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

Abstract

To provide novel antibody-drug conjugate (ADC) compounds having biological activity against cancer cells.SOLUTION: Antibody-drug conjugates comprises an Mcl-1 inhibitor drug moiety. The disclosure further relates to methods and compositions for use in the treatment of cancers by administering the antibody-drug conjugates. Linker-drug conjugates comprising an Mcl-1 inhibitor drug moiety and methods of making same are also disclosed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application was filed on May 20, 2019, the entire contents of which are incorporated herein by reference. 35 U.S.C. § 119( claiming the benefit of and priority to the filing date under e).

[0002] The present disclosure provides a method for the treatment of cancers by administering an Mcl-1 inhibitor to a subject, the subject, or a patient, comprising administering to said subject an Mcl-1 inhibitor and an antigen target, e.g., an antigen expressed on a tumor or other cancer cell. and an antibody or antigen-binding fragment thereof that binds the target antigen. The present disclosure further relates to ADCs for the treatment of cancers that express a target antigen and / or Useful in diagnosis and / or modulating Mcl-1 expression and / or activity The present invention relates to methods and compositions applicable to treatment with steroids, as well as methods for preparing said compositions. Linker-drug conjugates containing Mcl-1 inhibitor drug moieties and methods for their preparation are also disclosed. is shown. [Background technology]

[0003] Apoptosis, or programmed cell death, is crucial for embryonic development and the maintenance of tissue homeostasis. Apoptotic cell death is generally characterized by nuclear condensation and DNA fragmentation. Morphological changes such as oxidization, as well as the activity of caspases, which can damage key structural components of the cell. The regulation of apoptosis is complex and typically involves several Cory et al. (2002) Nature Review ew Cancer 2:647-656).

[0004] Deregulation of apoptosis is associated with certain pathological conditions, such as increased apoptosis. is associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, as well as ischemia. In addition, defects in apoptosis are associated with cancer development, chemotherapy resistance, autoimmune diseases, It may play a role in inflammatory diseases and viral infections. It is one of the phenotypic hallmarks of cancer (Hanahan et al. (2000) Cell 100:57-70). The cl-2 family of anti-apoptotic proteins is a key player in colon cancer, breast cancer, small cell lung cancer, and Non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, bone It is associated with many types of cancer, including myeloma and pancreatic cancer.

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

[0006] Mcl-1 mediates the proliferation of pro-apoptotic proteins such as Bim, Noxa, Bak, and Bax. It is thought to promote cell survival by binding to proteins and neutralizing their death-inducing activity. Inhibition of Mcl-1 releases these pro-apoptotic proteins, often resulting in survival deficits. Induce apoptosis in tumor cells that depend on Mcl-1 for their proliferation. Mcl-1 or its upstream and / or downstream in the apoptosis signaling pathway Therapeutic targeting of proteins has been shown to be a promising approach to treat various malignancies and to treat certain This could be a promising strategy to overcome drug resistance in various human cancers. Summary of the Invention

[0007] In some embodiments, the present disclosure provides, in part, novel compounds that have biological activity against cancer cells. The present invention provides a novel antibody-drug conjugate (ADC) compound, which can be administered to mammals. and / or can slow, inhibit, and / or reverse tumor growth in humans. More specifically, the present disclosure provides, in some embodiments, a method for treating cancer patients. In some embodiments, the present invention relates to ADC compounds that can bind and kill cancer cells. The ADC compounds disclosed herein bind Mcl-1 inhibitors to full-length antibodies or antigen-binding fragments. In some embodiments, the ADC compound contains a linker that binds the target molecule to the target cell. It can also be internalized.

[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 or an antigen-binding fragment thereof.

[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, In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is 1. The solubility is determined by chromatography-mass spectrometry (LC-MS).

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

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

[0012] [ka] (In the formula, R 1 is a linking group, L1 is a bridging spacer group, and E is a cleavable group. a linker-drug (or "linker-payload") moiety (LD) that is Includes.

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

[0014] [ka] Includes.

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

[0016] In some embodiments, the linking group is a maleimide group, a thiol group, a cyclooctyne group, and The polymer is formed from at least one reactive group selected from the group consisting of maleic acid, azide, and hydroxyl groups. The mido 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-. do.

[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 binds Mcl-1 via the phenyl-pyrimidinyl group. The inhibitor (D) is linked to a group.

[0037] In some embodiments, the linker comprises a linking group, at least one bridging spacer group, and It comprises 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 1 is a linking group, L1 is a bridging spacer, and Lp is 1 to 6 amino groups. is a peptide group containing a carboxylic acid residue, E is a cleavable group, and L2 is a bridging spacer. wherein 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 PEG1, PEG2, PEG3, PEG4, PEG5, PEG6 , PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14 and PEG15. In some cases, at least one crosslinked Bridge spacers * -C(O)-CH2-CH2-PEG1- ** , * -C(O)-CH 2-PEG3- ** , * -C(O)-CH2-CH2-PEG12 ** , * -NH-CH 2-CH2-PEG1- ** , polyhydroxyalkyl groups, and * -C(O)-N(CH 3) -CH2-CH2-N(CH3)-C(O)- ** (In the formula, ** The bond group has a small number of indicates the point of direct or indirect attachment of at least one bridge spacer, * is the peptide group and (b) a point of direct or indirect attachment of at least one of the cross-linking spacers do.

[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 1indicates the direct or indirect point of attachment of L1 to * is the direct connection of L1 with Lp (indicating a point of attachment or an indirect attachment).

[0043] In some embodiments, m is 1 and L is —C(O)—N(CH)—CH—CH 2-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. The peptide group (Lp) comprises 1 to 8 amino acid residues. The peptide group (Lp) comprises 1 to 6 amino acid residues. In some embodiments, the peptide group is In some embodiments, the peptide group contains 1 to 4 amino acid residues. In some embodiments, the peptide group contains 1 to 2 amino acid residues. In some cases, the amino acid residues are 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 (Al a), L-leucine (Leu), L-tryptophan (Trp) and L-tyrosine (T For example, the peptide group may be selected from Val-Cit, Val-Ala, ... It may contain l-Lys and / or sulfo-Ala-Val-Ala. In this state, the peptide group (Lp) is

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

[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 is para-aminobenzyl-carbamate, para-aminobenzyl-carbamate, para-amino-(sulfo)benzyl-ammonium, para- Amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG- para-amino-(polyhydroxycarboxytetrahydrofuran) para-amino-(polyhydroxy)- Benzyl-(2-carboxytetrahydropyranyl)alkyl-ammonium salts.

[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, R 1 is a linking group, L1 is a bridging spacer, and L p 1 to 6 mesh D is an Mcl-1 inhibitor, and G1-L2-A is a self-immolative peptide. L2 is a bond, methylene, neopentylene or C2-C3 alkenyl 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * indicates the bonding point with D, L3 is a spacer moiety, and R 2 is the hydrophilic part The linker drug group -(LD) is

[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, and Lp is 1 to 6 amino groups. A is a peptide group containing an acid, and 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * indicates the bonding point with D, L3 is a spacer moiety, and R 2 is the hydrophilic part The linker drug group -(LD) is

[0070] In some embodiments, L1 is

[0071] [ka] or * -CH(OH)CH(OH)CH(OH)CH(OH)- ** where: Each n is an integer from 1 to 12, where L1 * is the direct or indirect bond to Lp. Showing the point, L1 ** 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 *is the direct bond point with Lp or Indicate the indirect attachment point, L1 ** 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 point of attachment to Lp. And L1 ** 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. indicates L1 ** 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 * is the direct bond point with Lp or Indicate the indirect attachment point, L1 ** 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)(C H2) m NH(CH2) m - ** ; * -C(=O)(CH2) m NH(CH2) n C(=O)- ** ;* -C(=O)(CH 2) 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) m NHC(=O)(CH2) n X1(CH2) n - ** ; * -C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(C H2) 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 - ** With a bridging spacer containing where L1 * indicates the direct or indirect bond point with Lp, and ** teeth , 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 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 2 is polyethylene glycol, polyalkylene glycol, Polyol, polysarcosine, sugar, oligosaccharide, polypeptide, or 1-3

[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 , -CH2CH2N HC(=O)R a or -CH2CH2C(=O)OR a and R' is OH, -OC H3, CH2CH2NHC(=O)OR a , -CH2CH2NHC(=O)R a or- OCH2CH2C(=O)OR a and m and n are each between 2 and 25 (e.g., For example, polyethylene glycol (wherein r is an integer between 3 and 25) is included.

[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, -CH3, or -CH2CH2 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-, -N HC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or - NH-, where each R b is H, C1-C6 alkyl and C3-C8 cycloalkenyl Selected independently from the kill, 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-, -N HC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or - NH-, where each R b is H, C1-C6 alkyl and C3-C8 cycloalkenyl Selected independently from the kill,

[0098] X is -CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH -, -C 4-6 Cycloalkylene -OC(O)NHS(O)2NH-, -(CH2CH2 O) 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 and is 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 comprises a first reactive group attached to a linker and an antibody by reacting with a second reactive group that is attached to the antibody or is an amino acid residue of the antibody. It is formed by:

[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 is H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2C independently selected from H3, -N(CH3)2, -CN, -NO2 and -OH; Each R 7 is H, C 1~6 Benzyl substituted with alkyl, fluoro, -C(=O)OH Oxy, 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 can be.

[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 Alkyl, phenyl, or substituted with 1 to 3 -OH groups C 1~4 is alkyl, Each R 7 is H, C 1~6 Benzyl substituted with alkyl, fluoro, -C(=O)OH Oxy, 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, 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 amino acid residue is L-glycine. Glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid ( Sulfo-Ala), L-Lysine (Lys), L-Isoleucine (Ile), L-Phenyl Alanine (Phe), L-methionine (Met), L-asparagine (Asn), L-Pro Proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan In some embodiments, the amino acid sequence is selected from L-tyrosine (Tyr), L-amino acid (A ... The peptide group is Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Le u-Cit, Sulfo-Ala-Val and / or Sulfo-Ala-Val-Ala In some embodiments, Lp comprises:

[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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)-* and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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-, R is independently H, —CH, or —CHCHC(═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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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-, R is independently H, —CH, or —CHCHC(═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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)-* and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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)- * and here So, each R a are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Selected, A's * 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 is independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl. and A's * 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. is a methyl 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. the law of nature, 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 (C1-C6) alkyl group, a is a branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group , linear or branched (C1-C6) haloalkyl group, hydroxy group, hydroxy(C1 -C6) alkyl group, linear or branched (C1-C6) alkoxy group, -S-(C1- C6) Alkyl group, cyano group, nitro group, -Cy 08 , -(C0-C6) alkyl-NR 011 R011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C 1-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 01 1-C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R0 11 ', -SO2-NR 011 R 011 or -SO2-(C1-C6) alkyl the law of nature, R 02 , R 03 , R 04 and R 05 are independently hydrogen atoms, halogen atoms, and linear or branched (C1-C6) alkyl groups, linear or branched (C2-C6) alkene groups alkyl, linear or branched (C2-C6) alkynyl, linear or branched (C1- C6) haloalkyl, hydroxy group, hydroxy(C1-C6) alkyl group, linear or is a branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, cyano group, Toro group, -(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 , -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 aromatic rings containing 5 to 7 ring members. and optionally forming an aromatic or non-aromatic ring selected from O, S and N. 3 heteroatoms, where the resulting ring is not halogen, linear or branched (C1 ~C6) alkyl, (C0~C6) alkyl-NR 011 R 011 ', -NR 013 R0 13 ', -(C0-C6) alkyl-Cy 01 or oxo optionally substituted with two groups; R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl groups, linear or branched (C2-C6) alkenyl groups, linear or branched or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) haloalkynyl groups aryl, hydroxyl group, linear or branched (C1-C6) alkoxy group, -S-(C1-C 6) Alkyl group, cyano group, nitro group, -(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 , -(C 2-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 to two adjacent carbon atoms, together with the carbon atom to which it is 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 is substituted with a linear or branched (C1-C6) alkyl group, -NR 013 R 013', -(C0-C6) alkyl-Cy 01 or optionally substituted with oxo And, 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 group, aryl group, heteroaryl group, aryl (C1-C6) alkyl group or heteroaryl group an alkyl (C1-C6)aryl group, R 09 is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched branched (C2-C6) alkenyl groups, linear or branched (C2-C6) alkynyl groups, - Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy0 2. -(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 a branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, Aryl (C1-C6) alkyl groups, (C1-C6) cycloalkyl alkyl groups, linear or branched (C1-C6) haloalkyl or -(C1-C6) alkyl-O-CyO 4, Or pair (R 09 , R 010 ) when fused to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they form an aromatic or non-aromatic ring containing 5 to 7 ring members. and optionally containing 1 to 3 heteroatoms selected from O, S and N. , R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or a 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 5~ Forms an aromatic or non-aromatic ring containing seven ring members, which may optionally be joined to a nitrogen atom In addition, the alkyl group may contain 1 to 3 heteroatoms selected from O, S, and N, where nitrogen is a hydrogen atom. One or two atoms selected from a hydrogen atom and a linear or branched (C1-C6) alkyl group wherein the carbon atom of the linear or branched (C1-C6) alkyl group wherein one or more of 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 , -Cy05 -(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 , and -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are 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 'Moto -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, cycloalkyl group, (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 atoms to which they are attached form 5-7 form a non-aromatic ring consisting of four ring members, which, in addition to the nitrogen atom, contains oxygen and nitrogen may contain 1 to 3 heteroatoms selected from nitrogen, where nitrogen is linear or branched optionally substituted with a (C1-C6) alkyl group, Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are each independently a cycloalkyl group, a heterocycloalkyl group, an aryl group, and aryl or heteroaryl groups, each of which is optionally substituted. the law of nature, 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 ; Hydro Oxy; Hydroxy(C1-C6)alkyl; -(CH2) r0 -U0-(CH2) s0 - heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R 021 'Select from is a heteroaryl group substituted with a group 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 -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U 0-(CH2) s0 -heterocycloalkyl group, R 016 represents a hydrogen atom; a hydroxy group; a hydroxy(C1-C6) alkyl group; -(C H2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0- V0-OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + ) 2 units;-OS( O)2OR 020 Group;-S(O)2OR 020 Group;-(CH2) p0 -O-(CHR 01 8-CHR 019 -O) q0 -R 020 Group;-(CH2) p0 -OC(O)-NR 02 2nd Round 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 020Group: -CH2-P(O)(OR 020 ) 2 units, -OP(O)(OR 02 0) 2 groups;-OP(O)(O - M + )2 groups; Hydroxy group; Hydroxy (C1-C6) Alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U 0-(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. the law of nature, 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 independently a hydrogen atom, a linear or branched (C1 C6) alkyl group, or hydroxy(C1-C6) alkyl group, Or pair (R 021 , R 021 ') together with the nitrogen atom to which they are attached, Forms an aromatic or non-aromatic ring containing up to 7 ring members, which is optionally attached to the nitrogen atom Additionally, it contains 1 to 3 heteroatoms selected from O, S and N, wherein the obtained The ring is optionally substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group. It has been R022 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. the law of nature, Or pair (R 022 , R 023 ) together with the nitrogen atom to which they are attached form 5-1 Forms an aromatic or non-aromatic ring containing 8 ring members, which may optionally be joined to a nitrogen atom In addition, the resulting ring may contain from 1 to 5 heteroatoms selected from O, S and N, is a hydrogen atom, a linear or branched (C1-C6) alkyl group or a heterocycloalkyl group. and optionally substituted with aryl groups. R 024 and R 024 ' are independently a hydrogen atom or a linear or branched (C 1-C6) alkyl group, Or pair (R 024 , R 024 ') together with the nitrogen atom to which they are attached form 5~ Forms an aromatic or non-aromatic ring consisting of seven ring members, which, in addition to the nitrogen atom, , and may contain 1 to 3 heteroatoms selected from O, S and N, wherein the resulting The ring is optionally substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group. It has been R 025 is a hydrogen atom, a hydroxy group, or a hydroxy(C1-C6)alkyl group. the law of nature, R 026is 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 03 0) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -OS O2-O - Group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-O R 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 02 9' group, R 029 and R 029 ' are independently a hydrogen atom, a linear or branched (C1 C6) alkyl group or linear or branched amino(C1-C6) alkyl group, R 030 and R 030 ' are independently a hydrogen atom, a linear or branched (C1 C6) alkyl group or aryl(C1-C6) alkyl group, R 031 teeth

[0171] [ka] where the ammonium cation optionally exists in zwitterionic form or or 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 a linker, wherein the valence of the atom attached thereto is (multiple substituents not exceeding) or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt 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 each independently a cycloalkyl group, a heterocyclic group, a cycloalkyl group, an aryl group, or a heteroaryl group, each of which is -(C1-C6)alkoxy;-(C1-C6)haloalkyl;-(C1-C6)halo alkoxy;-(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-(C H2) q0 -NR 021 R 021 Optionally substituted with one or more groups selected from It has been replaced.

[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 Branched (C2-C6) alkenyl group, linear or branched (C2-C6) alkynyl group, linear or branched (C1-C6) haloalkyl group, hydroxy group, linear or branched (C1- C6) alkoxy group, -S-(C1-C6) alkyl group, 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 is a branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, Linear or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) halides alkyl, hydroxy group, linear or branched (C1-C6) alkoxy group, -S-( C1-C6) alkyl group, cyano group, nitro group, -(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-NR 011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 02 , R 03 ) or (R 03 , R 04 ) are the carbon atoms to which they are attached. Together with the atoms, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which may optionally optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is linear or branched (C1-C6) alkyl, -NR 013 R 013', -(C0~C6) Al Kill-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 groups, linear or branched (C2-C6) alkenyl groups, linear or branched or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) haloalkynyl groups aryl, hydroxyl group, linear or branched (C1-C6) alkoxy group, -S-(C1-C 6) Alkyl group, cyano group, nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2~C6) Arkenyl Lu-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 ',-(C 1-C6)Alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 01 1', or -SO2-(C1-C6)alkyl; Or pair (R 06 , R 07 ) when fused to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they 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, The resulting ring may be substituted with a linear or branched (C1-C6) alkyl group, -NR 013 R 01 3', -(C0-C6) alkyl-Cy 01 and oxo, optionally has been replaced by R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, an aryl group, Heteroaryl group, aryl-(C1-C6) alkyl group or heteroaryl (C1-C 6) an alkyl group; R 09 is a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C 6) Alkenyl group, linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C 1-C6)Alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2-C 6) Alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O- Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy0 3. Halogen atoms, cyano groups, -C(O)-R 014 , -C(O)-NR 014 R 014 ' and R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or a 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 5~ Forms an aromatic or non-aromatic ring containing seven ring members, which may optionally be joined to a nitrogen atom In addition, it contains 1 to 3 heteroatoms selected from O, S and N, where the N atom is Optionally substituted with a linear or branched (C1-C6) alkyl group, One or more of the carbon atoms of the cyclic or branched (C1-C6) alkyl group may optionally be It is deuterated accordingly, 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 , -NR0 11 -C(O)-R 011 ', -O-(C1-C6) alkyl-OR 011 , -SO2-R 011 , or -C(O)-OR 011 represents R013 , R 013 ', R 014 and R 014 ' are independently hydrogen atoms, or is 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 mutual independently an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted hydroxyl group; is a 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, , covalently attached to a linker) or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt 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 independently a hydrogen atom, an optionally substituted a 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, Forms an aromatic or non-aromatic ring containing up to 7 ring members, which is optionally attached to the nitrogen atom Additionally, it contains 1 to 3 heteroatoms selected from O, S, and N, where the N atoms are , one or more selected from a hydrogen atom or a linear or branched (C1-C6) alkyl group; is optionally substituted with two groups, 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 09is a linear or branched (C2-C6) alkynyl group or -Cy 02 and R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 or -C y 05 -(C0-C6) 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 has been replaced as necessary, 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, , covalently attached to a linker) or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt of any of the foregoing.

[0181] In some embodiments, Cy 01 , Cy 02 , Cy 05 , Cy 06 are independent of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; , each of which is halo; -(C1-C6)alkoxy; -(C1-C6)haloalkenyl Alkyl;-(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-(C H2) q0 -NR 021 R 021 Optionally substituted with one or more groups selected from It has been replaced.

[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 ' are hydrogen atoms or ', along with the nitrogen atom that holds them. A piperazinyl group which may be substituted with a linear or branched (C1-C6) alkyl group. (This is the case.)

[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 teeth , a hydrogen atom, a linear or branched (C1-C6) alkyl group or an aryl (C1-C6 ) represents an 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 independently of each other optionally substituted cyclohexane optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, an optionally substituted aryl or heteroaryl group, The substituents are optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl groups, optionally substituted substituted linear or branched (C2-C6) alkynyl groups, optionally substituted linear or branched (C1-C6) alkoxy, optionally substituted (C1-C6) alkoxy alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, silyl Anno, -C(O)-OR0', -OC(O)-R0', -C(O)-NR0'R0'' , -NR0'R0'', -(C=NR0')-OR0'', linear or branched (C1~ C6) haloalkyl, trifluoromethoxy, or halogen, where R ' and R0'' are each independently a hydrogen atom or an optionally substituted linear or or a branched (C1-C6) alkyl group, wherein the alkyl group is a linear or branched (C1-C6) One or more of the carbon atoms of an alkyl group is optionally deuterated.

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

[0191] In some embodiments, Cy 05 is selected from pyrazolyl and pyrimidinyl groups Includes heteroaryl groups.

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

[0193] In some embodiments, Cy05 is a pyrimidinyl group, and Cy 06 is a phenyl group .

[0194] In some embodiments, the linker (L) is a linker selected from L and having formula (I), (II), or (III): R 03 In some embodiments, the linker (L ) is a radical from L to R of formula (I), (II) or (III) 09 Covalently bonded to D are combined.

[0195] In some embodiments, D is

[0196] [ka]

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

[0198] In some embodiments, -(LD) is a compound or enantiomer selected from Table A. , diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts thereof The compounds in Table A are formed from acceptable salts according to their electronic charge. These compounds contain one pharmaceutically acceptable monovalent anionic counterion M - Contains In some embodiments, a monovalent anionic counterion M1 - is bromide, chloride compounds, iodides, acetic acid, trifluoroacetic acid, benzoic acid, mesylic acid, tosylic acid, triflic acid, In some embodiments, the monovalent anionic counterion may be selected from formic acid or the like. M1 - 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 any of the structures shown in Table 1a. It has a formula according to one.

[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 any of the structures shown in Table 1b. It has a formula according to one.

