a piperazinyl group which may be substituted with a group selected from (3) R ０３ But the formula: 【Chemistry 90】 (In the formula, R ０２７ is a hydrogen atom, and R ０２８ Ha-(CH ２ ) ｐ０ -SO ２ -OR ０３０ (based on Including, (4) R ０３ But the formula: 【Chemistry 91】 (In the formula, 【Chemistry 92】 is the bond to the linker) Including, (5) R ０９ Cy ０２ That is, (6) Cy ０２ is an unsubstituted or substituted aryl group; (7) Cy ０５ comprises a heteroaryl group selected from a pyrazolyl group and a pyrimidinyl group; (8) Cy ０５ is a pyrimidinyl group, or (9) The L is a group selected from L and R of formula (II) or (III) ０３ and / or said L is connected to D by a covalent bond from L to R of formula (II) or (III) ０９ is attached to D by a covalent bond The antibody-drug conjugate of claim 17.

19. (1) D is 【Chemistry 93】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (2) D is 【Chemistry 94】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (3) D is 【Chemistry 95】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (4) D is 【Chemistry 96】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (5) D is 【Chemistry 97】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (6) D is 【Chemistry 98】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (7) D is 【Hua99】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (8) D is 【Chemistry 100】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (9) D is 【Chemistry 101】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (10) D is 【Chemistry 102】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (11) D is 【Chemistry 103】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (12) D is 【Chemistry 104】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (13) D is 【Chemistry 105】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, (14) D is 【Chemistry 106】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof, or (15)-(LD) is formed from a compound in Table A or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or a pharmaceutically acceptable salt thereof; The antibody-drug conjugate of any one of claims 1 to 17.

20. 20. The antibody-drug conjugate of any one of claims 1 to 19, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

21. (1) (i) the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, or GPNMB; (ii) the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b; or (iii) the target antigen is BCMA, CD33, CD48, PCAD, or HER2; (2) The antibody or antigen-binding fragment is an anti-BCMA antibody or antigen-binding fragment. (3) The antibody or antigen-binding fragment thereof (a) three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3); or (b) the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2; (4) (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain; (b) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain, wherein the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at positions 152 and 375, or the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at positions 156 and 379; and / or (c) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; (5) The antibody or antigen-binding fragment is an anti-CD33 antibody or antigen-binding fragment. (6) (a) the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:23 (HCDR3), and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO:24 (LCDR1), SEQ ID NO:25 (LCDR2), and SEQ ID NO:26 (LCDR3); and / or (b) the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4; (7) (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain; (b) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain, wherein the IgG1 heavy chain constant domain comprises a glutamine (Q) at position 297; and / or (c) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; (8) The antibody or antigen-binding fragment is an anti-PCAD antibody or antigen-binding fragment. (9) (a) the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 33 (HCDR1), SEQ ID NO: 34 (HCDR2), and SEQ ID NO: 35 (HCDR3), and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 36 (LCDR1), SEQ ID NO: 37 (LCDR2), and SEQ ID NO: 38 (LCDR3); and / or (b) the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; (10) The antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment. (11) (a) the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of SEQ ID NO: 39 (HCDR1), SEQ ID NO: 40 (HCDR2), and SEQ ID NO: 41 (HCDR3), and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of SEQ ID NO: 42 (LCDR1), SEQ ID NO: 43 (LCDR2), and SEQ ID NO: 44 (LCDR3); and / or (b) the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10; (12) (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain; (b) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain, wherein the IgG1 heavy chain constant domain comprises a glutamine (Q) at position 297, or wherein the IgG1 heavy chain constant domain comprises a serine (S) at position 297; and / or (c) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; or (13) The antibody or antigen-binding fragment is an anti-CD38 antibody or antigen-binding fragment; an anti-CD46 antibody or antigen-binding fragment; an anti-CD48 antibody or antigen-binding fragment; or an anti-CD79b antibody or antigen-binding fragment. The antibody-drug conjugate of claim 20.

22. 22. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 1 to 21, wherein the average p of the antibody-drug conjugates in the composition is 2 to 16, 2 to 8, or 2 to 4.

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

24. 24. A pharmaceutical composition for use in a method for treating a subject having or suspected of having cancer, the pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate of any one of claims 1 to 21, the composition of claim 22, or the pharmaceutical composition of claim 23.

25. (1) the cancer expresses a target antigen, or (2) The cancer is a tumor or a blood cancer, or (3) The cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer or spleen cancer; 25. The pharmaceutical composition of claim 24.

26. 24. A pharmaceutical composition for use in a method for reducing or inhibiting tumor growth in a subject, the pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate of any one of claims 1 to 21, the composition of claim 22, or the pharmaceutical composition of claim 23.

27. (1) the tumor expresses a target antigen; (2) The tumor is breast cancer, stomach cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or splenic cancer; or (3) administration of the antibody-drug conjugate, composition or pharmaceutical composition reduces or inhibits the growth of the tumor by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

27. The pharmaceutical composition of claim 26.

28. 24. A pharmaceutical composition for use in a method of reducing or slowing the expansion of a cancer cell population in a subject, the pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate of any one of claims 1 to 21, the composition of claim 22, or the pharmaceutical composition of claim 23.

29. (1) the cancer cell population expresses a target antigen; (2) The cancer cell population is derived from a tumor or a blood cancer. (3) The cancer cell population is derived from breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer; or (3) administration of the antibody-drug conjugate, composition or pharmaceutical composition reduces the cancer cell population or slows the expansion of the cancer cell population by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

29. The pharmaceutical composition of claim 28.

30. 24. A pharmaceutical composition for use in a method of determining whether a subject having or suspected of having cancer will respond to treatment with the antibody-drug conjugate of any one of claims 1 to 21, the composition of claim 22, or the pharmaceutical composition of claim 23, the method comprising providing a biological sample from the subject; contacting the sample with the antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample.

31. (1) the cancer cells in the sample express a target antigen; (2) the cancer expresses a target antigen; (3) The cancer is a tumor or a blood cancer. (4) The cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer, or (5) The sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

31. The pharmaceutical composition of claim 30.

32. (i) The target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, F LT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, (ii) the target antigen is Nectin4, TROP2, LIV1, CD46, or GPNMB; (ii) the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b; or (iii) BCMA, CD33, CD48, PCAD, or HER2. The pharmaceutical composition of any one of claims 24 to 30.

33. 22. A method of making the antibody-drug conjugate of any one of claims 1 to 21, comprising reacting an antibody or antigen-binding fragment with a cleavable linker linked to an MCL1 inhibitor under conditions that allow conjugation.

34. 33. The pharmaceutical composition of any one of claims 24 to 32, wherein the method further comprises administering to the subject in need thereof at least one additional therapeutic agent.

35. and at least one additional therapeutic agent is navitoclax, ABT-737, BP1002, SPC2996, APG-1252, obatoclax mesylate, PNT2258, Zn-d5, BGB-11417, oblimersen, venetoclax, N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5 ,6,7,8-tetrahydroindolizine-1-carboxamide, or (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide).

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