[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 as disclosed herein, Refers to linker-drug or linker-compound, and is referred to as "L#-P#" and "L#-C#". The terms "linker-drug" and "linker-drug" are used interchangeably to refer to certain linker-drugs disclosed herein, On the other hand, the codes "P#" and "C#" refer to certain compounds unless otherwise specified. For example, "L1-C1" and "L1-P1" are both used interchangeably to refer to , refer to the same linker-payload structure disclosed herein, while "C1" and "P1 " includes enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and and / or any of the foregoing pharmaceutically acceptable salts of the same compounds disclosed herein. Shows.

[0271] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on a cancer cell. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD4 8, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL 1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGF R, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2 , Nectin 4, TROP2, LIV1, CD46, or GPNMB. In this state, the target antigens are 4-1BB, 5AC, 5T4, alpha-fetoprotein, and Geopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BE HAB, C242 antigen, C5, CA-125, CA-125 (mimic), CA-IX (charcoal Acid dehydratase 9), CCR4, CD140a, CD152, CD19, CD20, CD20 0, CD21(C3DR)I), CD22 (B cell receptor CD22-B isoform) , CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD 37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72( Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related anti- Hara, ch4D5, CLDN18.2, CRIPTO(CR, CRI, CRGF, TDGF 1), 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, Frizzle d receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, H ER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF -I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, IL FRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation Related 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI ), MPF, MSLN, SMR, mesothelin, megakaryocytes, PD-I, PDCDI, PDGF -R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hl g, 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, TR PM4B, transient receptor potential cation channel subfamily M, member 4), TWE AK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I In some embodiments, the target antigen is BCMA, VEGFR-2, or vimentin. , 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 is a fragment of SEQ ID NO: 15 (HCD R1), the amino acid sequences of SEQ ID NO: 16 (HCDR2) and SEQ ID NO: 17 (HCDR3) and three heavy chain complementarity determining regions (HCDRs) comprising SEQ ID NO: 18 (LCDR1), SEQ ID NO: Three light chains containing the amino acid sequences of SEQ ID NO: 19 (LCDR2) and SEQ ID NO: 20 (LCDR3) In some embodiments, the antibody or antigen-binding fragment comprises a complementarity determining region (LCDR). The fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a fragment comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody or antigen-binding fragment comprises an IgG1 In some embodiments, the I heavy chain constant domain comprises a modified IgG1 heavy chain constant domain. The gG1 heavy chain constant domain contains cysteine ​​residues (C) at positions 152 and 375. In some embodiments, the IgG1 heavy chain constant domain comprises cysteines at positions 156 and 379. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain. Contains a 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 is a fragment of SEQ ID NO: 21 (HCD R1), the amino acid sequences of SEQ ID NO: 22 (HCDR2) and SEQ ID NO: 23 (HCDR3) and three heavy chain complementarity determining regions (HCDRs) comprising SEQ ID NO: 24 (LCDR1), SEQ ID NO: Three light chains containing the amino acid sequences of SEQ ID NO: 25 (LCDR2) and SEQ ID NO: 26 (LCDR3) In some embodiments, the antibody or antigen-binding fragment comprises a complementarity determining region (LCDR). The fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a fragment comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the antibody or antigen-binding fragment comprises an IgG1 In some embodiments, the I heavy chain constant domain comprises a modified IgG1 heavy chain constant domain. The gG1 heavy chain constant domain comprises a glutamine residue (Q) at position 297. 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 is SEQ ID NO: 33 (HCD R1), the amino acid sequences of SEQ ID NO: 34 (HCDR2) and SEQ ID NO: 35 (HCDR3) and three heavy chain complementarity determining regions (HCDRs) comprising SEQ ID NO: 36 (LCDR1), SEQ ID NO: 37 (LCDR2), SEQ ID NO: 39 (LCDR3), SEQ ID NO: 40 (LCDR4), SEQ ID NO: 41 (LCDR5), SEQ ID NO: 42 (LCDR6), SEQ ID NO: 43 (LCDR7), SEQ ID NO: 44 (LCDR8), SEQ ID NO: 45 ( Three light chains containing the amino acid sequences of SEQ ID NO: 37 (LCDR2) and SEQ ID NO: 38 (LCDR3) In some embodiments, the antibody or antigen-binding fragment comprises a complementarity determining region (LCDR). The fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a fragment comprising the amino acid sequence of SEQ ID NO: 8. and a light chain variable region comprising the nucleotide sequence of the nucleotides 1, 2, 3, 4, 5,

[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 is SEQ ID NO: 39 (HCD R1), the amino acid sequences of SEQ ID NO: 40 (HCDR2) and SEQ ID NO: 41 (HCDR3) and three heavy chain complementarity determining regions (HCDRs) comprising SEQ ID NO: 42 (LCDR1), SEQ ID NO: Three light chains containing the amino acid sequences of SEQ ID NO: 43 (LCDR2) and SEQ ID NO: 44 (LCDR3) In some embodiments, the antibody or antigen-binding fragment comprises a complementarity determining region (LCDR). The fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a fragment comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment comprises an IgG In some embodiments, the antibody comprises a modified IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The IgG1 heavy chain constant domain contains a glutamine residue (Q) at position 297. In some embodiments, the IgG1 heavy chain constant domain contains 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 In some embodiments, the antibody or antigen-binding fragment is an anti-CD48 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 antibody-drug conjugates. a plurality of antibody-drug conjugates (e.g., any of the exemplary antibody-drug conjugates described herein) In some embodiments, the composition comprises an antibody-drug conjugate. The average p is about 2 to about 4.

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

[0279] Further provided herein, in some embodiments, are compounds comprising the ADC compounds described herein. and therapeutic uses for the products and compositions, for example, in the treatment of cancer. In some embodiments, the present disclosure provides methods for treating cancer (e.g., BCMA, CD33, PCAD, or HER2, ADCs targeting cancers that express the antigen targeted by the antibody or antigen-binding fragment of the ADC. In some embodiments, the present disclosure provides a method for expanding a cancer cell population in a subject. In some embodiments, the present disclosure provides a method for reducing or slowing the progression of cancer in a person having or experiencing cancer. or a subject suspected of having been treated with an ADC compound or composition disclosed herein. provides a method for determining whether to respond to

[0280] Exemplary embodiments include methods for treating a subject having or suspected of having cancer. The method comprises administering to a subject a therapeutically effective amount of an antibody-drug conjugate, composition or pharmaceutical composition (e.g., For example, the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein In some embodiments, the cancer is a cancer that 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, SLC 34A2, Nectin 4, TROP2, LIV1, CD46, or GPNMB. In this embodiment, the target antigen is 4-1BB, 5AC, 5T4, alpha-fetoprotein Angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCA N, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimic), CA- IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform form), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8 ), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, C D72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CE A-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16(LATI, SL C7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Ty ro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRH I (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extra domain-B, Fri zzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / n eu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase , IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF 2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor Translocation-related 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (D PEPI), MPF, MSLN, SMR, mesothelin, megakaryocytes, PD-I, PDCDI, PDGF-Ru, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSC A hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STE AP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related Gene I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, Tomo Regulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL -Rl, TRAIL-R2, T17M4(BR22450, FLJ20041, TRPM 4, TRPM4B, transient receptor potential cation channel subfamily M, member 4) , TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EG In some embodiments, the target antigen is VEGF-I, VEGFR-2, or vimentin. BCMA, CD33, PCAD, HER2, CD38, CD46, CD48, or CD7 In some embodiments, the target antigen is BCMA, CD33, CD48, PCA In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is a tumor or a blood cancer. Cancers include breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, stomach cancer, acute bone marrow cancer, and Myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal Cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B Lymphoid malignancies of cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non- If you have 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.

[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, In some embodiments, the antibody is Nectin4, TROP2, LIV1, CD46, or GPNMB. In this study, the target antigens were 4-1BB, 5AC, 5T4, alpha-fetoprotein, and angi. Opoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEH AB, C242 antigen, C5, CA-125, CA-125 (mimic), CA-IX (carbonate) Dehydratase 9), CCR4, CD140a, CD152, CD19, CD20, CD200 , CD21(C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD3 7, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72(L yb-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) 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, HE R3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF- I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILF RIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation receptor) Series 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, P CANAP 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, T RAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRP M4B, transient receptor potential cation channel subfamily M, member 4), TWEA KR, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, In some embodiments, the target antigen is BCMA, VEGFR-2, or vimentin. CD33, PCAD, HER2, CD38, CD46, CD48, or CD79b In some embodiments, the target antigen is BCMA, CD33, CD48, PCAD, or H In some embodiments, the target antigen is CD38 or CD48. In embodiments, 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 In some embodiments, the tumor is gastric cancer. In embodiments, administration of the antibody-drug conjugate, composition or pharmaceutical composition is Proliferation is increased by at least about 10%, at least about 20%, at least about 30%, at least about 4% 0%, at least about 50%, at least about 60%, at least about 70%, at least about 8 0%, at least about 90%, at least about 95%, or at least about 99% reduction or inhibition To harm.

[0282] Another exemplary embodiment is a method of reducing or slowing the expansion of a cancer cell population in a subject. administering to a subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., For example, the exemplary antibody-drug conjugates, compositions or pharmaceutical compositions disclosed herein In some embodiments, the cancer cell population is a target cell. In some embodiments, the target antigen is BCMA, CD33, HER2, C D38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD 123, 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, or the like. Protein, Angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD 20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B receptor isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFR SF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD7 0, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA , CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CR GF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16(LATI , SLC7A5), EGFL7, EphB2R(DRT, ERK, Hek5, EPHT3 , Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), F CRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPA PI, SPAP IB, SPAP IC), fibronectin extra domain-B, Frizzled receptors, GD2 and GD3 gangliosides, GEDA, HER1, and HER 2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor activator enzymes, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, I LGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily Lewis receptor translocation-related 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MD P(DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocytes, PD-I, PDC DI, PDGF-Ru, 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 genes I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2 , tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TR AIL-Rl, TRAIL-R2, T17M4(BR22450, FLJ20041, T RPM4, TRPM4B, transient receptor potential cation channel subfamily M, member -4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A In some embodiments, the target antibody is EGFR-I, VEGFR-2, or vimentin. The original antibody was BCMA, CD33, PCAD, HER2, CD38, CD46, CD48 or In some embodiments, the target antigen is BCMA, CD33, CD48, In some embodiments, the target antigen is CD38 or CD4. 48. In some embodiments, the cancer cell population is derived from a tumor or a blood cancer. In some embodiments, the cancer cell population is selected from the group consisting of breast cancer, multiple myeloma, plasma cell myeloma, leukemia, and the like. , lymphoma, stomach 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, bone marrow tumor, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer In some embodiments, the cancer cell population is derived from a lymphoma or a spleen cancer. In some embodiments, the antibody-drug conjugate, composition, or medicament is derived from a gastric cancer. Administration of the composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, 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 less In some embodiments, the antibody-drug conjugate, composition or Administration of the pharmaceutical composition reduces 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% slower.

[0283] Another exemplary embodiment is directed to the treatment of a subject having or suspected of having cancer. antibody-drug conjugates, compositions or pharmaceutical compositions for use in any of the exemplary antibody-drug conjugates, compositions or pharmaceutical compositions disclosed herein) In some embodiments, the cancer expresses a target antigen. The original immunohistochemistry was performed using BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, and C. D74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKI T, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, F OLR1, ENPP3, MET, AXL, SLC34A2, nectin4, TROP2, L In some embodiments, the target antigen is IV1, CD46, or GPNMB. B, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG65 9, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, C D140a, CD152, CD19, CD20, CD200, CD21(C3DR)I) , CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD 44 v6, CD51, CD52, CD70, CD72(Lyb-2, B cell differentiation antigen C D72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18 .2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR 5, 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), Fc RH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), Ibronectin extra domain-B, Frizzled receptor, GD2, GD3 cancer Gliosides, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DO B, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL 20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, I RTA2 (immunoglobulin superfamily receptor translocation-associated 2), Lewis-Y antigen, L Y64(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, SD CI, Sema Sb, STEAP I, STEAP2, PCNAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, Te Nasin C, TENB2, (TMEFF2, Tomoregulin, TPEF, HPPI, TR) , TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential Thione channel subfamily M, member 4), TWEAK-R, TYRP I (glycotransferase Protein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2 or vimen In some embodiments, the target antigen is BCMA, CD33, PCAD, HER2. 2, CD38, CD46, CD48, or CD79b. The antigen is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell carcinoma, or blood cancer. Myeloma, leukemia, lymphoma, stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic cancer Myeloid 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, In some embodiments, the cancer is prostate cancer, small cell lung cancer, or splenic cancer. Or stomach cancer.

[0284] Another exemplary embodiment is directed to the treatment of a subject having or suspected of having cancer. the antibody-drug conjugate, composition or pharmaceutical composition (e.g., the Exemplary antibody-drug conjugates, compositions or pharmaceutical compositions) are used in 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, C D56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR 1, ENPP3, MET, AXL, SLC34A2, Nectin 4, TROP2, LIV1 In some embodiments, the target antigen is 4-1BB, 5 AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, T CLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA- 125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD14 0a, CD152, CD19, CD20, CD200, CD21(C3DR)I), CD 22 (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, D LL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DR T, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETB R (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), Fibro Nectin extra domain-B, Frizzled receptors, GD2 and GD3 gangliosides CID, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, H LA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA 2 (immunoglobulin superfamily receptor translocation-associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP(DPEPI), MPF, MSLN, SMR, Meso Telin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PS CA (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, teneci C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TG F-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4(BR 22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation Channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin In some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, C In some embodiments, the target antigen is CD38, CD46, CD48, or CD79b. , BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. is a hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell bone marrow cancer, or Myeloma, leukemia, lymphoma, stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, Cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia Hematologic malignancies, 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, and prostate In some embodiments, the cancer is lymphoma or small cell lung cancer. It is stomach cancer.

[0285] Another exemplary embodiment is a method for treating a subject having or suspected of having cancer. an antibody-drug conjugate, composition or pharmaceutical composition ( For example, the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein In some embodiments, the cancer expresses a target antigen. In embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD7 9b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT 3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD7 1, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin In some embodiments, the target is IL-4, TROP2, LIV1, CD46, or GPNMB. Target antigens include 4-1BB, 5AC, 5T4, alpha-fetoprotein, and angiopoietin. 2, ASLG659, TCLI, BMPRIB, BCAN, BEHAB, C 242 antigen, C5, CA-125, CA-125 (mimic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD2 1(C3DR)I), CD22 (B cell receptor CD22-B isoform), CD22 1, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD 4, CD40, CD44 v6, CD51, CD52, CD70, CD72(Lyb-2 , B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4 D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CT LA-4, CXCR5, DLL4, DR5, E16(LATI, SLC7A5), EGF L7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), epithelia ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like receptor) Protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, S PAP IC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 gangliosides, GEDA, HER1, HER2 / neu, HER3, H GF, 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, RAN KL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANA PI, STAMP I, STEAP2, STMP, prostate cancer-associated 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, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGF In some embodiments, the target antigen is BCMA, CD33, or vimentin. , PCAD, HER2, CD38, CD46, CD48, or CD79b. In 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, multilineage cancer, or Myeloma, plasma cell myeloma, leukemia, lymphoma, stomach cancer, acute myeloid leukemia, bladder cancer Brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer Cell carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid tumors of T-cell or B-cell origin Malignant tumors, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or pancreatic cancer. The cancer is lymphoma or gastric cancer.

[0286] Another exemplary embodiment includes providing a biological sample from a subject; contacting the conjugate with cancer cells in the sample; and By detecting binding of the antibody, a subject having or suspected of having cancer can be diagnosed with the antibody. The body-drug conjugate, composition, or pharmaceutical composition (e.g., the exemplary compositions disclosed herein) whether the patient responds to treatment with the antibody-drug conjugate, composition, or pharmaceutical composition In some embodiments, the cancer cells in the sample express the target antigen. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is , BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD7 4, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOL R1, ENPP3, MET, AXL, SLC34A2, Nectin-4, TROP2, LIV In some embodiments, the target antigen is 4-1BB, CD46, or GPNMB. 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, CD1 40a, CD152, CD19, CD20, CD200, CD21(C3DR)I), C D22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor body), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD7 2), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2 , CRIPTO(CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (D RT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ET BR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH 2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), Fib Ionectin extra domain-B, Frizzled receptor, GD2, GD3 ganglionic acid Osid, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20 R(ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRT A2 (immunoglobulin superfamily receptor translocation-associated 2), Lewis-Y antigen, LY6 4(RP105), MCP-I, MDP(DPEPI), MPF, MSLN, SMR, Me sotelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, P SCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI , Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I , STEAP2, STMP, prostate cancer-associated gene I, TAG-72, TEMI, Tenay SynC, TENB2, (TMEFF2, Tomoregulin, TPEF, HPPI, TR), T GF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4(B R22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein Protein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2 or vimentin In some embodiments, the target antigen is BCMA, CD33, PCAD, HER2, In some embodiments, the target antigen is CD38, CD46, CD48, or CD79b. is BCMA, CD33, CD48, PCAD, or HER2. In some embodiments, the target antigen is CD38 or CD48. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell carcinoma, or hematological cancer. Myeloma, leukemia, lymphoma, stomach 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, bone marrow leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate In some embodiments, the cancer is lymphoma or small cell lung cancer. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample. is.

[0287] Methods of making the described ADC compounds and compositions are also disclosed. is a cleavable cleavable nucleotide linked to an Mcl-1 inhibitor under conditions that allow conjugation. Antibody-drug conjugates are prepared by reacting a linker with an antibody or antigen-binding fragment. This is a method for producing the above. [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 are described below in connection with the accompanying drawings, which form a part of this disclosure. This can be more readily understood by reference to the detailed description.

[0290] Throughout the text, the description refers to compositions and methods of using the compositions. When describing or claiming properties or embodiments related to a composition, such properties or embodiments The embodiments are equally applicable to methods of using the compositions. When describing or claiming features or embodiments relating to the method of using an item, Such features or embodiments are equally applicable to the composition.

[0291] When a range of values ​​is expressed, this includes embodiments using any specific value within the range. Further, references to values ​​stated in ranges include each and every value within that range. All ranges are inclusive and combinable. Similarly, values ​​may be expressed as approximations. When stated, the use of the antecedent "about" indicates that the particular value forms another embodiment. It is understood that reference to specific numerical values ​​is at least as accurate as possible unless the context clearly indicates otherwise. The use of "or" includes both the specific values ​​unless otherwise indicated in the particular context of its use. Unless otherwise specified, the term "and / or" is used to mean "and / or." All cited documents are incorporated by reference for any purpose. In such cases, the present specification takes precedence.

[0292] Unless otherwise indicated by the context of this specification, e.g., in the absence of symbols representing particular points of connection When a structure or fragment of a structure is depicted, it may be attached to itself or to other components of the ADC. can be used in any orientation, e.g., by attaching an antibody to a chemical moiety, e.g., a linker - Drugs can be attached at any suitable attachment point and used. In this case, the components of the ADC are bonded in the orientation shown in the given formula. For example, in 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] For clarity, the disclosed embodiments described herein may be presented in the context of separate embodiments. Certain features of the compositions and methods may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, in the context of a single embodiment, it will be appreciated that The various features of the disclosed compositions and methods described may also be used individually or as part of any combination. It may be provided in various combinations.

[0297] As used throughout this application, an antibody drug conjugate is a "target antigen / antibody- They can be identified using a naming convention of the general form "linker-payload". For example: When an antibody drug conjugate is referred to as "target X-L0-P0" only, Such a conjugate comprises an antibody that binds to target X, a linker designated L0, and a linker designated P0. Alternatively, the antibody drug conjugate may contain a payload named "anti-target X" When a conjugate is referred to as "antibody-L0-P0", such a conjugate comprises an antibody that binds to target X, It may include a linker designated L0 and a payload designated P0, or When an antibody drug conjugate is referred to as "AbX-L0-P0," such conjugate The conjugate comprises an antibody designated AbX, a linker designated L0, and a linker designated P0. A control antibody-drug conjugate containing a non-specific isotype control antibody will be used. The IgG1-L0-P0 and IgG1-L0-P0 It is sometimes referred to as ".

[0298] Any formula given herein represents unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds are also intended to represent isotopically labeled forms. except that atoms of are replaced by atoms having selected atomic masses or mass numbers. and having a structure represented by the formula set forth herein. Isotopes that can be identified include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, e.g. For example 3 H, 11 C. 13 C. 14 C. 15 N, 18 F and 36 Cl is one example. Thus, the present disclosure provides, for example, radioisotopes, e.g. 3 H and 14 The above isotopes, including C or a compound incorporating therein a non-radioactive isotope, e.g. 2 H and 13 It should be understood that this includes those in which C is present. The compounds tested were 14 C), reaction kinetics studies (e.g. 2 H or 3 H detection or imaging techniques, e.g., drug or substance tissue distribution assays In positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in the radiation treatment of patients. 18 F or labeled Compounds may be particularly desirable for PET or SPECT studies. The compounds are generally labeled by conventional techniques known to those skilled in the art, e.g., by previously employed labeling techniques. can be prepared using appropriate isotopically labeled reagents instead of unlabeled reagents. .

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

[0300] As used herein, the singular forms "one" ("a", "an") and "the" ("the") "The" includes the plural unless the context indicates otherwise. )," "having," "being of the chemical formula," "including ( The terms "including" and "containing" are open terms unless otherwise specified. (i.e., "including, but not limited to") "comprising" or another open-ended term is used in one embodiment Whenever possible, the same embodiment may be referred to using the intermediate term "consisting essentially of" or a closed It is understood that a narrower claim may be made using the term "consisting of."

[0301] The terms "about" or "approximately" when used in the context of numerical values ​​and ranges , are intended to be illustrative, not restrictive, and are not intended to be limiting, as would be apparent to one skilled in the art from the teachings contained herein. approximating or nearing a listed value or range, such that In some embodiments, about refers to plus or minus 20% of the quantity. , 15%, 10%, 5%, 1%, 0.5% or 0.1%. In one embodiment, The term "about" refers to a range of values ​​10% above or below a particular value. In embodiments, the term "about" refers to a range of values ​​that is 5% above or below a particular value. In another embodiment, the term "about" means a value that is 1% greater or less than the particular value. Refers to the range of.

[0302] "Antibody-drug conjugate," "antibody conjugate," "conjugate," "injection The terms "immunoconjugate" and "ADC" are used interchangeably and refer to one or more one or more therapeutic compounds (e.g., Mcl-1) linked to the antibody or antigen-binding fragment thereof In some embodiments, the ADC has the general formula: Ab-(LD) p (Formula 1) where Ab = antibody or antigen-binding fragment, L = linker moiety, D = drug moiety (e.g., M CL-1 inhibitor drug moiety) and p = number of drug moieties per antibody or antigen-binding fragment In ADCs containing an Mcl-1 inhibitor drug moiety, "p" is defined as the or the number of Mcl-1 inhibitor compounds linked to an antigen-binding fragment.

[0303] The term "antibody" in its broadest sense refers to any molecule that contains at least one of the variable regions of an immunoglobulin molecule. The target, e.g., a protein, polypeptide, carbohydrate, or polymer, is bound to the target through another antigen recognition site. Immunoglobulin molecules that recognize and specifically bind to oligonucleotides, lipids, or a combination of the above. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, derived from natural or recombinant sources. "Intact" antibodies are typically interconnected by disulfide bonds. It is a glycoprotein containing at least two heavy (H) chains and two light (L) chains. is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The chain constant region contains three domains, CH1, CH2 and CH3. The light chain constant region is composed of a variable region (abbreviated herein as VL) and a light chain constant region. The VH and VL regions are composed of one domain, CL. The complementarity-determining regions (CDRs) are separated by more conserved regions called FRs. Each VH and VL can be further subdivided into regions of hypervariability, which are Sequence: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus It consists of three CDRs and four FRs arranged towards the carboxyl terminus. The variable region of the light chain contains a binding domain that interacts with an antigen. It is involved in various cells of the immune system (e.g., effector cells) and the first component of the classical complement system. It can mediate the binding of immunoglobulins to host tissues or factors, including the phospholipase C1q (C1q). Antibodies can be monoclonal, human, humanized, or camelized. The antibody can be of any isotype (e.g., a chimeric antibody). IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, I IgG2, IgG3, IgG4, IgA1 and IgA2) or subclasses 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" are used herein. As used herein, the term "antigen (e.g., BCMA, CD33, PCAD, or HER2)" refers to a specific antigen. specifically interact with the epitope (e.g., binding, steric hindrance, stabilizing / destabilizing, spatial An antigen-binding fragment refers to a portion of at least one antibody that retains its ability to bind to the antibody. It may also retain the ability to be internalized into the original-expressing cells. Antibody, antibody fragment, antigen-binding fragment, etc. have explored the use of antibody-derived binding domains in the context of larger macromolecules, e.g., ADCs. A fragment of a full-length antibody is intended to encompass any fragment that can perform the antigen-binding function of the full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragment consisting of VH and CH1 domains, linear antibody, single domain antibody antibodies, such as sdAb (either VL or VH), camelid VHH domains, antibody fragments, For example, a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region. Multispecific antibodies formed from fragments of isolated CDRs or other epitopes of antibodies Antigen-binding fragments include single domain antibodies, maxibodies, minibodies, and the like. Di, nanobody, intrabody, diabody, triabody, tetrabody, bibody Specific or multispecific antibody constructs, ADCs, v-NARs and bis-scFvs (e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):112 6-36). Antigen-binding fragments can be constructed using polypeptide-based scaffolds, e.g. It can also be transplanted into fibronectin type III (Fn3) (fibronectin polypeptide See US Patent No. 6,703,199, which describes petideminibodies). The term "scFv" refers to at least one antigen-binding fragment containing the variable region of a light chain and and at least one antigen-binding fragment comprising a variable region of a heavy chain, Here, the light and heavy chain variable regions are linked together by, for example, a synthetic linker, e.g., a short, flexible polypeptide. They can be linked together via a linker and expressed as a single polypeptide chain. where the scFv retains the specificity of the intact antibody from which it is derived. The scFv can have the VL and VH variable regions in any order, e.g. The scFv contains VL-linker-VH at the N- and C-termini of the polypeptide. or may comprise a VH-linker-VL. Antigen-binding fragments can be prepared by those skilled in the art. and the binding fragments can be subjected to a utility (e.g., a method for the production of antibodies) in the same manner as intact antibodies. Antigen-binding fragments are screened for their binding affinity, internalization, etc. It can be prepared by cleavage of the intact protein, e.g., by protease or chemical cleavage. do.

[0305] The term "complementarity determining region" or "CDR" as used herein refers to an antigen It refers to the sequence of amino acids in the antibody variable region that confers specificity and binding affinity. Typically, each heavy chain variable region has three CDRs (e.g., HCDR1, HCDR2, and HCDR3). R3), each light chain variable region contains three CDRs (LCDR1, LCDR2, and LCDR The exact amino acid sequence boundaries of a given CDR are given in Kabat et al. (1991) "Seq. uences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, N National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); -Lazikani et al. (1997) J Mol Biol. 273(4):927-48 ("Chothia" numbering sequence) scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77)( Any of a number of well-known schemes, including those described by the "IMGT" numbering scheme The CDR region (e.g., For example, HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR Combined Kabat and Chothia sequence numbers for LC CDR2 or LC CDR3 In some embodiments, the coding scheme may include a CDR that is part of a Chothia CDR. The amino acid residues defined as part of the Kabat CDRs, along with the amino acid residues defined as part of the Kabat CDRs, are: As used herein, the "Chothia" numbering scheme corresponds to The CDRs are sometimes referred to as "hypervariable loops."

[0306] In some embodiments, the CDR amino acids in the heavy chain variable domain (VH) according to Kabat The acid residues are 31-35 (HCDR1) (e.g., insertion after position 35), 50-65 (HCDR2) R2) and 95-102 (HCDR3); in the light chain variable domain (VL) The CDR amino acid residues of 1 through 56 (LCDR2) and 89 through 97 (LCDR3). In this state, under Chothia, the CDR amino acids in VH are 26 to 32 (HCDR1). (e.g., insertion after position 31), 52–56 (HCDR2) and 95–102 (HCDR 3); amino acid residues in VL are numbered 26 to 32 (LCDR1) (e.g., 30 (insertion after position), numbered 50–52 (LCDR2) and 91–96 (LCDR3) By combining both Kabat and Chothia CDR definitions, In some embodiments, the CDRs comprise, for example, amino acid residues 26-35 in human VH (HCD R1), 50–65 (HCDR2) and 95–102 (HCDR3) in human VL Amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). In some embodiments, under IMGT, V The CDR amino acid residues in H are approximately 26-35 (CDR1) and 51-57 (CDR2). and 93 to 102 (CDR3), and the CDR amino acid residues in VL are numbered as follows: The sequences are numbered 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the CDR regions of the antibody are designated by the program This can be determined using IMGT / Domain Gap Align.

[0307] The term "monoclonal antibody" as used herein refers to a substantially homogenous antibody. Refers to antibodies obtained from a population of the body, i.e., the individual antibodies that make up the population occur in small amounts Monoclonal antibodies are identical except for possible naturally occurring mutations that may occur. It is highly specific and directed against a single antigen epitope. Reclonal antibody preparations typically contain multiple antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" refers to the production of substantially homogeneous antibodies. The characteristics of antibodies as obtained from a population and the ability to identify the required antibodies by any particular method are described. For example, the monoclonal antibodies to be used in accordance with the present disclosure are not to be construed as being made Antibodies can be prepared, for example, using hybridoma antibodies, as first described by Kohler et al. (1975) Nature 256:495. They can be produced by the lysoma method or by recombinant DNA techniques (see, e.g., U.S. Pat. Nos. 4,849,923, ... and 4,849,923). Monoclonal antibodies can be produced by the method described in US Pat. No. 16,567. The body is described, for example, in Clackson et al. (1991) Nature 352:624-8, and Marks et al. (1991) J Mol Biol. 222:581-97, from a phage antibody library. The term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. vinegar.

[0308] The monoclonal antibodies described herein may be non-human, human, or humanized. The term specifically includes "chimeric" antibodies, in which the heavy and / or light chains The moiety may be a corresponding antibody derived from a particular species or belonging to a particular antibody class or subclass. the sequence is identical or homologous to that in the antibody that Antibodies belonging to different antibody classes or subclasses, and their specificity with the target antigen In such antibody fragments, It is identical to or homologous to the corresponding sequence.

[0309] The term "human antibody," as used herein, refers to an antibody produced by a human or The term refers to an antibody having the amino acid sequence of an antibody produced by a human or a human. and antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Additionally, if the antibody contains a constant region, the constant region may also contain such human sequences, e.g., human human germline sequences, or mutated versions of human germline sequences, or Knappik et al. al. ((2000) J Mol Biol. 296(1):57-86) Derived from antibodies containing consensus framework sequences derived from sequence analysis. The structure and location of globulin variable domains, e.g., CDRs, are numbered according to well-known numbering schemes, e.g., For example, the Kabat numbering scheme, the Chothia numbering scheme, or the Kabat and Chothia in combination with ImMunoGenTics (IMGT) The human antibodies of the present invention can be defined using a numbering system. Unidentified amino acid residues (e.g., random or site-specific mutations in vitro) Mutations induced by mutagenesis or by in vivo somatic mutations, or conservative substitutions to facilitate stability or production). The term "human antibody" as used herein refers to antibodies from other mammalian species, e.g., mice. Includes antibodies in which germline-derived CDR sequences have been grafted onto human framework sequences. It is not intended to be.

[0310] The term "recombinant human antibody" as used herein refers to an antibody prepared by recombinant means. , expressed, produced or isolated human antibodies, e.g., human immunoglobulin genes transgenic or transchromosomal animals (e.g., mice) or therefrom Antibodies isolated from the prepared hybridomas, transformed to express human antibodies antibodies isolated from host cells, e.g., transfectomas; recombinant combinatorial Human immunoglobulins isolated from human antibody libraries and other DNA sequences prepared, expressed, or by any other means involving splicing of all or part of the gene sequence. Such recombinant human antibodies refer to antibodies that have been developed, generated, or isolated. and variable regions in which the CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are prepared by in vitro mutagenesis. (or, if transgenic animals for human Ig sequences are used, in In vivo somatic mutagenesis) and thus the VH and VH sequences of the recombinant antibody can be The amino acid sequences of the VL regions are derived from and related to human germline VH and VL sequences, , sequences that would not naturally occur in the human antibody germline repertoire in vivo is.

[0311] The term "chimeric antibody" as used herein refers to an antibody that is an amino acid sequence of an immunoglobulin molecule. Refers to antibodies whose amino acid sequences are derived from more than one species. In some cases, both the heavy and light chains The variable regions of an antibody from one species have the desired specificity, affinity, and activity. The constant regions correspond to the nucleotide sequences of the target gene, while the constant regions minimize immune responses in other species (e.g., humans). Therefore, they are homologous to antibodies derived from the latter species.

[0312] As used herein, a "humanized antibody" refers to a non-human (e.g., murine) antibody and a human antibody. It refers to forms of antibodies that contain sequences from non-human immunoglobulins. A type of chimeric antibody that contains minimal sequence derived from a human. 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 from human immunoglobulin sequences and substantially all of the antibody will contain at least one, and typically two, variable domains. Humanized antibodies optionally contain immunoglobulins, typically those of a human immunoglobulin. The humanized antibody will also contain at least a portion of the IgG constant region (Fc). In order to improve and optimize affinity and / or activity, the Fv framework regions and and / or further modified by substitution of residues in any of the substituted non-human residues. It is possible.

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

[0314] "Internalization" as used herein in reference to an antibody or antigen-binding fragment Upon binding to the cell, the ATP passes through the lipid bilayer membrane of the cell and enters an internal compartment, preferably a compartment within the cell. Antibody or antigen binding proteins that can be taken up into the lytic compartment (i.e., "internalized") For example, internalization of an anti-HER2 antibody occurs after binding to HER2 on the cell membrane. In some embodiments, the compounds described herein are capable of being taken up into cells. The antibodies or antigen-binding fragments used in the disclosed ADCs can bind to cell surface antigens (e.g., B Internalizing antibodies or antigens targeting CMA, CD33, PCAD, or HER2 It is a binding fragment (i.e., the ADC translocates through the cell membrane after antigen binding). In this embodiment, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. Internalizing antibodies or internalizing antigen-binding fragments that target receptors on the cell membrane are receptor-mediated In some embodiments, an internalizing antibody or an endothelial cell can induce endocytosis. The localized 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 In some embodiments, the term refers to an antibody or antigen-binding fragment that remains on the cell surface when bound to a cell. In some embodiments, the antibodies or antigen-binding fragments used in the ADCs disclosed herein are target a cell surface antigen and are non-internalizing antibodies or non-internalizing antigen-binding fragments (i.e., ADCs remain on the cell surface after antigen binding and do not translocate across the cell membrane. In this embodiment, 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, CA12 Antibodies that bind to non-internalized antigen targets are also known in the art. knowledge (e.g., Bast et al. (1981) J Clin Invest. 68(5):1331-7; Scholler and Urb an (2007) Biomark Med. 1(4):513-23; and Boudousq et al. (2013) PLoS One 8(7):e (See 69613).

[0316] The term "B cell maturation antigen" or "BCMA" as used herein refers to human B cell maturation antigen (BCMA). This refers to any naturally occurring form of BCMA (tumor necrosis factor receptor superfamily member 17) (TNFRSF17). This term refers to full-length human BCMA (e.g., U niProt Reference Sequence: Q02223; SEQ ID NO: 72), and derived from cellular processing. The term encompasses any form of human BCMA that can be expressed by the human BCMA receptor, including, but not limited to: Splice variants, allelic variants and one or more live variants of human BCMA Functional variants or fragments of human BCMA, including isoforms that retain functional properties, are also available. (i.e., the context requires that the term be used to refer only to wild-type proteins. (Variants and fragments are included unless otherwise indicated.) BCMA can be isolated from humans. and can be produced recombinantly or by synthetic methods.

[0317] The terms "anti-BCMA antibody" or "antibody that binds BCMA" as used herein When the antibody or its antigen-binding fragment binds to, e.g., specifically binds to, BCMA, The term refers to any form of fragment of a monoclonal antibody (including full-length monoclonal antibodies). ), polyclonal antibodies, and antibodies that bind to BCMA, e.g., specifically bind and biologically functional antigen-binding fragments thereof. WO 2012 / 163805 The brochure provides representative BCMA binding sequences, including representative anti-BCMA antibody sequences. , which are incorporated herein by reference. The anti-BCMA antibodies used in the indicated ADCs are internalizing antibodies or internalizing antigen-binding fragments. J6M0 (International Publication No. 2012 / 163805) is a representative It is an anti-BCMA antibody.

[0318] The term "myeloid cell surface antigen CD33" or "CD33" as used herein means When used herein, it refers to any native form of human CD33 (sialic acid-binding Ig-like lectin 3 (SIG) This term refers to full-length human CD33 (e.g., UniPro t Reference sequence: P20138; SEQ ID NO: 73), and human tRNAs that can result from cellular processing. This term includes any form of CD33, including, but not limited to, human CD3 Splice variants, allelic variants that retain one or more biological functions of 3 and functional variants or fragments of human CD33, including isoforms thereof ( That is, unless the context indicates that the term is used to refer only to wild-type proteins. CD33 can be isolated from humans and It can be produced recombinantly or by synthetic methods.

[0319] The terms "anti-CD33 antibody" or "antibody that binds to CD33" are used herein. When the antibody or its antigen-binding fragment binds to, e.g., specifically binds to, CD33, The term refers to any form of fragment of a monoclonal antibody (including full-length monoclonal antibodies). including polyclonal antibodies, and antibodies that bind to CD33, e.g., specifically bind to CD33. , including biologically functional antigen-binding fragments. U.S. Patent Application Publication No. 2013 / 007 No. 8241 provides representative CD33 binding sequences, including representative anti-CD33 antibody sequences. In some embodiments, the present invention provides a method for the preparation of a medicament for the treatment ... The anti-CD33 antibodies used in the ADCs disclosed in MuMy9-6ch (US Patent Application Publication No. 2013 / 0078241) (Detailed description) is a representative anti-CD33 antibody.

[0320] The term "P-cadherin" or "PCAD" as used herein refers to human It refers to any naturally occurring form of PCAD (also known as cadherin 3, type 1 or CDH3). The term refers to the 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 includes, but is not limited to, one or more biological mechanisms of human PCAD. Includes functional splice variants, allelic variants, and isoforms , also encompasses functional variants or fragments of human PCAD (i.e., the term refers to wild-type Unless the context indicates that it is used to refer only to proteins, variants and fragments PCAD can be isolated from humans, recombinantly or synthetically produced. It can be made by

[0321] The terms "anti-PCAD antibody" or "antibody that binds to PCAD" are used herein. When the antibody or its antigen-binding domain binds to, e.g., specifically binds to, PCAD, The term refers to any form of fragment of a monoclonal antibody (including full-length monoclonal antibodies). ), polyclonal antibodies, and antibodies that bind to PCAD, e.g., specifically bind and biologically functional antigen-binding fragments thereof. WO 2016 / 203432 The brochure provides representative PCAD binding sequences, including representative anti-PCAD antibody sequences. , which are incorporated herein by reference. The anti-PCAD antibodies used in the indicated ADCs are internalizing antibodies or internalizing antigen-binding fragments. It is a fragment. NOV169N31Q (International Publication No. 2016 / 203432 Pamphlet) is a representative anti-PCAD antibody.

[0322] The terms "human epidermal growth factor receptor 2," "HER2," or "HER2 / NEU" As used herein, refers to any naturally occurring form of human HER2. Human HER2 (e.g., UniProt Reference Sequence: P04626; SEQ ID NO: 75), and This term encompasses any form of human HER2 that may result from cellular processing. splices that are not intended to be spliced ​​together but retain one or more biological functions of human HER2 Functional characteristics of human HER2, including variants, allelic variants, and isoforms It also encompasses variants or fragments (i.e., the term refers only to wild-type proteins). (Variants and fragments are included unless the context indicates otherwise.) HER2 can be isolated from humans, produced recombinantly or by synthetic methods .

[0323] The terms "anti-HER2 antibody" or "antibody that binds to HER2" are used herein. When administered, the antibody or its antigen-binding fragment binds, e.g., specifically binds, to HER2. The term refers to any form of fragment of a monoclonal antibody (including full-length monoclonal antibodies). ), polyclonal antibodies, and antibodies that bind to HER2, e.g., specifically bind to HER2. , including biologically functional antigen-binding fragments. and 6,870,034 disclose representative sequences of anti-HER2 antibodies. HER2 binding sequences are provided, which are incorporated herein by reference. In embodiments, the anti-HER2 antibodies used in the ADCs disclosed herein are internalizing antibodies. or an internalized antigen-binding fragment. Trastuzumab (U.S. Patent No. 5,821,337 and No. 6,870,034; 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 means Refers to any native form of human CD38 (ADP-ribosyl cyclase / cyclic ADP-ribosyl cyclase) This term refers to full-length human CD38 (e.g., UniP rot Reference sequence: P28907; SEQ ID NO: 76), and may result from cellular processing This term includes, but is not limited to, any form of human CD38. Splice variants, allelic barriers, that retain one or more biological functions of D38 The term also encompasses functional variants or fragments of human CD38, including fragments and isoforms. (i.e., unless the context indicates otherwise, the term is used to refer exclusively to the wild-type protein. (CD38 can be isolated from humans and is therefore intended to be a nucleotide sequence that can be used to identify specific CD38 polypeptides.) It can be produced recombinantly or by synthetic methods.

[0325] The term "cluster of differentiation 48" or "CD48" as used herein means Refers to any native form of human CD48 (B-lymphocyte activation marker) ion marker) (BLAST-1) or signaling lymphocyte activation molecule 2 (signaling It is also known as lymphocytic activation molecule 2 (SLAMF2). The term refers to 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 includes, but is not limited to, antibodies that retain one or more biological functions of human CD48. Human CD4, including splice variants, allelic variants, and isoforms 8 also encompasses functional variants or fragments of the wild-type protein (i.e., (Unless the context indicates that the term is used to refer only to a specific molecule, variants and fragments are included.) CD48 can be isolated from humans and produced recombinantly or by synthetic methods. This can be done.

[0326] The term "cluster of differentiation 79b" or "CD79b" as used herein In this case, it refers to any native form of human CD79b (B-cell antigen receptor complex-associated protein base This term refers to full-length human CD79b (see, e.g., UniProt Reference Reference sequence: P40259; SEQ ID NO: 78), and human CD40 that may result from cellular processing. The term includes, but is not limited to, any form of human CD79b. Splice variants, allelic variants that retain one or more biological functions of b and functional variants or fragments of human CD79b, including isoforms thereof. (i.e., unless the context indicates that the term is used to refer exclusively to the wild-type protein) (This includes variants and fragments as long as they are isolated from humans.) It can be produced recombinantly or by synthetic methods.

[0327] The term "binding specificity" as used herein refers to the specificity of an individual antibody or antigen binding This refers to the ability of a fragment to react preferentially with one antigenic determinant over different antigenic determinants. The degree to which an antibody or fragment preferentially binds to one antigenic determinant over different antigenic determinants As used herein, the terms "specific" and "specifically bind" refer to the degree of specificity. The terms "specifically binds" and "binds specifically" are used interchangeably. Antibodies or antigen-binding fragments (e.g., anti-H) in heterogeneous populations of proteins and other biologics The term refers to the binding reaction between an antibody (antibody) and a target antigen (e.g., HER2). Compare binding to the appropriate antigen with binding to an irrelevant antigen or antigen mixture under a set of conditions. The specificity of binding can be tested by performing a quantification test. or antigen mixture with at least 2-fold, 5-fold, 7-fold, or 10-fold greater affinity to the appropriate antigen. If it binds, it is considered specific. The antibody binds only to the target antigen (e.g., BCMA, CD33, PCAD, or HER2). but do not bind (or show minimal binding to) other antigens. In this state, the antibody specifically binds to the target antigen (e.g., BCMA, CD33, PCAD, or HER2). The antibody or antigen-binding fragment to be combined is 1x10 -6 Under M, 1x10 -7 Under M, 1x1 0 -8 Under M, 1x10 -9 Under M, 1x10 -10 Under M, 1x10 -11 Less than M, 1 x10 -12 M or 1x10 -13 K less than M D In some embodiments, K D In some embodiments, K D is 500pM to 1μM, 1μ Between M and 100 nM or 100 mM and 10 nM.

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

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

[0330] "k off " or "k d The term "antibody dissociation" refers to the dissociation of an antibody from the antibody / antigen complex. This rate is determined by standard assays, e.g., table Determine using surface plasmon resonance, biolayer interferometry, or ELISA assays It is possible.

[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 calculated using standard assays such as surface plasmon resonance, It can be determined using iolayer interferometry or an ELISA assay.

[0332] The term "epitope" refers to the region that is specifically recognized by an antibody (or antigen-binding fragment). Epitopes generally refer to the portion of an antigen that can be bound by an amino acid sequence. or carbohydrate or sugar side chains, and form specific three-dimensional structures. It can have structural and specific charge characteristics. If the antigen is a polypeptide, Epitopes are juxtaposed by consecutive amino acids or tertiary folding of a polypeptide. Epitopes can be "linear" or "steric" and can be formed from non-contiguous amino acids. Conformational and linear epitopes can be differentiated by the presence of denaturing solvents. The distinction is made between antibodies in that they lose their binding to the former but not to the latter. The epitope bound by an antibody (or antigen-binding fragment) is the direct site of the antigen-antibody complex. X-ray crystallography for epitope identification by visualization and antibody fragments or Monitoring binding to mutated variants or binding of different portions of the antibody and antigen methods known in the art, including monitoring solvent accessibility The antibody epitope can be identified using any epitope mapping technique. Exemplary strategies for mapping include, but are not limited to, array mapping. array-based oligo-peptide scanning, limited hydrolysis (limited proteolysis), site-directed mutagenesis, High-throughput mutagenesis mapping, hydrogen deuterium hydrogen-deuterium exchange, and mass spectrometry (e.g., Ger Shoni et al. (2007) BioDrugs 21:145-56; and Hager-Braun and Tomer (2005) Exper (See Rev Proteomics 2:745-56).

[0333] Competitive binding and epitope binning also identify antibodies that share the same or overlapping epitopes. Competitive binding can be determined using cross-blocking assays, e.g. “Antibodies, A Laboratory Manual,” Cold Spring Harbor Laboratory, Harlow and Evaluated using the assay described in Lane (1st edition 1988, 2nd edition 2014). In some embodiments, competitive binding can be evaluated by comparing the binding activity of a test antibody or binding protein with that of a test antibody or binding protein. but a reference antibody to a target antigen, e.g., BCMA, CD33, PCAD, or HER2, or Binding proteins (e.g., CDRs selected from those identified in Tables 3-5) and / or variable domain-containing binding proteins) in cross-blocking assays. at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 9 9%, 99.5% or more, or any percentage in between) In some embodiments, competitive binding is achieved by covalent or may be due to similar (e.g., particularly overlapping) epitopes or by antibodies or binding proteins. The quality of the nucleotides may be due to steric hindrance of binding to nearby epitopes (e.g., Tzartos, Metho ds in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66)). In some embodiments, competitive binding selects a group of binding proteins that share similar epitopes. For example, binding proteins that compete for binding can be "Binning" into groups of binding proteins with overlapping or nearby epitopes Those that do not compete are those that do not have overlapping or nearby epitopes. They are placed in a separate group of proteins.

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

[0335] A "recombinant" protein is made using recombinant techniques, e.g., through the expression of a recombinant nucleic acid. It refers to a protein (e.g., an antibody) produced by a specific antibody.

[0336] An "isolated" protein is one 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 polynucleotide that exists in a living organism. The polypeptide has not been isolated, but separated from some or all of the coexisting substances in the organism. The same polynucleotide or polypeptide obtained by subjecting a sample to a specific mutation is isolated. This definition is understood by those skilled in the art. This includes producing 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 isolated from the components (by weight) of its source environment. ), e.g., a hybridoma cell culture or preparation thereof. These antibodies have been identified and isolated from different cell culture components used for In some embodiments, the separation may be for an otherwise desired use (e.g., therapeutic use). This is done to thoroughly remove components that may interfere with the suitability of the antibody. Methods for preparing ribozymes are known in the art and include, without limitation, protein A chromosomes. chromatograph, anion exchange chromatography, cation exchange chromatography, These include virus retentive filtration and ultrafiltration.

[0338] As used herein, the term "variant" refers to a variant of a reference nucleic acid sequence or amino acid sequence. Nucleic acid sequences or sequences that differ from each other but retain one or more biological properties of the reference sequence A variant refers to a sequence of one or more amino acids that differs from a reference sequence. Substitutions, deletions and / or insertions (or corresponding codon substitutions, deletions and / or insertions) The changes in the nucleic acid variant may be inconsistent with the sequence encoded by the reference nucleic acid sequence. The amino acid sequence of the peptide may not be altered, or amino acid substitutions, additions, deletions, In some embodiments, the presently disclosed The nucleic acid variants encoded by the unmodified nucleic acid encode the same amino acid sequence as that encoded by the unmodified nucleic acid. Modifications that retain one or more functional properties of the unmodified amino acid sequence. The changes in the sequence of a peptide variant are typically limited or are conservative, so that the sequences of the unmodified peptide and the variants are closely similar overall. In some embodiments, peptide variants are unmodified The variants and unmodified peptides retain one or more functional properties of the original peptide sequence. A variant is one that differs in amino acid sequence by any combination of one or more substitutions, additions, and deletions. This may happen.

[0339] Nucleic acid or peptide variants may be naturally occurring variants or naturally occurring. Nucleic acid and peptide variants can be variants for which the sequence is unknown. By mutagenesis techniques, by direct synthesis, or other techniques known in the art Variants can be generated by any method that does not necessarily require physical manipulation of a reference sequence. To the extent that a sequence contains different nucleic acids or amino acids compared to a reference sequence, this does not Any degree of synthesis is considered a "variant." A variant has high sequence identity (i.e., 60% or higher) compared to the reference sequence. In some embodiments, the polypeptide has a nucleic acid or amino acid sequence identity. a reference sequence or a corresponding segment (e.g., a functional fragment) of a reference sequence, e.g., one of the reference sequences or at least 60%, at least 65%, with variants that retain multiple functions similarly; At least 70%, at least 75%, at least 80%, at least 85%, at least 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 Peptide variants may contain amino acid substitutions, deletions, or other similar sequences as long as they share 99% amino acid sequence identity. In some embodiments, the polynucleotides include polypeptides with deletions and / or insertions. The nucleic acid sequence is at least identical to the reference sequence or a corresponding segment (e.g., a functional fragment) of the reference sequence. 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%, less At least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98%, or at least 99% nucleic acid sequence identity. The term encompasses polynucleotides having amino acid substitutions, deletions and / or insertions.

[0340] The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to nucleic acid sequences, conservatively modified variants are identical or essentially identical. A nucleic acid that encodes a single amino acid sequence. Due to the degeneracy of the genetic code, many functionally distinct sequences exist. The same nucleic acid encodes any given protein. For example, the codons GCA, GCC, GCG and GCU all code for the amino acid alanine. At every position specified by a codon, a codon may alter the encoded polypeptide. The codons may be changed to any of the corresponding codons described without any restriction. The acid variation is a "silent variation," which means that the amino acid is conservatively modified. Any nucleic acid herein encoding a polypeptide is one type of modified variant. A nucleic acid sequence also describes every possible silent variation of a nucleic acid. Each codon in the It is possible to modify the nucleotides (except for the only codon in the nucleotide sequence, TGG) to obtain a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide Conservatively modified amino acids are implicit in each described sequence. The variants include individual substitutions, deletions, or additions to the polypeptide sequence, and are chemically This results in the substitution of an amino acid with a functionally similar amino acid. Conservative substitutions are well known in the art.

[0341] The term "conservative sequence modifications" as used herein refers to modifications that modify, e.g., an amino acid sequence. Amino acids that do not significantly affect or alter the binding properties of the antibody or antigen-binding fragment they contain. Conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be made by standard techniques known in the art, such as site-directed mutagenesis and and PCR-mediated mutagenesis can be introduced into antibodies or antigen-binding fragments. Conservative amino acid substitutions are those 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 are known in the art. These families include those with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., For example, glycine, asparagine, glutamine, serine, threonine, tyrosine, and cysteine , tryptophan), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, leucine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan Thus, in some embodiments, antibodies may be One or more amino acid residues in the The modified antibodies can be assayed using the functional assays described herein. can be tested.

[0342] The terms "homologous" or "identity" as used herein refer to the degree to which two polymers between molecules, e.g., two nucleic acid molecules, e.g., two DNA molecules or two RNA molecules It refers to the subunit sequence identity between two polypeptide molecules. The subunit positions in both molecules are occupied by the same monomer subunit, e.g. For example, if each position in two DNA molecules is occupied by an adenine, then they The homology between two sequences is the ratio of the number of matching or homologous positions to the number of identical positions. It is a linear function. For example, half the positions in the two sequences (e.g., a length of 10 subunits) If five positions in a given polymer are matched or homologous, the two sequences are said to be 50% identical. If 90% (e.g., 9 out of 10) of the positions are matched or homologous, the two The sequences are 90% homologous.

[0343] The percentage of "sequence identity" is calculated based on the sequence identity of two optimally aligned sequences over the comparison window. The amino acid sequence fragments in the comparison window can be determined by comparing the sequences obtained. The fragments are compared to a reference sequence (containing no additions or deletions) for optimal alignment of the two sequences. The fragment may contain additions or deletions (e.g., gaps or overhangs). The percentage matches determines the number of positions where identical amino acid residues occur in both sequences. Obtaining the number of positions, dividing the number of matching positions by the total number of positions in the comparison window, and The percentage of sequence identity can be calculated by multiplying the result by 100. The output is the percent identity of the subject sequence to the query sequence. The percent identity between the two sequences needs to be calculated for optimal alignment of the two sequences. The number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap Generally, the proteins disclosed herein and the target antigen (e.g., BCM A, CD33, PCAD or HER2) variants and antibody variable domain barriers and the amino acid identity between the variant (including each variant CDR) and the variant. or homology is at least 80% of the sequences shown herein, e.g., at least 8 5%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 9 9%, nearly 100% or 100% identity or homology.

[0344] The comparison of sequences and determination of percent identity between two sequences can be performed using numerical algorithms. In some embodiments, a fragment between two amino acid sequences can be achieved using a fragment size of 100 kb. The identity of the primates is determined by either the Blossum62 matrix or the PAM250 matrix, and Gap weights of 16, 14, 12, 10, 8, 6 or 4 and or 6 length weights in the GAP program in the GCG software package. The Needleman and Wunsch ((1970) J Mol Biol. 48:444-53) algorithm is incorporated. In some embodiments, the percent identity between two nucleotide sequences is determined using The unity is determined by the NWSgapdna.CMP matrix, as well as the 40, 50, 60, 70 or 80 GCG software uses a gap weight of and a length weight of 1, 2, 3, 4, 5, or 6. Determined using the GAP program in the wear package. Typical parameters The set has a gap penalty of 12, a gap extend penalty of 4, ty) and Blossum 62 score with a frameshift gap penalty of 5 The percent identity between two amino acid or nucleotide sequences is calculated using the PAM PAM120 weight residue table, gap length penalty of 12, and and in the ALIGN program (version 2.0) using a gap penalty of 4. We use the algorithm of Meyers and Miller ((1989) CABIOS 4:11-17) incorporated in It can also be determined.

[0345] The term "drug" includes chemical compounds, mixtures of chemical compounds, biological macromolecules, biological The term "compound" is used herein to refer to an extract made from a compound, a plant, or a combination of two or more thereof. The term "therapeutic agent" or "drug" is used to describe a biological process and / or refers to an agent capable of modulating the biological activity of Mcl-1 as described herein. Inhibitors and ADCs containing them are representative therapeutic agents.

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

[0347] The term "myeloid cell leukemia 1" or "Mcl-1" as used herein means In this case, human Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, The term refers to any naturally occurring form of full-length human Mcl-1 (e.g., UniProt Reference Sequence :Q07820; SEQ ID NO:71), and human Mcl-1, which may result from cellular processing The term includes, but is not limited to, human Mcl-1. splice variants, allelic variants, and Also encompassed are functional variants or fragments of human Mcl-1, including isoforms (i.e., That is, unless the context indicates that the term is used to refer only to the wild-type protein, Mcl-1 can be isolated from humans and expressed in tissues. They can be made by recombinant or synthetic methods.

[0348] The terms "inhibit" or "inhibition" or "inhibiting" are used herein. By "decreasing" it is meant reducing a biological activity or process by a measurable amount, but not completely. In some embodiments, "inhibition" can include, but does not require, complete prevention or inhibition. Expression of Mcl-1 and / or one or more of its upstream regulators or downstream targets It means to reduce the expression and / or activity of a substance.

[0349] The term "Mcl-1 inhibitor" as used herein refers to an inhibitor of Mcl-1 and / or or the expression and / or activity of one or more upstream regulatory factors or downstream targets thereof These drugs are capable of reducing the activity of Mcl-1. (including representative inhibitors) are listed in WO 2015 / 097123; WO 2015 / 097123 Brochure No. 2016 / 207216; Brochure No. 2016 / 207217 Lett; International Publication No. 2016 / 207225 Brochure; International Publication No. 2016 / 20 Pamphlet No. 7226; Pamphlet No. 2017 / 125224; Pamphlet No. 2017 / 125224 Brochure No. 2019 / 035899, Brochure No. International Publication No. 2019 / 035911 Lett, International Publication No. 2019 / 035914, International Publication No. 2019 / 03 No. 5927, U.S. Patent Application Publication No. 2019 / 0055264, International Publication No. 2016 / 033486, International Publication No. 2017 / 147410 brochure, WO 2018 / 183418 brochure and WO 201 No. 7 / 182625, each of which is incorporated herein by reference. Representative Mcl-1 inhibitors, including representative Mcl-1 inhibitors, that can be included as drug moieties in C The disclosed ADCs are incorporated by reference herein as cl-1 regulators. Representative Mcl-1 inhibitors that can be included as the drug moiety of the formula:

[0350] [ka] (wherein each variable is a value in accordance with International Publication No. 2019 / 035911; International Publication No. 201 9 / 035899 Brochure; International Publication No. 2019 / 035914 Brochure; or as defined in WO 2019 / 035927 ) Specific examples include, for example:

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

[0352] As used herein, "Mcl-1 inhibitor drug moiety," "Mcl-1 inhibitor," and the like The present invention is characterized by the following characteristics: ADCs that retain qualitatively the same, similar, or enhanced biological function or activity. In some embodiments, the composition provides a modified compound structure for binding to The Mcl-1 inhibitor drug moiety is component (D) in the ADC of formula (1).

[0353] The term "cancer" as used herein refers to a cell type that is typical of cancer-causing cells. properties such as unlimited proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or It refers to the presence of cells with certain morphological characteristics. In many cases, cancer cells are found in tumors. Such cells may be present singly in a subject or in the form of a cluster or mass. or may circulate in the bloodstream as isolated cells, e.g., leukemia or lymphoma cells The term "cancer" includes hematological cancers, solid tumors, sarcomas, carcinomas and other solid and non-solid tumors. This includes all types of cancer and cancer metastasis, including hematologic cancers. Hematologic cancers include B-cell malignancies. Cancer of the blood (leukemia), cancer of the plasma cells (myeloma, e.g. multiple myeloma), or Cancer of the lymph nodes (lymphoma) is one example. Typical B-cell malignancies include chronic Lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large bowel disease Leukemia includes acute lymphocytic leukemia (ALL), acute myeloid leukemia (ACLL), and thyroid cancer. Myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Examples include chronic myelomonocytic leukemia (CMML) and acute monocytic leukemia (AMoL). Examples of lymphoma include Hodgkin's lymphoma and non-Hodgkin's lymphoma. 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, stomach cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, etc. In some embodiments, the cancer may include breast cancer, multiple myeloma, plasma cell Myeloma, leukemia, lymphoma, stomach 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, bone Myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate In some embodiments, the cancer is a lymphoma or adenocarcinoma, small cell lung cancer, or splenic cancer. is stomach cancer.

[0354] As used herein, the term "tumor" refers to a tumor, either benign or malignant, Refers to any mass of tissue resulting from excessive cell growth or proliferation, including cancerous lesions. In embodiments, the tumor is selected from the group consisting of 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 In some embodiments, the tumor is a pancreatic cancer or a pancreatic cancer.

[0355] The terms "tumor cell" and "cancer cell" may be used interchangeably herein. and individual cells derived from a tumor or cancer, including both non-tumorigenic cells and cancer stem cells. The term "tumor cell" and "cancer cell" refers to a cell or a whole population of cells. When referring only to cells that have lost the ability to differentiate and differentiate, these cells are referred to as cancer stem cells. To distinguish it from other tumorigenic tumors, it is qualified by the term "non-tumorigenic."

[0356] The terms "target negative," "target antigen negative," or "antigen negative" are used herein. "Target positive", "target antigen expression" refers to the absence of target antigen expression by cells or tissues. The term "positive" or "antigen positive" refers to the presence of target antigen expression. For example, Cells or cell lines that do not express the target antigen can be described as target negative, while cells or cell lines that do not express the target antigen can be described as target negative. Cells or cell lines expressing the target can be described as target positive.

[0357] The terms "subject" and "patient" are used interchangeably herein and refer to a person in need of treatment. Non-human animals include all vertebrates, e.g., mammals. Non-limiting examples of mammals include: Includes humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, Non-limiting examples of non-mammals include dogs, cats, rats, mice, and guinea pigs. 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 person who is in need of treatment (e.g., treatment with any one or more of the representative ADC compounds described herein) "Targeted" refers to a subject who would benefit biologically, medically, or in quality of life from a therapeutic agent.

[0359] As used herein, the terms "treat," "treating," or "treatment" The term refers to any improvement in any outcome of a disease, disorder or condition, such as increased survival, reduced morbidity, or and / or reduction in side effects resulting from alternative treatments. In this context, treatment is defined as delaying or reversing a disease, disorder, or condition (i.e., the progression of the disease or its clinical manifestations). delaying, arresting, or reducing the onset of at least one symptom. In some embodiments, treatment involves the physical treatment of a disease, disorder, or condition, including those that may not be recognized by the patient. Some implementations include delaying, mitigating, or improving at least one of the clinical parameters. In some embodiments, treatment can be achieved by alleviating a disease, disorder, or condition physically (e.g., stabilizing discernible symptoms). ), physiologically (e.g., stabilizing body parameters), or both In some embodiments, the treatment includes administering to a subject a therapeutically effective amount of a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, ... The treatment includes administering to a subject, e.g., a patient, a described ADC compound or composition. , a disease, disorder or condition (e.g., cancer), a symptom of a disease, disorder or condition (e.g., cancer), or to cure, ameliorate, or mitigate the onset of a disease, disorder, or condition (e.g., cancer); Delay, prevent, mitigate, alter, force, improve, ameliorate, improve In some embodiments, the therapeutic agent may be for treating or affecting a disease, disorder, or condition. In addition to treating a subject having a disease or condition, the compositions disclosed herein may also be used to treat the disease or condition. Prophylactically providing to prevent or reduce the likelihood of developing a disease, disorder or condition It is also possible.

[0360] As used herein, "prevent" or "preventing" a disease, disorder, or condition means Alternatively, the term "prevention" may refer to the prophylactic treatment of a disease, disorder, or condition, or the prevention of a disease, disorder, or condition. or delaying the onset or progression of a condition.

[0361] As used herein, a "pharmaceutical composition" refers to at least one pharmaceutical composition suitable for administration to a subject. other (and optionally more than one other) components, e.g., a pharmaceutically acceptable carrier , stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients in addition to the composition, For example, the pharmaceutical compositions provided herein refer to formulations of ADC compounds or compositions. and subsequently providing the intended biological activity of the active ingredient and / or therapeutic effect. The pharmaceutical compositions provided herein are preferably in a form such that the formulation It does not contain additional components that are unacceptably toxic to the subject to whom it will be administered.

[0362] As used herein, "pharmaceutically acceptable carrier" and "physiologically acceptable The terms "carrier" and "carrier" can be used interchangeably and do not cause significant irritation to the subject, of the administered ADC compound or composition and / or any additional therapeutic agent in the composition A pharmaceutically acceptable carrier refers to a carrier or diluent that does not abrogate biological activity or properties. To strengthen or stabilize the composition or to facilitate preparation of the composition Pharmaceutically acceptable carriers include those known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329), solvents, dispersion media, coatings, surfactants, antioxidants, Preservatives (e.g., antibacterial and antifungal agents), isotonicity agents, absorption delaying agents ), salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavors, dyes, etc. and combinations thereof. Any conventional carriers are acceptable provided they are not incompatible with the active ingredient. Unless otherwise specified, its use in therapeutic or pharmaceutical compositions is contemplated. selected to minimize harmful side effects and / or to minimize degradation of the active ingredient. Adjuvants may also be included in any of these formulations.

[0363] As used herein, the term "excipient" refers to a substance that further facilitates administration of an active ingredient. It refers to an inactive substance added to a pharmaceutical composition to enhance its effect. Excipients, such as sterile water or saline, polyalkylene glycols, such as polyethylene glycols, Other typical examples include polyethylene glycol, vegetable oil, or hydrogenated naphthalene. Excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, and starch types, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymers particles, as well as surfactants, including, for example, Polysorbate 20.

[0364] The term "pharmaceutically acceptable salt" as used herein refers to a compound of the present invention. does not inhibit the biological activity and properties of the compound and does not cause significant irritation to the subject to which it is administered. Examples of such salts include, but are not limited to: (a) inorganic acids, e.g. Acid addition salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and organic acids, For example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid Acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, poly liglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, Salts formed with 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).

[0365] In some embodiments, the antibody-drug conjugates (ADCs) described herein The linker, payload, and linker-payload are monovalent anions depending on their charges. Ionic counterion M1 - Any suitable anionic counterion may be used. In certain embodiments, the monovalent anionic counterion can be a pharmaceutically acceptable salt. In certain embodiments, the monovalent anionic counterion is AEON M1 - are bromide, chloride, iodide, acetate, and trifluoroacetate. , benzoate, mesylate, tosylate, triflate, formate, etc. In some embodiments, a monovalent anionic counterion M1 - is trifluoroa It is an acetate or a formate.

[0366] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to a The desired therapeutic outcome (i.e., reduction or inhibition of enzyme or protein activity, improvement of symptoms, Alleviating symptoms or conditions, slowing disease progression, reducing tumor size, inhibiting tumor growth, preventing metastasis a compound described herein, such as an ADC described herein, to provide In some embodiments, a therapeutically effective amount refers to an amount of a compound or composition that does not cause undesired side effects. In some embodiments, a therapeutically effective amount does not induce or cause side effects. induce and induce only those actions permitted by the treating physician in light of the patient's condition. In some embodiments, a therapeutically effective amount is a therapeutically effective amount that reduces the growth or spread of cancer cells, tumor size, or or number, and / or other levels, stages, progression and / or severity of cancer This term refers to the detectable killing, reduction and / or inhibition of a target induces a specific response in cells, such as reducing, slowing or inhibiting cell proliferation This also applies to dosage. A therapeutically effective amount is achieved by administering a low dose initially, followed by a dose that is sufficient to achieve the desired effect. A therapeutically effective amount can be determined by gradually increasing the dose until the intended therapeutic effect is achieved. the use (in vitro or in vivo) being undertaken or the subject being treated and Varies depending on the disease state, such as the weight and age of the subject, the severity of the disease state, the method of administration, etc. These can be readily determined by one skilled in the art. For example, the specific pharmaceutical composition, the subject and their age and pre-existing health condition or conditions the risks involved, the medication regimen you will be following, the severity of your disease, and whether it is being used in combination with other medications. Whether and when it is administered, the tissue to which it is administered, and the The therapeutic potential of ADCs in cancer is highly variable, depending on the physical delivery system used. The effective amount is a dose that reduces the number of cancer cells, reduces tumor size, and inhibits (e.g., delays or inhibit (e.g., slow or stop) tumor growth, and / or can alleviate several symptoms.

[0367] As used herein, the terms "prophylactically effective amount" or "prophylactically effective dose" are not necessarily used. The compounds disclosed herein are effective to achieve the desired prophylactic result at the required dosages and for the required duration. Typically, the amount of a compound, such as an ADC compound or composition described herein, is: Since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, a prophylactically effective amount is generally a therapeutically effective amount. In some embodiments, a prophylactically effective amount is less than the onset of disease symptoms, including symptoms associated with cancer. can be prevented.

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

[0369] Antibody-drug conjugates The antibody-drug conjugate (ADC) compounds of the present disclosure, including those with anti-cancer activity, In particular, ADC compounds are compounds conjugated to a drug moiety (e.g., an Mcl-1 inhibitor). (i.e., covalently linked by a linker) antibody or antigen-binding fragment, wherein the drug The biological moiety, when not conjugated to an antibody or antigen-binding fragment, is a cytotoxic or In some embodiments, the drug moiety is an antibody or antigen-binding fragment thereof. When not conjugated to a fragment, Mcl-1 and / or one or more thereof It is possible to decrease the expression and / or activity of an upstream regulatory factor or a downstream target. Without being bound by theory, targeting Mcl-1 expression and / or activity may By doing so, in some embodiments, the ADCs disclosed herein have potent anti-cancer properties. Furthermore, without being bound by theory, it is possible to provide a drug moiety that is effective in treating tumors. by conjugating to antibodies that bind to antigens associated with tumor cells or cancer development , ADCs may exhibit improved activity, better activity, or both, compared to the drug moiety when administered alone. may result in reduced cytotoxicity specificity and / or off-target killing. Cut.

[0370] In some embodiments, the components of an ADC therefore include (i) an isolated antibody and and (ii) an antibody or (iii) maintain the specific binding properties of the antigen-binding fragment; and (iv) adjust the drug loading and drug-to-antibody ratio. (iv) optimizing the binding of the drug moiety via stable conjugation to the antibody or antigen-binding fragment; (v) allowing migration or delivery to a target site, intact (vi) Maintain the stability of the ADC as a conjugate; (vi) Optimize the aggregation of the ADC before and after administration; (vii) after cleavage or other release mechanism in the cellular environment, the therapeutic effect of the drug moiety (viii) an isolated antibody and drug moiety, e.g., capable of producing a cytotoxic effect; (ix) exhibiting in vivo anti-cancer treatment efficacy equivalent to or superior to that of the drug and / or (x) minimize off-target killing by the moiety; and / or (x) achieve desirable pharmacokinetics and The drug was evaluated to demonstrate its mechanical properties, formulatability, and toxicological / immunological profile. Each of these properties provides an improved ADC for therapeutic use. (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0371] The ADC compounds of the disclosure are administered in an effective amount of a cytotoxic or cytostatic agent to cancer cells or In some embodiments, the cytotoxicity of the ADC can be selectively delivered to tumor tissue. and / or the cytostatic activity is dependent on the expression of a target antigen in the cell. In this embodiment, the disclosed ADCs target cancers that express the target antigen while minimizing off-target killing. In some embodiments, the disclosed ADCs are particularly effective at killing cells that express a target antigen. It does not exhibit cytotoxic and / or cytostatic effects on cancer cells that do not express the drug.

[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 and pancreatic cancer. , lymphomas, and leukemias (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, and intrauterine cancer. These include membranous, ovarian, pancreatic, bladder, prostate, 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, and bladder cancer. urothelial cell carcinoma, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous carcinoma) uterine serous endometrial carcinoma, salivary duct cancer, cervical cancer, uterus These include endometrial cancer and ovarian cancer (English et al. (2013) Mol Diagn Ther. 17:85-9 9).

[0376] In certain embodiments, an antibody or antigen-binding fragment (Ab) thereof, an Mcl-1 inhibitor drug an ADC compound comprising a moiety (D) and a linker moiety (L) that covalently links an Ab to D, Provided herein are antibodies or antigens thereof that target cancer cells. a binding fragment (Ab), an Mcl-1 inhibitor drug moiety (D), and covalently linking the Ab to D Provided herein are ADC compounds that include a linker moiety (L). In some embodiments, The antibody or antigen-binding fragment may bind to a tumor-associated antigen (e.g., BCMA, CD33, PCAD, or It is possible for the antibody to bind to HER2 or HER3 with high specificity and high affinity. In some embodiments, the antibody or antigen-binding fragment, upon binding, binds to a target cell, e.g., a cell In some embodiments, the ADC binds to the target cell and is internalized into a degradable compartment within the target cell. Upon receipt of the antibody, it is internalized and degraded, releasing the Mcl-1 inhibitor drug moiety and killing the cancer cell. The Mcl-1 inhibitor drug moiety is not degraded by enzymatic action, hydrolysis, oxidation or any other mechanism. and can be released from the antibody and / or linker moiety of the ADC.

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

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

[0379] In some embodiments, the antibody or antigen-binding fragment has two heavy chains and two light chains. It is a four-chain antibody (also called an immunoglobulin or a full-length or intact antibody) that binds to the IgG antibody. 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 has the ability to bind to a target cancer antigen. immunoglobulins, which retain their potency and / or provide at least one function of an immunoglobulin It is an antigen-binding fragment of globulin.

[0380] In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or an internalizing antigen thereof. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof is They bind to target cancer antigens expressed on the surface of cells and enter the cells upon binding. In embodiments, the Mcl-1 inhibitor drug moiety of the ADC is a compound that inhibits the activity of the ADC against a target cancer antigen expressing the target cancer antigen. After entering and present in the cell (i.e., after the ADC is internalized), e.g., by cleavage , by degradation of the antibody or antigen-binding fragment, or by any other suitable release mechanism; It is released from the antibody or antigen-binding fragment of the ADC.

[0381] In some embodiments, the antibody is a cytotoxic agent that inhibits antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cell cytotoxicity (CCL). This includes mutations that reduce or completely mediate CDC. In some embodiments, these mutations are Fc silencing, Fc silent, or These are known as Fc silent mutations. In some embodiments, the IgG1 constant region The amino acid residues L234 and L235 are replaced by A234 and A235 ("LAL In some embodiments, amino acid residue N297 of the IgG1 constant region is , substituted at A297 (also known as "N297A"). In some embodiments, the IgG 1. The amino acid residues D265 and P329 in the constant region were replaced with A265 and A329. (also known as "DAPA"). Other antibody Fc silencing mutations may also be used. In some embodiments, the Fc silencing mutations can be in combination, e.g., D Used in 265A, N297A and P329A (also known as "DANAPA") will be done.

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

[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 are Any set of heavy and light chain variable domains listed in the table above, or The present invention provides a method for preparing a human genomic DNA comprising administering to a mammalian subject the present invention, ... a method for administering to a mammalian subject the present invention, and a method for administering to a mammalian subject the present invention. In some embodiments, the antibody or antigen-binding domain of the ADCs disclosed herein can be The fragments are then injected into the target cancer antigen (e.g., 1x10 -8 K less than M D (with) join and retain the ability to retain one or more functional properties (e.g., internal localization, the ability to bind to antigenic targets, such as antigens expressed on tumors or other cancer cells Conservatively modified and / or homologous to the sequences listed in the table above, so long as they retain the It can contain an amino acid sequence such as

[0402] In some embodiments, the antibodies or antigen-binding fragments of the ADCs disclosed herein are human For example, the disclosed ADCs further comprise heavy and light chain constant domains or fragments thereof. The antibody or antigen-binding fragment of In some embodiments, the recombinant human IgG1A vector can include a human kappa or lambda light chain constant domain. The antibody or antigen-binding fragment of the indicated ADC is human immunoglobulin G subtype 1 (I gG1) 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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 15 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 16, heavy chain CDR3 consisting of SEQ ID NO: 17 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 18, SEQ ID NO: 19 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 20. R3).

[0405] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 1. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the overlapping sequence of SEQ ID NO: 1. the light chain variable region amino acid sequence of SEQ ID NO: 2, or the light chain variable region amino acid sequence of SEQ ID NO: 3, In some embodiments, the anti-BCMA antibody comprises a sequence that is at least 95% identical to a sequence that is The antibody or antigen-binding fragment thereof may have at least 96%, at least 97%, or at least 99% identity with SEQ ID NO:1. heavy chain variable region amino acid sequences that are at least 98% or at least 99% identical, and / or SEQ ID NO: 2 with at least 96%, at least 97%, at least 98% or They have light chain variable region amino acid sequences that are at least 99% identical.

[0406] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-BCMA antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain is wild-type (unmodified) numbered according to the EU numbering system. Cysteines at amino acid positions corresponding to 152 and 375 in the IgG1 heavy chain constant domain In some embodiments, the IgG1 heavy chain constant domain comprises a wild-type (unmodified) ) Cysteines at amino acid positions corresponding to 156 and 379 in the IgG1 heavy chain constant domain In some embodiments, the anti-BCMA antibody comprises a human Ig kappa light chain constant domain (C). domain or a modified Ig kappa light chain constant domain.

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

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

[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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 21 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 22, heavy chain CDR2 consisting of SEQ ID NO: 23 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 24, SEQ ID NO: 25 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 26. R3).

[0411] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 3. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the overlapping sequence of SEQ ID NO:3. the light chain variable region amino acid sequence of SEQ ID NO: 4, or the light chain variable region amino acid sequence of SEQ ID NO: 5, In some embodiments, the anti-CD33 antibody comprises a sequence that is at least 95% identical to a sequence that is The antibody or antigen-binding fragment thereof may have at least 96%, at least 97%, or at least 99% identity with SEQ ID NO:3. heavy chain variable region amino acid sequences that are at least 98% or at least 99% identical, and / or SEQ ID NO: 4 with at least 96%, at least 97%, at least 98% or They have light chain variable region amino acid sequences that are at least 99% identical.

[0412] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-CD33 antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain corresponds to 297 in the wild-type (unmodified) IgG1 heavy chain constant domain In some embodiments, the anti-CD33 antibody comprises a glutamine residue (Q) at the amino acid position corresponding to the 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 has a heavy chain amino acid sequence of SEQ ID NO: 59 or the sequence a sequence that is at least 95% identical to SEQ ID NO: 59, and the 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-C The D33 antibody has a heavy chain amino acid sequence of SEQ ID NO: 59 and a light chain amino acid sequence of SEQ ID NO: 60. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-CD33 antibody has a sequence identity of at least 96%, at least 97%, or at least 100% with SEQ ID NO: 59. heavy chain amino acid sequence that is at least 98% or at least 99% identical to SEQ ID NO: 60, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-CD33 antibody has a light chain amino acid sequence similar to MuMy9-6. ch (U.S. Patent Application Publication No. 2013 / 0078241) or an antigen-binding fragment thereof It is one piece.

[0414] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is MuMy9-6c h, three heavy chain CDRs and three light chain CDRs, wherein the CDRs are HCDR1 ( Sequence number 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) , containing no more than 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[0415] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises three antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 27 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 28, heavy chain CDR3 consisting of SEQ ID NO: 29 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 30, SEQ ID NO: 31 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 32. R3).

[0416] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:5. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof comprises the overlapping sequence of SEQ ID NO:5. the light chain variable region amino acid sequence of SEQ ID NO: 6, or the light chain variable region amino acid sequence of SEQ ID NO: 7, In some embodiments, the anti-CD33 antibody comprises a sequence that is at least 95% identical to a sequence that is The antibody or antigen-binding fragment thereof may have at least 96%, at least 97%, or at least 99% identity with SEQ ID NO:5. heavy chain variable region amino acid sequences that are at least 98% or at least 99% identical, and / or SEQ ID NO: 6 with at least 96%, at least 97%, at least 98% or They have light chain variable region amino acid sequences that are at least 99% identical.

[0417] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-CD33 antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain is wild-type (unmodified) numbered according to the EU numbering system. Cysteines at amino acid positions corresponding to 152 and 375 in the IgG1 heavy chain constant domain Contains residue (C).

[0418] In some embodiments, the anti-CD33 antibody has a heavy chain amino acid sequence of SEQ ID NO: 61 or the sequence a sequence that is at least 95% identical to SEQ ID NO: 61, and the 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-C The D33 antibody has a heavy chain amino acid sequence of SEQ ID NO: 61 and a light chain amino acid sequence of SEQ ID NO: 62. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-CD33 antibody has at least 96%, at least 97%, or at least 100% identity with SEQ ID NO: 61. heavy chain amino acid sequences that are at least 98% or at least 99% identical to SEQ ID NO: 62, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-CD33 antibody has a light chain amino acid sequence similar to gemtuzumab or or an antigen-binding fragment thereof.

[0419] In some embodiments, the anti-CD33 antibody or antigen-binding fragment thereof is a 3'-amino acid sequence of gemtuzumab. and three light chain CDRs, wherein the CDRs are HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), HCDR3 (SEQ ID NO: 3), HCDR4 (SEQ ID NO: 4), HCDR5 (SEQ ID NO: 5), HCDR6 (SEQ ID NO: 6), HCDR7 (SEQ ID NO: 7), HCDR8 (SEQ ID NO: 8), HCDR9 (SEQ ID NO 27), HCDR2 (SEQ ID NO: 28), HCDR3 (SEQ ID NO: 29); LCDR1 (SEQ ID NO: No. 30), LCDR2 (SEQ ID NO: 31) and LCDR3 (SEQ ID NO: 32) 1, 2, Contains no more than 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 33 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 34, heavy chain CDR3 consisting of SEQ ID NO: 35 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 36, SEQ ID NO: 37 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 38. R3).

[0422] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 7. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises the overlapping sequence of SEQ ID NO:7. the light chain variable region amino acid sequence of SEQ ID NO: 8, or the light chain variable region amino acid sequence of SEQ ID NO: 9, In some embodiments, the anti-PCAD antibody comprises a sequence that is at least 95% identical to a sequence that is The antibody or antigen-binding fragment thereof may have at least 96%, at least 97%, or at least 99% identity with SEQ ID NO:7. heavy chain variable region amino acid sequences that are at least 98% or at least 99% identical, and / or SEQ ID NO: 8 with at least 96%, at least 97%, at least 98% or They have light chain variable region amino acid sequences that are at least 99% identical.

[0423] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-PCAD antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain is wild-type (unmodified) numbered according to the EU numbering system. Cysteines at amino acid positions corresponding to 152 and 375 in the IgG1 heavy chain constant domain Contains residue (C).

[0424] In some embodiments, the anti-PCAD antibody has a heavy chain amino acid sequence of SEQ ID NO: 63 or the sequence a sequence that is at least 95% identical to SEQ ID NO: 63, and the 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-P The CAD antibody has a heavy chain amino acid sequence of SEQ ID NO: 63 and a light chain amino acid sequence of SEQ ID NO: 64. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-PCAD antibody has a sequence identity with SEQ ID NO: 63 by at least 96%, at least 97%, or at least heavy chain amino acid sequence that is at least 98% or at least 99% identical to SEQ ID NO: 64, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-PCAD antibody has a light chain amino acid sequence similar to that of NOV169N. 31Q (WO 2016 / 203432) or an antigen-binding fragment thereof is.

[0425] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof is NOV169N3 HCDR1 ( SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35); LCDR 1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37) and LCDR3 (SEQ ID NO: 38) Contains no more than 1, 2, 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[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 of the following: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 39 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, heavy chain CDR3 consisting of SEQ ID NO: 41 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 42, SEQ ID NO: 43 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 44. R3).

[0428] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 9. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof comprises the sequence of SEQ ID NO: 9. The heavy chain variable region amino acid sequence of SEQ ID NO: 10, and the light chain variable region amino acid sequence of SEQ ID NO: 11, or In some embodiments, the anti-HER2 antibody comprises a sequence that is at least 95% identical to the sequence shown. 2. The antibody or antigen-binding fragment thereof has at least 96%, at least 97%, or both an affinity to SEQ ID NO: 9. heavy chain variable region amino acid sequences that are at least 98% or at least 99% identical, and and / or at least 96%, at least 97%, at least 98% identical to SEQ ID NO: 10 or have a light chain variable region amino acid sequence that is at least 99% identical.

[0429] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-HER2 antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain corresponds to 297 in the wild-type (unmodified) IgG1 heavy chain constant domain In some embodiments, the IgG1 heavy chain constant comprises a glutamine residue (Q) at the amino acid position corresponding to the IgG1 heavy chain constant. The constant domain contains the amino acid sequence 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 acid position. Wild-type (unmodified) IgG1 heavy chain constant domain numbered according to the EU numbering system It contains cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in In embodiments, the anti-HER2 antibody comprises a human Ig kappa light chain constant domain or a modified Ig kappa light chain constant domain. Contains the light chain constant domain.

[0430] In some embodiments, the anti-HER2 antibody has a heavy chain amino acid sequence of SEQ ID NO: 65 or the sequence a sequence that is at least 95% identical to SEQ ID NO: 65, and the 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-H The ER2 antibody has a heavy chain amino acid sequence of SEQ ID NO: 65 and a light chain amino acid sequence of SEQ ID NO: 66. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-HER2 antibody has a similar affinity to SEQ ID NO: 65 by at least 96%, at least 97%, or at least heavy chain amino acid sequences that are at least 98% or at least 99% identical to SEQ ID NO: 66, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-HER2 antibody has a light chain amino acid sequence similar to that of trastuzumab. (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 is.

[0431] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof is three heavy chain CDRs and three light chain CDRs, wherein the CDRs are HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), HCDR3 (SEQ ID NO: 3), HCDR4 (SEQ ID NO: 4), HCDR5 (SEQ ID NO: 5), HCDR6 (SEQ ID NO: 6), HCDR7 (SEQ ID NO: 7), HCDR8 (SEQ ID NO: 8), HCDR No. 39), HCDR2 (SEQ ID NO: 40), HCDR3 (SEQ ID NO: 41); LCDR1 (SEQ ID NO: 1, 2 of LCDR2 (sequence number 42), LCDR2 (sequence number 43) and LCDR3 (sequence number 44) , containing up to 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 45 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 46, heavy chain CDR3 consisting of SEQ ID NO: 47 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 48, SEQ ID NO: 49 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 50. R3).

[0434] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 11. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 1. the heavy chain variable region amino acid sequence of SEQ ID NO: 1 and the light chain variable region amino acid sequence of SEQ ID NO: 12, comprises a sequence that is at least 95% identical to a disclosed sequence. The D38 antibody or antigen-binding fragment thereof has an affinity to SEQ ID NO: 11 at least 96%, at least heavy chain variable region amino acid sequences that are 97%, at least 98%, or at least 99% identical and / or SEQ ID NO: 12 and at least 96%, at least 97%, at least 9 They have light chain variable region amino acid sequences that are 8% or at least 99% identical.

[0435] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-CD38 antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain is wild-type (unmodified) numbered according to the EU numbering system. Cysteines at amino acid positions corresponding to 152 and 375 in the IgG1 heavy chain constant domain Contains residue (C).

[0436] In some embodiments, the anti-CD38 antibody has a heavy chain amino acid sequence of SEQ ID NO: 67 or the sequence a sequence that is at least 95% identical to SEQ ID NO: 67, and the 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-C The D33 antibody has a heavy chain amino acid sequence of SEQ ID NO: 67 and a light chain amino acid sequence of SEQ ID NO: 68. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-CD38 antibody has a sequence identity of at least 96%, at least 97%, or at least 100% with SEQ ID NO: 67. heavy chain amino acid sequences that are at least 98% or at least 99% identical to SEQ ID NO: 68, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-CD38 antibody is daratumumab or or an antigen-binding fragment thereof.

[0437] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is 3'- or 4'-dimer of gemtuzumab. and three light chain CDRs, wherein the CDRs are HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), HCDR3 (SEQ ID NO: 3), HCDR4 (SEQ ID NO: 4), HCDR5 (SEQ ID NO: 5), HCDR6 (SEQ ID NO: 6), HCDR7 (SEQ ID NO: 7), HCDR8 (SEQ ID NO: 8), HCDR9 (SEQ ID NO 45), HCDR2 (SEQ ID NO: 46), HCDR3 (SEQ ID NO: 47); LCDR1 (SEQ ID NO: No. 48), LCDR2 (SEQ ID NO: 49) and LCDR3 (SEQ ID NO: 50) 1, 2, Contains no more than 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[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 As described in incorporated WO 2018 / 089807 In some embodiments, the anti-CD46 antibody or antigen-binding fragment thereof comprises the antigen of SEQ ID NO: 90. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-CD46 antibody or antigen-binding fragment thereof comprises SEQ ID NO:9. 0, and the light chain variable region amino acid sequence of SEQ ID NO: 91, comprises a sequence that is at least 95% identical to a disclosed sequence. The D46 antibody or antigen-binding fragment thereof has an affinity to SEQ ID NO: 90 at least 96%, at least heavy chain variable region amino acid sequences that are 97%, at least 98%, or at least 99% identical and / or SEQ ID NO: 91 and at least 96%, at least 97%, at least 9 They have light chain variable region amino acid sequences that are 8% or at least 99% identical.

[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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 51 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 52, heavy chain CDR3 consisting of SEQ ID NO: 53 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 54, SEQ ID NO: 55 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 56. R3).

[0442] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof has the amino acid sequence of SEQ ID NO: 13. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 14, 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 SEQ ID NO: 1. 3, and the heavy chain variable region amino acid sequence of SEQ ID NO: 14, comprises a sequence that is at least 95% identical to a disclosed sequence. The D48 antibody or antigen-binding fragment thereof has an affinity to SEQ ID NO: 13 with at least 96% or at least heavy chain variable region amino acid sequences that are 97%, at least 98%, or at least 99% identical and / or SEQ ID NO: 14 and at least 96%, at least 97%, at least 9 They have light chain variable region amino acid sequences that are 8% or at least 99% identical.

[0443] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof is an internalizing antibody or In some embodiments, the anti-CD48 antibody is a human IgG1 complex. In some embodiments, the antibody comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The G1 heavy chain constant domain is wild-type (unmodified) numbered according to the EU numbering system. Cysteines at amino acid positions corresponding to 152 and 375 in the IgG1 heavy chain constant domain Contains residue (C).

[0444] In some embodiments, the anti-CD48 antibody has a heavy chain amino acid sequence of SEQ ID NO: 69 or the sequence a sequence that is at least 95% identical to SEQ ID NO:69, and the 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-C The D48 antibody has a heavy chain amino acid sequence of SEQ ID NO: 69 and a light chain amino acid sequence of SEQ ID NO: 70. In some embodiments, the disclosed sequences include sequences that are at least 95% identical to the disclosed sequences. The anti-CD48 antibody has a sequence identity with SEQ ID NO:69 that is at least 96%, at least 97%, or at least heavy chain amino acid sequence that is at least 98% or at least 99% identical to SEQ ID NO: 70, at least 96%, at least 97%, at least 98% or at least 99% identical In some embodiments, the anti-CD48 antibody has a light chain amino acid sequence similar to SGN-48A. or an antigen-binding fragment thereof.

[0445] In some embodiments, the anti-CD48 antibody or antigen-binding fragment thereof is 3 times the activity of gemtuzumab. and three light chain CDRs, wherein the CDRs are HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), HCDR3 (SEQ ID NO: 3), HCDR4 (SEQ ID NO: 4), HCDR5 (SEQ ID NO: 5), HCDR6 (SEQ ID NO: 6), HCDR7 (SEQ ID NO: 7), HCDR8 (SEQ ID NO: 8), HCDR9 (SEQ ID NO 51), HCDR2 (SEQ ID NO: 52), HCDR3 (SEQ ID NO: 53); LCDR1 (SEQ ID NO: No. 54), LCDR2 (SEQ ID NO: 55) and LCDR3 (SEQ ID NO: 56) 1, 2, Contains no more than 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[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 antibodies: and three light chain CDRs: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 82 ), heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 83, heavy chain CDR2 consisting of SEQ ID NO: 84 R3 (HCDR3); light chain CDR1 (LCDR1) consisting of SEQ ID NO: 85, SEQ ID NO: 86 and a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 87. R3).

[0448] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof has the sequence of SEQ ID NO: 80. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 81; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82. In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof comprises a region selected from the group consisting of SEQ ID NO: 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 that is at least 95% identical to a disclosed sequence. The anti-CD79B antibody or antigen-binding fragment thereof may have at least 96% identity with SEQ ID NO: 80, at least 96% identity with SEQ ID NO: 80. heavy chain variable region amino acids that are at least 97%, at least 98%, or at least 99% identical and / or a sequence at least 96%, at least 97%, or at least Both have light chain variable region amino acid sequences that are 98% or at least 99% identical.

[0449] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof is an internalizing antibody or is an internalizing antigen-binding fragment. In some embodiments, the anti-CD79B antibody is a human IgG In some embodiments, the antibody comprises a modified IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. The IgG1 heavy chain constant domain is a wild-type (unmodified) The IgG1 heavy chain constant domain contains amino acids at positions corresponding to 152 and 375. Contains a cysteine ​​residue (C).

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

[0451] In some embodiments, the anti-CD79B antibody or antigen-binding fragment thereof is three heavy chain CDRs and three light chain CDRs, wherein the CDRs are HCDR1 (SEQ ID NO: 1), HCDR2 (SEQ ID NO: 2), HCDR3 (SEQ ID NO: 3), HCDR4 (SEQ ID NO: 4), HCDR5 (SEQ ID NO: 5), HCDR6 (SEQ ID NO: 6), HCDR7 (SEQ ID NO: 7), HCDR8 (SEQ ID NO: 8), HCDR SEQ ID NO: 82), HCDR2 (SEQ ID NO: 83), HCDR3 (SEQ ID NO: 84); LCDR1 (SEQ ID NO: 85); 1, 2 of LCDR2 (sequence number 85), LCDR2 (sequence number 86) and LCDR3 (sequence number 87) , containing up to 3, 4, 5 or 6 amino acid additions, deletions or substitutions.

[0452] Residues in two or more polypeptides occupy similar positions in the polypeptide structure. Similar positions in two or more polypeptides are said to correspond to each other. The sequence of the gene is determined by comparing the sequence of the gene based on the similarity of the amino acid sequence or structure. Those skilled in the art will appreciate that gaps can be introduced into either sequence to produce a good alignment. Understand that it may be necessary to introduce

[0453] In some embodiments, the amino acid substitutions are of a single residue. It occurs with approximately 20 amino acid residues, but the biological function (e.g., binding to the target antigen) is maintained. Deletions are usually from about 1 to about 20 amino acids. The deletions may range from 0 to 100% of the base residues, but in some cases the deletions may be much larger. Deletions, insertions or any combination thereof may be performed to arrive at the final derivative or variant. Generally, these changes can be used to modify the structure of molecules, particularly antigen-binding proteins. This is done on a small number of amino acids to minimize alterations in immunogenicity and specificity of the antibody. However, larger changes may be tolerated in certain circumstances. This can be done according to the chart below, shown in Table 7.

[0454] [Table 9]

[0455] In some embodiments where variant antibody sequences are used in ADCs, the variants are typically They exhibit the same quality of biological activity and induce the same immune response, but the variants can be used to Alternatively, variants may be selected to modify the properties of the original binding protein. 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 are used in the ADCs used herein to target cancer cells. As shown below, the linker-payload in the ADCs disclosed herein can be This approach is highly effective when using antibodies that target different tumor antigens. Suitable proteins that are not expressed in normal cells or are expressed at higher levels in cancer cells than in healthy cells Antigens are known in the art as are antibodies directed against them. Further antibodies against the original target can be prepared by one skilled in the art. These antibodies include: Use with the linkers and Mcl-1 inhibitor payloads disclosed herein In some embodiments, the antibody or antigen-binding fragment targets BCMA and The MA-targeted antibody or antigen-binding fragment is J6M0. In some embodiments, the antibody or The antigen-binding fragment targets CD33 and in some embodiments is a CD33-targeted antibody or anti-CD33 antibody. In some embodiments, the antibody or antigen-binding fragment is MuMy9-6ch. The fragment targets PCAD and in some embodiments is a PCAD-targeting antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is H In some embodiments, the HER2-targeting antibody or antigen-binding fragment is a trastuzumab. In some embodiments, the disclosed linker and Mcl-1 inhibitor pair is stuzumab. While erode is highly effective with several different tumor-targeting antibodies, BCMA Targeted antibodies, e.g., J6M0, CD33 targeted antibodies, e.g., MuMy9-6ch, PCAD targeted antibodies Targeted antibodies, such as NOV169N31Q, and HER2-targeted antibodies, such as trastuzumab, , particularly improved drug:antibody ratios, aggregation levels, stability (i.e., in vitro and and in vivo stability), tumor targeting (i.e., cytotoxicity, efficacy), minimized The improved treatment efficacy was observed in vivo. This can be measured in vitro or in vivo and may result in reduced tumor growth rate and / or may include reduced tumor volume.

[0457] In some embodiments, alternative antibodies to the same target or antibodies to different antigen targets are used. The bodies are used to obtain the advantageous functional properties described above (e.g., improved stability, improved Some of the results achieved provide at least some of the advantages of the present invention (e.g., improved tumor targeting, improved treatment efficacy, etc.). In embodiments, some or all of these advantageous functional properties are achieved by the disclosed linkers and and Mcl-1 inhibitor payloads instead targeting BCMA, CD33, CD46, CD48, When conjugated to PCAD or HER2-targeting antibodies or antigen-binding fragments, In some other embodiments, some or all of these advantageous functional properties are The disclosed linkers and Mcl-1 inhibitor payloads are directed to BCMA-targeting antibodies or antigens. In some embodiments, this is observed when the antibody or The antigen-binding fragment targets BCMA. In some embodiments, the BCMA-targeted antibody or In another embodiment, the antigen-binding fragment is J6M0. Some or all of the disclosed linkers and Mcl-1 inhibitor payloads may be linked to CD33 This is observed when conjugated to a target antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets CD33. 33 targeting antibody or antigen-binding fragment is MuMy9-6ch. Some or all of these advantageous functional properties may be achieved by the disclosed linkers and Mcl- 1. Inhibitor payload conjugated to 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 NOV169N3 In other embodiments, some or all of these advantageous functional properties are achieved by the development of The indicated linkers and Mcl-1 inhibitor payloads are HER2-targeting antibodies or antigen-binding In some embodiments, the antibody or antigen The binding fragment targets HER2. In some embodiments, the HER2-targeting antibody or antigen The binding fragment is trastuzumab.

[0458] Linker In some embodiments, the linker in the ADC is sufficiently cellular to be therapeutically effective. In some embodiments, the linker is stable extracellularly, allowing the ADC remains intact when present in extracellular conditions (e.g., before transport or delivery into cells) The term "intact" as used in the context of ADCs means that the antibody or antigen-binding fragment is This means that the molecule remains bound to the moiety (eg, an Mcl-1 inhibitor).

[0459] As used herein, a "stable" linker in the context of a linker or an ADC that includes a linker. "Non-specific" means that 20% or less of the linker in a sample of the ADC is present when the ADC is in extracellular conditions. , about 15% or less, about 10% or less, about 5% or less, about 3% or less, or about 1% or less (or any percentage between these) are cleaved (or the entire ADC is otherwise intact) In some embodiments, the linkers and and / or the ADC may comprise an alternative linker and / or an alternative linker and / or or more stable than ADCs with Mcl-1 inhibitor payloads. In some embodiments, the ADCs disclosed herein can be administered for more than about 48 hours, more than 60 hours, more than about 72 hours, It may remain intact for more than about 84 hours, or for more than about 96 hours.

[0460] Whether a linker is stable extracellularly can be determined, for example, by dissolving the ADC in plasma for a predetermined period of time. (e.g., 2, 4, 6, 8, 16, 24, 48, or 72 hours), and then The stability can be determined by quantifying the amount of free drug moiety present in the to localize to target cancer cells and indiscriminately damage both normal and cancerous tissues This prevents premature release of the drug moiety, which can reduce the therapeutic index of the ADC. In some embodiments, the linker may be a cytotoxic agent, such as a cytotoxic agent, to prevent the ADC from reacting with the target cell. The ADC is stable on the outside and releases the drug moiety once inside the cell, allowing the drug to can bind to its target. Thus, useful linkers include: (i) antibodies or (ii) maintain the specific binding properties of the antigen-binding fragment; and (iii) stabilize the antibody or antigen-binding fragment. (iii) ADCs that allow for the delivery of a drug moiety, e.g., intracellular delivery, via a suitable bond; (iv) remain stable and intact until transported or delivered to the target site; and or alternative release mechanisms, allowing for the therapeutic effect, e.g., cytotoxic effect, of the drug moiety.

[0461] The linker can affect the physicochemical properties of the ADC. Many cytotoxic agents Being hydrophobic in nature, linking them to antibodies with additional hydrophobic moieties Aggregation can occur due to the insolubility of ADC aggregates, which can lead to loss of available drug content on the antibody. This often limits drug loading, which may negatively impact the efficacy of the ADC. Protein aggregation in biologics is also commonly associated with increased immunogenicity. As shown, the linkers disclosed herein provide low levels of aggregation and desirable levels of This results in an ADC with a drug loading.

[0462] Linkers can be "cleavable" or "non-cleavable" (Ducry and Stump (2012)). 010) Bioconjugate Chem. 21:5-13). Cleavable linkers are used to enhance the binding of cleavable linkers to cleavable linkers when exposed to certain environmental factors. When the drug moiety (e.g., Mcl-1) is internalized within the target cell, e.g., when the drug moiety ... Inhibitors), whereas non-cleavable linkers are generally designed to release the antibody or or by degradation of the antigen-binding fragment itself.

[0463] The term "alkyl," as used herein, consists solely of carbon and hydrogen atoms. It refers to a straight or branched hydrocarbon chain radical that is free of unsaturation. The term "alkyl," as used herein, means a group consisting solely of carbon and hydrogen atoms. It contains no unsaturation, has 1 to 6 carbon atoms, and is attached to the rest of the molecule by a single bond. refers to a straight or branched hydrocarbon chain radical. Typical examples are 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) butyl (C4 alkyl), n-pentyl (C5 alkyl), isopentyl hexyl (C6 alkyl), neopentyl (C5 alkyl), and hexyl (C6 alkyl). Examples include:

[0464] The term "alkenyl" as used herein refers to an alkyl group consisting solely of carbon and hydrogen atoms. a linear or branched hydrocarbon chain radical group containing at least one double bond; The term "C2-C6 alkenyl" as used herein refers to a group of carbon and consisting only of hydrogen atoms, containing at least one double bond, and having 2 to 6 carbon atoms; A straight or branched hydrocarbon chain radical group 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 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 "alkenyl" as used herein means a group consisting solely of carbon and hydrogen atoms. , containing at least one double bond, having 2 to 3 carbon atoms, and connected to the rest of the molecule by single bonds. refers to a straight or branched hydrocarbon chain radical group attached to the C2-C3 alkyl group. Non-limiting examples of "alkenyl" groups include ethenyl (C2 alkenyl) and prop-1- enyl (C3 alkenyl).

[0465] The term "alkylene" as used herein refers to an alkylene group consisting solely of carbon and hydrogen atoms. "C" refers to a divalent linear or branched hydrocarbon chain radical consisting of 2-(2-methyl-2-phenyl-2-propanol) and containing no unsaturation. The term "C1-C6 alkylene" as used herein refers to a group of carbon and hydrogen atoms. Divalent straight or branched chain alkyl groups containing 1 to 6 carbon atoms, containing no unsaturation. refers to a hydrocarbon chain radical. Non-limiting examples of "C1-C6 alkylene" groups include methyl C1 alkylene, ethylene (C2 alkylene), 1-methylethylene (C3 alkylene) 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) alkylene), isopentylene (C5 alkylene), neopentylene (C5 alkylene), and and hexylene (C6 alkylene).

[0466] The term "alkenylene" as used herein means an alkenylene bond containing only carbon and hydrogen atoms. a divalent linear or branched hydrocarbon chain radical containing at least one double bond, The term "C2-C6 alkenylene" as used herein refers to a carbonyl group. consisting only of hydrogen and oxygen atoms, containing at least one double bond, and having 2 to 6 carbon atoms "C2-C6 alkene" refers to a divalent linear or branched hydrocarbon chain radical group having the formula: Non-limiting examples of "enylene" groups include ethenylene (C2 alkenylene), prop-1-enylene, Nylene (C3 alkenylene), but-1-enylene (C4 alkenylene), penta-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 hexa-2-,4-dienylene (C6 alkenylene) and hexa-2-,4-dienylene (C6 alkenylene) The term "C2-C6 alkenylene" as used herein means a carbon atom or a carboxylic acid. consisting only of hydrogen and oxygen atoms, containing at least one double bond, and having 2 to 3 carbon atoms "C2-C3 alkene" refers to a divalent linear or branched hydrocarbon chain radical group having the formula: Non-limiting examples of "enylene" groups include ethenylene (C2 alkenylene) and propane-1 -enylene (C3 alkenylene).

[0467] The terms "cycloalkyl" or "C3-C8 cycloalkyl" are used herein to mean When used, it 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]pen. hexane, 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 Non-limiting examples of monocyclic C3-C8 cycloalkyl groups include benzoyl, ... Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, and cyclohexyl. Examples include cycloheptyl and cyclooctyl groups.

[0468] The term "haloalkyl" as used herein refers to any of the hydrogen atoms along a hydrocarbon chain. refers to a linear or branched alkyl chain substituted with one or more halogen groups instead of Examples of halogen groups suitable for substitution on haloalkyl groups include fluorine, bromine, chlorine, and iodine. Haloalkyl groups have multiple aryl groups replacing hydrogen atoms in the alkyl chain. wherein the halogen group is substituted with a halogen group in the alkyl chain They can be attached to the same carbon or different carbons.

[0469] As used herein, alkyl, alkenyl, alkynyl, alkoxy, amino , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl groups, optionally substituted linear or is a branched (C2-C6) alkynyl group, optionally substituted linear or branched (C (1-C6)alkoxy, optionally substituted (C1-C6)alkyl-S-, hydro Oxy, oxo (or N-oxide, where appropriate), nitro, cyano, -C(O)-O R0', -OC(O)-R0', -C(O)-NR0'R0'', -NR0'R0'' , -(C=NR0')-OR0'', linear or branched (C1-C6) haloalkyl, optionally substituted with 1 to 4 groups selected from trifluoromethoxy, or halogen; wherein R0' and R0'' each independently represent a hydrogen atom or is a linear or branched (C1-C6) alkyl group substituted as required by Alternatively, one or more of the carbon atoms of a branched (C1-C6) alkyl group may be It is deuterated accordingly.

[0470] The terms "polyoxyethylene," "polyethylene glycol," or "PEG" As used herein, straight chain, branched or cyclic alkyl groups comprised of (OCH2CH2) groups are In certain embodiments, the polyethylene or PEG group is —(O CH2CH2) t * - (wherein t is 1 to 40 or 4 to 40, where "-" is , indicating the end pointing towards the self-immolative spacer, and * -" 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 —(CH2CH2O) t * -(formula wherein t is 1 to 40 or 4 to 40, where "-" indicates a self-immolative spacer. indicates the end that is * -" indicates the point of attachment to the terminal group R'', where R'' is H , CH3 or CH2CH2C(=O)OH). For example, "PEG12" and The term "t" as used herein means that t is 12.

[0471] The term "polyalkylene glycol" as used herein refers to a group consisting of (O(CH 2) m ) n It refers to a linear, branched, or star-shaped configuration composed of groups. In this state, the polyethylene or PEG group is -(O(CH2) m ) t * - (wherein m is 1 t is 1 to 40 or 4 to 40, where "-" is a self-immolating space. The end pointing towards the sir, * -" indicates the point of attachment to the terminal group R', where R' is OH, OCH3, or OCH2CH2C(=O)OH). In the example, the polyethylene or PEG group is -((CH2) m O) t * - (wherein m is 1 to 10, and t is 1 to 40 or 4 to 40, where "-" represents a self-immolative spacer. - indicates the end pointing towards 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, refers to a group that is a functional group of an antibody, antibody fragment, or antibody fragment. Alternatively, it can form a covalent bond with the functional group of another reactive group attached to the antibody fragment. Non-limiting examples of such functional groups include those provided herein. Examples of reactive groups that can be used include those listed in Table 8.

[0473] The term "attachment group" or "coupling group" means As used herein, a bivalent moiety that links a bridging spacer and an antibody or fragment thereof A bond or linking group is formed by reaction between a reactive group and a functional group on an antibody or fragment thereof. Non-limiting examples of such divalent moieties include those described herein. Examples of divalent chemical moieties include those shown in Tables 8 and 9 provided in the specification.

[0474] The term "bridging spacer," as used herein, refers to one or more phosphorus Carrier moieties that are covalently linked together to form a bivalent moiety, which is a bivalent peptide spectrophotometer. The linker and the reactive group are linked, and the bivalent peptide spacer and the linking group are linked or bonded. The term "linker" refers to a linker moiety that connects a group to at least one cleavable group. In this embodiment, the "bridging spacer" is linked to the N-terminus of the bivalent peptide spacer via an amide bond. It contains a carboxyl group attached to the end.

[0475] The term "spacer moiety" as used herein refers to a group of molecules covalently linked together. , one or more linkers forming the moiety connecting the self-immolative spacer and the hydrophilic moiety -Refers to the ingredient.

[0476] The term "bivalent peptide spacer" as used herein refers to a peptide spacer that is covalently bonded together one or more of which are combined to form a portion connecting the bridging spacer and the self-immolative spacer It refers to a bivalent linker containing multiple amino acid residues. One or more amino acid residues can be 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 Anthracene (Trp), Tyrosine (Tyr), Citrulline (Cit), Norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (P yl), homoserine, homocysteine, and desmethylpyrrolysine It may be the residue of a carboxylic acid.

[0477] In certain embodiments, a "bivalent peptide spacer" is a peptide in which each residue is an alanine (Al a), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), Phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagus 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, independently selected from amino acid residues selected from A combination of 2 to 4 amino acid residues, for example, -ValCit * ;-CitVal * ;-AlaAla * ;-AlaCit * ;-CitAla * ;-AsnCit * ;-C itAsn * ;-CitCit * ;-ValGlu * ;-GluVal * ;-SerCi t * ;-CitSer * ;-LysCit * ;-CitLys * ;-AspCit * ;- CitAsp * ;-AlaVal * ;-ValAla * ;-PheAla * ;-AlaP he * ;-PheLys * ;-LysPhe * ;-ValLys * ;-LysVal * ; -AlaLys * ;-LysAla * ;-PheCit * ;-CitPhe* ;-Leu Cit * ;-CitLeu * ;-IleCit * ;-CitIle * ;-PheArg * ;-ArgPhe * ;-CitTrp * ;-TrpCit * ;-PhePheLys * ; -LysPhePhe * ;-DPhePheLys * ;-DLysPhePhe * ;-G lyPheLys * ;-LysPheGly * ;-GlyPheLeuGly-[SEQ ID NO: No. 160];-GlyLeuPheGly-[SEQ ID NO: 161];-AlaLeuAla Leu-[SEQ ID NO: 162], -GlyGlyGly * ;-GlyGlyGlyGly- -GlyPheValGly- [SEQ ID NO: 164]; and -Gl yValPheGly- [SEQ ID NO: 165], where "-" is the bridging spacer It indicates the connection point with * " indicates the point of attachment to the self-immolative spacer.

[0478] The term "linker moiety," as used herein, refers to a chemical compound that is part of a linker. Examples of linker moieties include: alkylene groups; linear or can be either branched -(CH2) n - (where n is 1 to 18); Alkenylene group; Alkynylene group; Alkenyl group; Alkynyl group; Ethylene glycol group Unit: -OCH2CH2- or -CH2CH2O-; Polyethylene glycol unit To: (-CH2CH2O-) x (wherein x is 2 to 20); -O-;- S-; Carbonyl: -C(=O); Ester: C(=O)-O or OC(=O); Carbon Acid salts: -OC(=O)O-; amines: -NH-; tertiary amines; amides: -C(=O)- NH-, -NH-C(=O)- or -C(=O)N(C 1~6 alkyl); carbamate Urea: -NHC(=O)NH; Sulfonamide: -S(O)2NH- or -NHS(O)2; Ether: -CH2O- or or -OCH2-; carboxy, sulfonic acid, hydroxyl, amine, amino acid, sugar, alkyl substituted with one or more groups independently selected from phosphoric acid and phosphonic acid; carboxylic, sulfonic, hydroxyl, amine, amino acid, sugar, phosphate and and phosphonic acid; Carboxylic, sulfonic, hydroxyl, amine, amino acid, sugar, phosphate and phospho alkynylene substituted with one or more groups independently selected from carboxylic acids; In the formula, multiple methylene groups are replaced with one or more -S-, -NH-, or -O- moieties. C1~C 10 Alkylene; a ring system with two available points of attachment, e.g., phenyl (including 1,2-, 1,3-, and 1,4-disubstituted phenyl), C5-C6 heteroaryl C3-C8 cycloalkyl (1,1-disubstituted cyclopropyl, cyclobutyl, cyclopropyl, pentyl or cyclohexyl, and 1,4-disubstituted cyclohexyl), and A divalent ring selected from C4-C8 heterocycloalkyl; alanine (Ala), cysteine 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 (Se r), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), Selenocysteine ​​(Sec), pyrrolidine (Pyl), homoserine, homocysteine, and and desmethylpyrrolidine; each residue is alanine (Ala ), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine ( Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagi Ascending nucleotides (Asn), proline (Pro), glutamine (Gln), arginine (Arg), cerebrospinal fluid (CF), Phosphorus (Ser), Threonine (Thr), Valine (Val), Tryptophan (Trp) , tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine ( Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine and desmethylpyrrolysine, combinations of two or more amino acid residues, e.g., Val-Cit; Cit-Val; A la-Ala;Ala-Cit;Cit-Ala;Asn-Cit;Cit-Asn;C it-Cit;Val-Glu;Glu-Val;Ser-Cit;Cit-Ser;L ys-Cit;Cit-Lys;Asp-Cit;Cit-Asp;Ala-Val;V al-Ala;Phe-Lys;Lys-Phe;Val-Lys;Lys-Val;A la-Lys;Lys-Ala;Phe-Cit;Cit-Phe;Leu-Cit;C it-Leu;Ile-Cit;Cit-Ile;Phe-Arg;Arg-Phe;C it-Trp; and Trp-Cit; and a self-immolative spacer, which is capable of withstanding acid-induced cleavage. cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, Phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, one or more molecules that are susceptible to lipase-induced cleavage or disulfide bond cleavage A self-immolative spacer containing a protecting (trigger) group.

[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, the linker component is 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 pyridinyl and R in Table 8 35 is H, C 1~6 Alkyl, phenyl, or 1 to 3 -O C substituted with H group 1~4 alkyl, and each R in Table 8 7 is H, C1~6 Alkyl, Fluoro, benzyloxy substituted with -C(=O)OH, benzyl, C(=O)OH-substituted 1~4 Alkoxy, and -C(=O)O C substituted with H 1~4 alkyl; 37 H, Feni In Table 8, q is 0, 1, 2, or 3; R in 8 8 and R 13 is H or methyl, and R in Table 8 9 and R 14 H, R in Table 8 is H or any suitable substituent; R in 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 mean: Acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage One or more of the cleavage sites are activated by autocatalytic cleavage, lipase-induced cleavage, or disulfide bond cleavage. refers to a moiety containing multiple trigger groups (TG), and after activation, the protecting groups are removed, thereby This results in a cascade of decomposition reactions leading to the time-sequential release of leaving groups. Suitable cascades include, but are not limited to, 1,4-, 1,6-, or 1,8-elimination reactions. It could be.

[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 cis 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 - It is described in 7509.

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

[0499] [ka] where Lp is an enzyme-cleavable bivalent peptide spacer, 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 moiety having the formula: It is a tertiary amine.

[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 the hydrophilic moiety of the drug moiety (D) of the present invention. have hydrophilic properties that increase the water solubility of the drug moiety (D) when attached to the linker group; Examples of such hydrophilic groups include, but are not limited to, polyethylene Glycol, polyalkylene glycol, sugar, oligosaccharide, polypeptide, 1-3 units of

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

[0507] Several different reactions can be performed to bind the drug moiety and / or linker moiety to the antibody or antigen. These are often available for covalent attachment to functional fragments, such as the amine groups of lysines, glutamines, and The free carboxylic acid groups of phosphate and aspartic acid, the sulfhydryl groups of cysteine, and One or more of the antigen-binding fragments of the antibody or antigen-binding fragment contain various portions of aromatic amino acids in the For example, nonspecific covalent attachment can be achieved by reaction of amino acid residues on the drug moiety. oxy (or amino) groups and amino (or carboxy) groups on antibodies or antigen-binding fragments In addition, dialdehyde or isopropyl alcohols can be used in combination with carbodiimide reactions to link the Bifunctional agents such as imidoesters also bind to amino groups on the drug moiety and to amino groups on the antibody or antigen-binding fragment. It may be used to link the amino group of a drug (e.g., an Mcl-1 inhibitor) to the The Schiff base reaction can also be used to attach the agent. Periodate oxidation of drugs containing an hydroxy group, thereby forming an aldehyde, which The binding involves the formation of a Schiff base with the amino group of the binding agent. Isothiocyanates are also used as coupling agents to covalently attach drugs to binders. Other techniques are known to those skilled in the art and are not within the scope of this disclosure. Various chemistries known in the art can be used to generate and bind to antibodies or antigen-binding fragments. Examples of drug moieties that can be linked include Mcl-1 inhibitors, such as those described herein. These include the Mcl-1 inhibitors described and exemplified above.

[0508] Suitable drug moieties are compounds of formula (I), (II), (III), or enantiomers thereof: isomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts In addition, the drug moiety may comprise an addition salt with an acceptable acid or base. The compound may include any compound that is an Mcl-1 inhibitor (D).

[0509] As used herein, "atropisomers" refers to isomers that are different from each other due to steric strain or other contributing factors. The resulting energy difference is high enough to allow for the isolation of individual conformers. Stereoisomers that arise because of restricted rotation around a single bond, creating a barrier to (Bringmann et al. Angew. Chem. Int. Ed. 2005, 44, 5384-5427). For example, For the compounds of formula (II) according to the 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 are described in International Patent Application Publication Nos. WO2015 / 097123; WO20 No. 16 / 207216; No. WO2016 / 207217; No. WO2016 / 20722 No. 5; No. WO2016 / 207226; No. WO2017 / 125224; No. WO20 No. 19 / 035899; No. WO2019 / 035911; No. WO2019 / 03591 No. 4; No. WO2019 / 035927; No. WO2016 / 033486; No. WO20 17 / 147410; WO2018 / 183418; and WO2017 / 18 2625, and U.S. Patent Application Publication No. 2019 / 0055264 (each of which (which is incorporated herein by reference in its entirety) It can be either one.

[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. is a methyl 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. the law of nature, 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 (C1-C6) alkyl group, a is a branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group , linear or branched (C1-C6) haloalkyl group, hydroxy group, hydroxy(C1 -C6) alkyl group, linear or branched (C1-C6) alkoxy group, -S-(C1- C6) Alkyl group, cyano group, nitro group, -Cy 08 , -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6) alkyl-NR 011 R 011 ', -O-(C 1-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 01 1-C(O)-OR 011 ', -(C1-C6) alkyl-NR 011 -C(O)-R0 11 ', -SO2-NR 011 R 011 or -SO2-(C1-C6) alkyl the law of nature, R 02 , R 03 , R 04 and R 05 are independently hydrogen atoms, halogen atoms, and linear or branched (C1-C6) alkyl groups, linear or branched (C2-C6) alkene groups C2-C6 alkyl groups, linear or branched (C1- C6) haloalkyl, hydroxy group, hydroxy(C1-C6) alkyl group, linear or is a branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, cyano group, Toro group, -(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 aromatic rings containing 5 to 7 ring members. and optionally forming an aromatic or non-aromatic ring selected from O, S and N. 3 heteroatoms, where the resulting ring is not halogen, linear or branched (C1 ~C6) alkyl, (C0~C6) alkyl-NR 011 R 011 ', -NR 013 R0 13 ', -(C0-C6) alkyl-Cy 01 or oxo optionally substituted with two groups; R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl groups, linear or branched (C2-C6) alkenyl groups, linear or branched or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) haloalkynyl groups aryl, hydroxyl group, linear or branched (C1-C6) alkoxy group, -S-(C1-C 6) Alkyl group, cyano group, nitro group, -(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 , -(C 2-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 to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they 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, The resulting ring may be a linear or branched (C1-C6) alkyl group, -NR 013 R0 13 ', -(C0-C6) alkyl-Cy 01 or oxo optionally substituted the law of nature, 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 group, aryl group, heteroaryl group, aryl (C1-C6) alkyl group or heteroaryl group an alkyl (C1-C6)aryl group, R 09 is a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched Branched (C2-C6) alkenyl group, linear or branched (C2-C6) alkynyl group, - Cy 02 , -(C1-C6) alkyl-Cy 02 , -(C2-C6)alkenyl-Cy0 2. -(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 a branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, Aryl (C1-C6) alkyl groups, (C1-C6) cycloalkyl alkyl groups, linear or branched (C1-C6) haloalkyl or -(C1-C6) alkyl-O-CyO 4, Or pair (R 09 , R 010 ) when fused to two adjacent carbon atoms, together with the carbon atom to which it is 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; R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or a 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 5~ Forms an aromatic or non-aromatic ring containing seven ring members, which may optionally be joined to a nitrogen atom In addition, it contains 1 to 3 heteroatoms selected from O, S and N, where the N atom is substituted with one or two groups selected from linear or branched (C1-C6) alkyl groups; wherein one of the carbon atoms of the linear or branched (C1-C6) alkyl group is or more 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)-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 independently hydrogen atoms, or is 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 'Moto -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, cycloalkyl group, (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 5 to 7 which, in addition to the nitrogen atom, also contains oxygen and nitrogen wherein the nitrogen may be in a linear or branched form. optionally substituted with a (C1-C6) alkyl group; 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, optionally substituted heterocycloalkyl groups, optionally substituted aryl groups 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 ; Hydro Oxy; Hydroxy(C1-C6)alkyl; -(CH2) r0 -U0-(CH2) s0 - heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R 021 'Select from is a heteroaryl group substituted with a group 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 -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U 0-(CH2) s0 -heterocycloalkyl group, R 016 represents a hydrogen atom; a hydroxy group; a hydroxy(C1-C6) alkyl group; -(C H2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0- V0-OP(O)(OR 020 ) 2 groups;-OP(O)(O - M + ) 2 units;-OS( O)2OR 020 Group;-S(O)2OR 020 Group;-(CH2) p0 -O-(CHR 01 8-CHR 019 -O) q0 -R 020 Group;-(CH2) p0 -OC(O)-NR 02 2nd Round 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 02 0) 2 groups;-OP(O)(O- M + )2 groups; Hydroxy group; Hydroxy (C1-C6) Alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U 0-(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. the law of nature, 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 independently a hydrogen atom, a linear or branched (C1 C6) alkyl group, or hydroxy(C1-C6) alkyl group, Or pair (R 021 , R 021 ') together with the nitrogen atom to which they are attached form 5~ Forms an aromatic or non-aromatic ring containing seven ring members, which may optionally be joined to a nitrogen atom In addition, the resulting ring may contain from 1 to 3 heteroatoms selected from O, S and N, is optionally substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group. It is R 022 represents a (C1-C6) alkoxy(C1-C6) alkyl group, -(CH2) p0 -NR 024 R024 ' 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. the law of nature, Or pair (R 022 , R 023 ) together with the nitrogen atom to which they are attached form 5-1 Forms an aromatic or non-aromatic ring containing 8 ring members, which may optionally be joined to a nitrogen atom In addition, the resulting ring may contain from 1 to 5 heteroatoms selected from O, S and N, is a hydrogen atom, a linear or branched (C1-C6) alkyl group or a heterocycloalkyl group. and optionally substituted with aryl groups. R 024 and R 024 ' are independently a hydrogen atom or a linear or branched (C 1-C6) alkyl group, Or pair (R 024 , R 024 ') together with the nitrogen atom to which they are attached form 5~ Forms an aromatic or non-aromatic ring consisting of seven ring members, which, in addition to the nitrogen atom, , and may contain 1 to 3 heteroatoms selected from O, S and N, wherein the resulting The ring is optionally substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group. It has been R 025 is a hydrogen atom, a hydroxy group, or a hydroxy(C1-C6)alkyl group. the law of nature, R 026 is a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group or a cyano group, R 027is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 028 is -OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 03 0) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -OS O2- group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-OR0 30 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 ' It is the basis, R 029 and R 029 ' are independently a hydrogen atom, a linear or branched (C1 C6) alkyl group or linear or branched amino(C1-C6) alkyl group, R 030 and R 030 ' are independently a hydrogen atom, a linear or branched (C1 C6) alkyl group or aryl(C1-C6) alkyl group, R 031 teeth

[0517] [ka] wherein the ammonium ion is optionally present in zwitterionic form or 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, , covalently attached to a linker; where the valency of the atom is not exceeded by one or more substituents attached to it. or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt 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 Branched (C2-C6) alkenyl group, linear or branched (C2-C6) alkynyl group, linear or branched (C1-C6) haloalkyl group, hydroxy group, linear or branched (C1- C6) alkoxy group, -S-(C1-C6) alkyl group, 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 is a branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, Linear or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) halides alkyl, hydroxy group, linear or branched (C1-C6) alkoxy group, -S-( C1-C6) alkyl group, cyano group, nitro group, -(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-NR 011 R 011 ',or -SO2-(C1-C6) alkyl, Or pair (R 02 , R 03 ) or (R 03 , R 04 ) are the carbon atoms to which they are attached. Together with the atoms, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which may optionally optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is linear or branched (C1-C6) alkyl, -NR 013 R 013', -(C0~C6) Al Kill-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 groups, linear or branched (C2-C6) alkenyl groups, linear or branched or branched (C2-C6) alkynyl groups, linear or branched (C1-C6) haloalkynyl groups aryl, hydroxyl group, linear or branched (C1-C6) alkoxy group, -S-(C1-C 6) Alkyl group, cyano group, nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 , -(C0-C6) alkyl-Cy 01 , -(C2~C6) Arkenyl Lu-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 ',-(C 1-C6)Alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 01 1', or -SO2-(C1-C6)alkyl; Or pair (R 06 , R 07 ) when fused to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they 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, The resulting ring may be substituted with a linear or branched (C1-C6) alkyl group, -NR 013 R 01 3', -(C0-C6) alkyl-Cy 01 and oxo, optionally has been replaced by R 08 is a hydrogen atom, a linear or branched (C1-C8) alkyl group, an aryl group, Heteroaryl group, aryl-(C1-C6) alkyl group or heteroaryl (C1-C 6) an alkyl group; R 09 is a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C 6) Alkenyl group, linear or branched (C2-C6) alkynyl group, -Cy 02 , -(C 1-C6)Alkyl-Cy 02 , -(C2-C6)alkenyl-Cy 02 , -(C2~C 6) Alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C2-C6)alkynyl-O- Cy 02 , -Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-Cy0 3. Halogen atoms, cyano groups, -C(O)-R 014 , -C(O)-NR 014 R 014 ' and R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or a 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 5~ Forms an aromatic or non-aromatic ring containing seven ring members, which may optionally be joined to a nitrogen atom In addition, it contains 1 to 3 heteroatoms selected from O, S and N, where the N atom is Optionally substituted with a linear or branched (C1-C6) alkyl group, One or more of the carbon atoms of the cyclic or branched (C1-C6) alkyl group may optionally be It is deuterated accordingly, R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 , -Cy0 5-(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 , R013 ', R 014 and R 014 ' are independently hydrogen atoms, or is 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 mutual independently an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted hydroxyl group; is a 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, , covalently attached to a linker) or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt 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 R 011 'or

[0524] [ka] and where R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted a 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, Forms an aromatic or non-aromatic ring containing up to 7 ring members, which is optionally attached to the nitrogen atom Additionally, it contains 1 to 3 heteroatoms selected from O, S, and N, where the N atoms are , one or more selected from a hydrogen atom or a linear or branched (C1-C6) alkyl group; is optionally substituted with two groups, 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 09is a linear or branched (C2-C6) alkynyl group or -Cy 02 and R 012 -Cy 05 , -Cy 05 -(C0-C6) alkyl-Cy 06 or -C y 05 -(C0-C6) 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 has been replaced as necessary, 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, , covalently attached to a linker) or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt 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 Cy010 are independently of each other optionally substituted cyclohexane optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, an optionally substituted aryl or heteroaryl group, The substituents are optionally substituted linear or branched (C1-C6) alkyl, optionally substituted linear or branched (C2-C6) alkenyl groups, optionally substituted substituted linear or branched (C2-C6) alkynyl groups, optionally substituted linear or branched (C1-C6) alkoxy, optionally substituted (C1-C6) alkoxy alkyl-S-, hydroxy, oxo (or N-oxide, where appropriate), nitro, cyano ノ、-C(O)-OR0'、-OC(O)-R0'、-C(O)-NR0'R0''、 -NR0'R0'', -(C=NR0')-OR0'', linear or branched (C1-C 6) selected from haloalkyl, trifluoromethoxy, or halogen, where R ' and R0'' each independently represent a hydrogen atom or an optionally substituted linear or or branched (C1-C6) alkyl group, wherein 6) One or more of the carbon atoms of the alkyl group are optionally deuterated. do.

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

[0528] [ka]

[0529] [ka] or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt 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) is a compound in Table A or an enantiomer, diastereoisomer, atropisomer, or may include isomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing. do.

[0534] Drug Load Drug loading is represented by p, also referred to herein as the drug-to-antibody ratio (DAR). Drug loading 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. 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 In some embodiments, p is an integer from 2 to 10, from 2 to 9, from 2 to 8, from 2 to 10 ... is an integer from 1 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 may be an antibody or antigen-binding Antibody or antigen binding via chemically active groups on one or more amino acid residues in the fragment For example, the linker may be a free amino, imino, hydroxyl, or thiol or to the antibody or antigen-binding fragment via a carboxyl group (e.g., N- or C- At the terminus, the epsilon amino group of one or more lysine residues is linked to one or more glutamate residues. to the free carboxylic acid group of a carboxylic acid residue of a carboxylic acid or aspartic acid residue, or to one or more cysteines The site where the linker is attached may be the site of the antibody or Although the amino acid sequence of the antigen-binding fragment may be a naturally occurring residue, it may be a residue that has been modified by, for example, DNA recombinant technology. by techniques (e.g., by introducing cysteine ​​residues into the amino acid sequence) or by protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis) ), may be introduced into an antibody or antigen-binding fragment.

[0536] In some embodiments, a drug that can be conjugated to an antibody or antigen-binding fragment The number of functional moieties is limited by the number of free cysteine ​​residues. In the case of thiol groups, the antibody may have only one or a few cysteine ​​thiol groups. Even if the linker is attached, there is only one or a few sufficiently reactive thiols to which the linker can be attached. Generally, antibodies have many free and reactive groups that can be linked to a drug moiety. In fact, most cysteine ​​thiol groups in antibodies The disulfide residues are involved in either inter- or intra-chain disulfide bonds. In embodiments, conjugation to a cysteine ​​requires at least partial reduction of the antibody. When excess linker-toxin is bound to the antibody, disulfide bonds are formed. The stability of the antibody is compromised by the reduction of available cysteine ​​residues for synthesis. As a result, an optimal drug:antibody ratio increases the potency of the ADC (1 antibody per by increasing the number of drug moieties attached to the antibody or antigen-binding fragment. In some embodiments, the optimal ratio is 2, 4, 6, or may be 8. In some embodiments, the optimal ratio may be 2 or 4.

[0537] In some embodiments, the antibody or antigen-binding fragment contains one or more free cysteines. The antibody is exposed to reducing conditions prior to conjugation to generate the hydroxyl group. In some embodiments, a reducing agent, such as dithiothreitol (DTT) or Tris(2 -carboxyethyl)phosphine (TCEP) under partial or total reduction conditions The unpaired cysteine ​​may be reduced with a hydroxyl group to generate a reactive cysteine ​​thiol group. may be produced via partial reduction with a reduced molar equivalent of TCEP, which and heavy chains (one pair per HL pair) and two heavy chains in the hinge region (human IgG In the case of 1, the interchain disulfide bonds that connect the HH pairs (2 pairs per HH pair) are reduced, and at the same time, the intrachain Disulfide bonds can remain intact (Stefano et al. (2013) Methods Mo l Biol. 1045:145-71). In embodiments, disulfide bonds within antibodies can be cleaved, e.g., by reduction and It is electrochemically reduced by using a working electrode to which an alternating oxidizing and reducing voltage is applied. This approach allows for the detection of disulfide bond reduction in analytical devices (e.g., electrochemical detection devices). device, NMR spectrometer, or mass spectrometer) or chemical separation device (e.g., liquid chromatography chromatography (e.g., HPLC) or electrophoresis devices (e.g., U.S. Pat. App. No. 6,233,629). online coupling to the In some embodiments, the antibody is subjected to denaturing conditions to allow the amino acid residues , which indicates a reactive nucleophilic group, for example, cysteine.

[0538] Drug loading of ADCs can be achieved in different ways, for example: (i) a molar excess of drug relative to antibody; (ii) limiting the linker intermediate or linker reagent; (iii) limiting the time or temperature for cysteine ​​thiol modification; and / or (iv) the number and position of cysteine ​​residues. The position of the antibody can be modified to control the number and / or location of linker-drug bonds. The amino acid sequence may be controlled by genetic engineering using recombinant techniques.

[0539] In some embodiments, the free cysteine ​​residue is at the amino acid sequence of the antibody or antigen-binding fragment. For example, one or more amino acids of the parent antibody are replaced with a cysteine ​​amino acid. Cysteine ​​engineered antibodies may be prepared by altering the cysteine ​​residues of the antibody. For example, a parent Fab antibody fragment may be engineered to have a " Cysteine ​​engineered Fabs, called "ThioFabs," may also be generated. A single site mutation may be used to engineer a clonal antibody to form a "ThioMab." This results in a single engineered cysteine ​​residue in ThioFab, while a single Mutation of the site in ThioMab due to the dimeric nature of IgG antibodies Two engineered cysteine ​​residues are obtained. Amino acid sequence variants of the parent polypeptide DNA encoding the gene can be prepared by a variety of methods known in the art. (See, for example, the method described in International Publication No. WO 2006 / 034488.) (See references below.) These methods include, but are not limited to, polypeptide site-directed (or oligonucleotide-mediated) insertion of the initially prepared DNA encoding Preparation by performing mutagenesis, PCR mutagenesis, and cassette mutagenesis Recombinant antibody variants can also be generated by restriction fragment engineering using synthetic oligonucleotides. or by overlap extension PCR. These include, but are not limited to, 1, 2, 3, or 4 engineered cysteines. There are antibodies containing α-amino acids (Lyon et al. (2012) Methods Enzymol. 502:123-38). In some embodiments, one or more free cysteine ​​residues are not engineered. already present in the antibody or antigen-binding fragment, in which case the existing free cysteine ​​residues The group may be used to conjugate the antibody or antigen-binding fragment to a drug moiety.

[0540] In a reaction mixture comprising multiple copies of an antibody or antigen-binding fragment and a linker moiety , more than one nucleophilic group is present in the drug-linker intermediate or linker moiety reagent, followed by the drug When reacting with the partial reagent, the resulting product then becomes an antibody or antigen-binding molecule in the mixture. Mixtures of ADC compounds with distribution of one or more drug moieties attached to each copy of the fragment In some embodiments, a mixture of ADCs obtained from a conjugation reaction may be used. Drug loading in the product ranges from 1 to 16 conjugated drug moieties per antibody or antigen-binding fragment. The average number of drug moieties per antibody or antigen-binding fragment (i.e., the average drug load) The average p) can be determined by any conventional method known in the art, for example, Mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC-MS)) and / or 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 In some embodiments, the amount of ATP is determined by chromatography-mass spectrometry (LC-MS). 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 0.5, about 6.5 to about 8.5, or about 7.5 to about 9.5. , 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 0.5, approx. 1.6, approx. 1.7, approx. 1.8, approx. 1.9, approx. 2, approx. 2.1, approx. 2.2, approx. 2.3 , about 2.4, or about 2.5. In some embodiments, the antibody or antigen-binding fragment or The average number of drug moieties per tablet is two.

[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 0.5, approx. 3.6, approx. 3.7, approx. 3.8, approx. 3.9, approx. 4, approx. 4.1, approx. 4.2, approx. 4.3 , about 4.4, or about 4.5. In some embodiments, the antibody or antigen-binding fragment or The average number of drug moieties per tablet is four.

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

[0544] Individual ADC compounds or "species" can be identified in a mixture by mass spectroscopy, e.g., UPLC or HPLC, e.g., hydrophobic interaction chromatography (HIC-HPLC) In some embodiments, homogeneous or Nearly homogeneous ADC products can be obtained by, for example, electrophoresis or chromatography. It may be isolated from the gation mixture.

[0545] In some embodiments, high drug load (e.g., p>16) may be beneficial for certain antibody-drug combinations. This may result in aggregation of the conjugate, insolubility, toxicity, or loss of cell permeability. Drug loading can also negatively impact the pharmacokinetics (e.g., clearance) of certain ADCs. In some embodiments, a low drug load (e.g., p<2) may be sufficient to inhibit target-expressing cells. In some embodiments, the present invention provides a method for the treatment of cancer, which may reduce the efficacy of certain ADCs against cancer cells. The drug loading for the indicated ADCs may range from about 2 to about 16, from about 2 to about 10, from about 2 to about 8; in the range of 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 be.

[0546] In some embodiments, the drug load and / or average drug load of about 2 is, e.g., This is achieved using partial reduction of intrachain disulfides of the antibody or antigen-binding fragment, resulting in beneficial effects. In some embodiments, a drug load of about 4 or about 6 or about 8 and / or Or the average drug load can be, for example, the fraction of intrachain disulfides of an antibody or antigen-binding fragment. In some embodiments, the reduction is less than about 2 Drug load and / or average drug load may be at unacceptably high levels of unconjugated resulting in antibody species, which may compete with the ADC for binding to the target antigen, and In some embodiments, a concentration of more than about 16 Drug load and / or average drug load may be increased to accommodate unacceptably high levels of product heterogeneity and Drug loading greater than about 16 and / or ADC aggregation may result. The average drug load may also affect the stability of the ADC, which may affect the stability of the antibody or antigen. due to loss of one or more chemical bonds required to stabilize the binding fragment do.

[0547] The present disclosure includes methods of producing the described ADCs. Briefly, ADCs are antibodies or The antibody or antigen-binding fragment itself and a drug moiety (e.g., an Mcl-1 inhibitor) and a linker connecting the drug moiety and the antibody or antigen-binding fragment. In this embodiment, the ADC is a compound that covalently binds a drug moiety to an antibody or antigen-binding fragment. In some embodiments, the antibody may be prepared using a linker having a reactive functional group Alternatively, the antigen-binding fragment may contain a functional group that is reactive with the linker or drug-linker intermediate. For example, in some embodiments, antibodies or antigen-binding fragments are functionalized to prepare The cysteine ​​thiol of the In some embodiments, an antibody or antigen-binding The fragments were prepared using bacterial transglutaminase (BTG), which is a cyclooctyltransferase. BCN(N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yne-9- [[1,8-diamino-3,6-dioxaoctane]-1,8-diamino-3,6-dioxaoctane) moiety In some embodiments, the reactive glutamine is specifically functionalized with an amine containing , linker or drug-linker intermediate to the BCN portion of the antibody or antigen-binding fragment. Site-specific conjugation can be achieved, for example, by using a method as described and exemplified herein. The generation of ADCs can be accomplished by techniques known to those skilled in the art.

[0548] In some embodiments, an ADC comprises an antibody or antigen-binding fragment, a linker, and a drug moiety. (e.g., an Mcl-1 inhibitor) in a sequential manner, resulting in first an antibody or In the method, the antigen-binding fragment is covalently linked to a linker, and then a preformed antibody-linker is prepared. The antibody-linker intermediate is produced by reacting the antibody-linker intermediate with the drug moiety. In other embodiments, the drug moiety may or may not be contacted with the drug moiety after undergoing a preparation step. ADCs are produced by reacting an antibody or antigen-binding fragment with a linker and a drug moiety. The drug is produced by contacting a preformed linker-drug compound with a preformed linker-drug compound. The resulting linker-drug compound is subjected to a purification step before being purified to produce an antibody or antigen-binding fragment. In other embodiments, the antibody or antigen-binding fragment may or may not be contacted with 1 contacting the linker and drug moiety in one reaction mixture with the antibody or antigen-binding fragment and the linker; A allows for the simultaneous formation of covalent bonds between the linker and the drug moiety. This method of producing DCs involves contacting antibodies or antigen-binding fragments with the DCs. The reaction may involve contacting the linker with the hydroxyl group and then adding the linker to the reaction mixture, or vice versa. In some embodiments, an ADC comprises an antibody or antigen-binding fragment and a drug moiety, e.g., The linker linked to the Mcl-1 inhibitor is reacted under conditions that allow conjugation. It is produced by reacting

[0549] ADCs prepared according to the methods described above may be subjected to a purification step. any biochemical method known in the art for purifying proteins, or Any combination of these methods may be involved, including but not limited to: Although not a standard method, tangential flow filtration (TFF), affinity chromatography, charge- or isoelectric-based chromatography. Fee, mixed mode chromatography, e.g., CHT (ceramic hydroxyapatite) hydrophobic interaction chromatography, size exclusion chromatography, dialysis, filtration The method may be filtration, selective precipitation, or any combination thereof.

[0550] Therapeutic Uses and Compositions The disclosure herein provides a method for treating a subject with a disorder, such as cancer, using the compounds described herein. and methods of using the compositions described therein, such as the disclosed ADC compounds and compositions. The composition, e.g., ADC, may be used alone or in combination with at least one additional inactive agent and and / or other active agents, such as at least one additional therapeutic agent. and may be administered in any pharmaceutically acceptable formulation, dosage, and dosing regimen. The effectiveness of the treatment may be assessed with respect to toxicity as well as efficacy indicators, and the results may be analyzed accordingly. Efficacy measures include, but are not limited to, in vivo cytostatic and / or cytotoxic effects observed in vitro or in vivo; There is a reduction in tumor volume, inhibition of tumor growth, and / or prolongation of survival.

[0551] Determine whether the ADC has a cytostatic and / or cytotoxic effect on cells. For example, the cytotoxic or cytostatic activity of an ADC can be determined by, for example, mammalian cells expressing the target antigen of the ADC are exposed in cell culture medium; the cells are incubated for approximately 6 hours. Culture for a period of 1 to 6 days; measure cell viability (e.g., CellTiter -Glo® (CTG or MTT cell viability assays) Cell-based in vitro assays may be used to measure viability (proliferation), Cytotoxicity and induction of apoptosis (caspase activation) of the ADC may also be measured.

[0552] To determine cytotoxicity, necrosis or apoptosis (programmed cell death) was measured. Necrosis is typified by increased plasma membrane permeability, cell swelling, and plasma membrane rupture. Apoptosis ...

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. Antibody-drug conjugates of

2. p is an integer of 1 to 6 or 2 to 4, or p is 2 or 4, or and p is determined by liquid chromatography-mass spectrometry (LC-MS). The antibody-drug conjugate according to claim 1.

3. L, a linking group; at least one bridging spacer group; at least one cleavable group, optionally a pyrophosphate group and / or a self-immolative group; and at least one cleavable group comprising The antibody-drug conjugate of claim 1 or 2, comprising:

4. -(LD) is a compound of formula (A): 【Chemistry 1】 (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 3,

5. the cleavable group comprises a pyrophosphate group, or the cleavable group is 【Chemistry 2】 The antibody-drug conjugate of claim 3 or 4, comprising:

6. The bridging spacer group is (i) a polyoxyethylene (PEG) group; (ii) PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14 and a PEG group selected from PEG15; (iii)-CO-CH ２ -CH ２ -PEG12-based; (iv) butanoyl, pentanoyl, hexanoyl, heptanoyl or octanoyl or (v) hexanoyl group The antibody-drug conjugate of claim 3 or 4, comprising:

7. (i) The binding group is selected from the group consisting of a maleimide group, a thiol group, a cyclooctyne group, and an azide group. and optionally wherein a) the maleimide group has the structure: 【Transformation 3】 and b) the azide group has the structure: -N=N ＋ = N － and c) the cyclooctyne group has the structure: 【Chemistry 4】 where 【Transformation 5】 is the binding to the antibody, or d) the cyclooctyne group has the structure: 【Transformation 6】 and where: 【Transformation 7】 is the binding to the antibody, or (ii) the linking group is 【Transformation 8】 and having a formula comprising where: 【Chemistry 9】 The antibody-drug conjugate of claim 6, wherein: is bound to the antibody.

8. The antibody 【Chemistry 10】 and is connected to the linker (L) by a linking group selected from where: 【Chemistry 11】 is the binding to the antibody, wherein 【Chemistry 12】 is the bond to the bridging spacer group. 。

9. The bridging spacer group is —CO—CH ２ -CH ２ -PEG12- The antibody-drug conjugates described above.

10. The bridging spacer group is linked to a cleavable group, and optionally the cleavable group The group is -pyrophosphate-CH ２ -CH ２ -NH ２ The antibody according to claim 8 or 9, - Drug conjugates.

11. The cleavable group is linked to the Mcl-1 inhibitor (D) or The phenyl-pyrimidinyl group is linked to the Mcl-1 inhibitor (D) via a phenyl-pyrimidinyl group. The antibody-drug conjugate according to any one of claims 8 to 10,

12. 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 any one of claims 1 to 3, comprising:

13. -(LD) is a compound of formula (B): 【Chemistry 13】 (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 14】 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 12,

14. (i) The binding group is a maleimide group, a thiol group, a cyclooctyne group, and / or an azo group. formed from at least one reactive group comprising a dihydrogen group, optionally wherein: a) the maleimide group has the structure: 【Chemistry 15】 and b) the azide group has the structure: -N=N ＋ = N － and c) the cyclooctyne group has the structure: 【Chemistry 16】 where 【Chemistry 17】 is the binding to the antibody, or d) the cyclooctyne group has the structure: [Chemistry 18] and where: 【Chemistry 19】 is the binding to the antibody, or (ii) the linking group is 【Chemistry 20】 and having a formula comprising where: 【Chemistry 21】 The antibody-drug conjugate of claim 12 or 13, wherein: 。

15. (i) at least one crosslinking spacer comprises a PEG group, and optionally said PEG group is PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG 8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14 and P EG15, or (ii) at least one bridging spacer is ＊ —C(O)—CH ２ -CH ２ -PEG 1- ＊＊ 、 ＊ -C(O)-CH ２ -PEG3- ＊＊ 、 ＊ -C(O)-CH ２ -CH ２ -P EG12 ＊＊ , ＊ -NH-CH ２ -CH ２ -PEG1- ＊＊ , polyhydroxyalkyl group and ＊ -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ )-C(O)- ＊＊ ( During the ceremony, ＊＊ is the point of direct attachment of said at least one bridging spacer to said linking group, or indicates the point of indirect attachment, ＊ the direct connection of said at least one bridging spacer with said peptide group; (indicating a direct or indirect connection point) The antibody-drug conjugate of any one of claims 12 to 14, selected from 。

16. L １ が、 ＊ -C(O--32 ２ -32 ２ 0.111- ＊＊ 、 ＊ -C(O--32 ２ -P EG3- ＊＊ 、 ＊ -C(O)-CH ２ -CH ２ -PEG12 ＊＊ 、 ＊ -NH-CH ２ -C H ２ -PEG1- ＊＊ and polyhydroxyalkyl groups, ＊＊ is R １ With L １ of indicates the point of direct or indirect attachment, ＊ is Lp and L １ Direct or indirect attachment point of The antibody-drug conjugate of any one of claims 12 to 15, wherein the ugate.

17. m is 1, and L ２ -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ )-C The antibody-drug conjugate of any one of claims 12 to 16, which is (O)-. 。

18. (i) the peptide group is 1 to 6, 1 to 4, 1 to 3, or 1 to 2 amino acid residues; and optionally the amino acid residue is L-glycine (Gly), L-valine (V) al), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methyl Methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine L-amino acids L-leucine (Ala), L-leucine (Leu), L-tryptophan (Trp) and L-tyrosine (Tyrosine) (Tyr), (ii) the peptide group is Val-Cit, Val-Ala, Val-Lys, and and / or sulfo-Ala-Val-Ala, (iii) the peptide group is 【Chemistry 22】 The antibody-drug conjugate of any one of claims 12 to 17, selected from 。

19. (i) the cleavable group comprises a pyrophosphate group and / or a self-immolative group; and (ii) (iii) the cleavable group comprises a self-immolative group, or (iii) the cleavable group comprises a para-amino group. para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(s para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, Para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino -(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate to or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl 19. A compound according to any one of claims 12 to 18, which comprises a self-immolative group comprising -benzyl-ammonium. The antibody-drug conjugates described herein.

20. m is 0 or 1, or m is 1, and the bridging spacer is 【Chemistry 23】 The antibody-drug conjugate of any one of claims 13 to 19, comprising:

21. -(LD) is 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 21. The method according to claim 13, wherein the compound is selected from the group consisting of Antibody-drug conjugates.

22. -(LD) is 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 and where: 【Chemistry 26】 The antibody-drug complex according to any one of claims 13 to 21, wherein Indugegate.

23. -(LD) is a compound of formula (C): 【Chemistry 27】 (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)— ＊ , 【Chemistry 28】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, L ３ is the spacer moiety, R ２ is the hydrophilic moiety) The antibody-drug conjugate of claim 1 or 2,

24. -(LD) is a compound of formula (D): 【Chemistry 29】 (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)— ＊ , 【Transformation 30】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, L ３ is the spacer moiety, R ２ is the hydrophilic moiety) 24. The antibody-drug conjugate of claim 23, or a pharmaceutically acceptable salt thereof, Salt to be used.

25. (1) L １ but, 【Chemistry 31】 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 ＊ is the direct bond point with Lp indicates the point of attachment or indirect attachment, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (2) L １ but, 【Chemistry 32】 and n is an integer from 1 to 12, or n is 1, or n is 12; So, L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ is R １ and indicates the direct or indirect point of attachment of (3) L １ but, 【Transformation 33】 and n is an integer from 1 to 12, where L １ of ＊ is the direct bond point to Lp or indicates the point of indirect attachment, and L １ of ＊＊ is R １ indicates the point of direct or indirect attachment to (4) L １ but, 【Transformation 34】 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(=0)(CH ２ ) ｍ - ＊＊ ; ＊ -C(=0)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)(C H ２ ) ｍ NH(CH) ２ ) ｍ - ＊＊ ; ＊ -C(=0)(CH ２ ) ｍ NH(CH) ２ ) ｎ C(=0)- ＊＊ ; ＊ -C(=0)(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(=0)(CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ - ＊＊ ; ＊ -C(=0)(CH ２ ) ｍ NHC(=0)(CH ２ ) ｎ X １ (CH) ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ X １ (C) H ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ C(=0)NH(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ C (R ３ ) ２ - ＊＊ or ＊ -C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - ＊＊ With a bridging spacer containing where L １ of ＊ indicates the point of direct or indirect attachment to Lp, and L １ of ＊＊ teeth , R １ indicates the point of direct or indirect attachment to X １ teeth, 【Chemistry 35】 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 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, independently selected from Each R ３ is H and C １ ~C ６ 23 or 2, independently selected from alkyl 5. The antibody-drug conjugate according to claim 4.

26. R ２ However, polyethylene glycol, polyalkylene glycol, polyol, polysulfone Cosine, sugar, oligosaccharide, polypeptide, or 1 to 3 【Transformation 36】 C substituted with a group ２ ~C ６ 26. Any of claims 23 to 25, wherein the hydrophilic moiety is alkyl-containing. The antibody-drug conjugate according to any one of claims 1 to 4.

27. R ２ but, 【Chemistry 37】 wherein n is an integer between 1 and 6. 【Transformation 38】 The antibody-drug conjugate of any one of claims 23 to 26, wherein

28. The hydrophilic portion is (i) Polysarcosine, for example, the following moiety: 【Chemistry 39】 (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 40】 or polyethylene glycol of the following formula: (Wherein, R is H, —CH ３ , C.H. ２ CH ２ NHC(=O)OR ａ , -CH ２ CH ２ N HC(=O)R ａ or -CH ２ CH ２ C(=O)OR ａ and R' is OH, -OC 8 ３ 、-32 ２ 38 ２ 883(4) 92 ａ 、-32 ２ 38 ２ 883(4)2 ａ または -OCH ２ CH ２ C(=O)OR ａ where R ａ is H or OH or C １ ～４ C optionally substituted with either alkoxyl １～４ alkyl, m and and each of n is independently an integer between 2 and 25 The antibody-drug conjugate of claim 23 or 24, comprising:

29. The hydrophilic portion is 【Chemistry 41】 28. The antibody-drug conjugate of any one of claims 23 to 27, comprising:

30. (i) L ３ But the structure 【Chemistry 42】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(= O)C(R ｂ ) ２ NXC(=O)O-、 -NHC(=O)C(R ｂ ) ２ NH-、-NHC(=O)C(R ｂ ) ２ NXC(=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-, () ２ !!.、!\H(()) ２ 、!C!!!QQまたは! NH—, where each R ｂ is H, C １ ~C ６ Alkyl and C ３ ~C ８ Cycloal Selected independently from the kill, X is a bond, triazolyl or —CH ２ -triazolyl-) or a spacer moiety having (ii) L ３ But the structure 【Chemistry 43】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(= O)C(R ｂ ) ２ NXC(=O)O-、 -NHC(=O)C(R ｂ ) ２ NH-、-NHC(=O)C(R ｂ ) ２ NXC(=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(=0)NH-, -CH ２ NR ｂ C(=0)NR ｂ -、-NHC(=O)-、-NHC(=O)O-、-N HC(=O)NH-, -OC(=O)NH-, () ２ !!.、!\H(()) ２ 、!C!!!QQまたは! NH—, where each R ｂ is H, C １ ~C ６ Alkyl and C ３ ~C ８ Cycloal Selected independently from the kill, 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 and is 1, 2 or 3) The antibody-drug of any one of claims 23 to 29, wherein the spacer moiety has the formula: Conjugates.

31. 3 to 5, wherein the linking group is formed by a reaction involving at least one reactive group.

31. The antibody-drug conjugate of any one of claims 30.

32. The linking group is a first reactive group attached to the linker; a second reactive group that is attached to the antibody or is an amino acid residue of the antibody; wherein, optionally, (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 -NHH-C(=O)-、 ketones, vinyl sulfone, Aziridine, amino acid residues, 【Chemistry 44】 !-ONH ２ 、-NH ２ 、 【Chemistry 45】 、-N ３ 、 【Chemistry 46】 、-SH、-SR ３ 、-SSR ４ 、-S(=O) ２ (CH=CH ２ )、-(CH ２ ) ２ S (=0) ２ (CH=CH ２ )、-NHS(=O) ２ (CH=CH ２ )、-NHC(=O) CH ２ Br、-NHC(=O)CH ２ I、 【Chemistry 47】 、-C(O)NHNH ２ 、 【Chemistry 48-1】 【Chemistry 48-2】 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 C H ３ , -N(CH ３ ) ２ , -CN, -NO ２ and —OH, Each R ７ is H, C １～６ benzyl substituted with alkyl, fluoro, or —C(═O)OH Oxy, 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 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 49】 、 amines and [Transformation 50] ,or CoA or CoA analog and serine residue 32. The antibody-drug conjugate of any one of claims 3 to 31, comprising:

33. The linking group is 【Chemistry 51-1】 【Chemistry 51-2】 【Chemistry 51-3】 【Chemistry 51-4】 and where: R ３２ is H, C １～４ alkyl, phenyl, pyrimidine or pyridine; R ３５ is H, C １～６ alkyl, phenyl, or substituted with 1 to 3 —OH groups C １～４ is alkyl, Each R ７ is H, C １～６ benzyl substituted with alkyl, fluoro, or —C(═O)OH Oxy, 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, 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. Antibody-drug conjugates of

34. The peptide group may contain 1 to 4, 1 to 3, or 1 or 2 amino acid residues. and optionally the amino acid residue is L-glycine (Gly), L-valine (Val), ), L-citrulline (Cit), L-cysteic acid (Sulfo-Ala), L-lysine (L L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine L-asparagine (Asn), L-proline (Pro), L-alanine ( Ala), L-leucine (Leu), L-tryptophan (Trp) and L-tyrosine (Tyr) Jugate.

35. The peptide group is Val-Cit, Phe-Lys, Val-Ala, Val-Ly s, Leu-Cit, Sulfo-Ala-Val and / or Sulfo-Ala-Val- 34. The antibody-drug conjugate of any one of claims 23 to 33, comprising Ala.

36. Lp is, 【Chemistry 52】 The antibody-drug conjugate of any one of claims 23 to 35, selected from 。

37. -(LD) is a compound of the formula: （１） 【Chemistry 53】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemistry 54】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （２） 【Transformation 55】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Transformation 56】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （３） 【Chemistry 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)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （４） 【Chemistry 59】 (In the formula, Each R is H, —CH ３ and -CH ２ CH ２ C(═O)OH; A is a bond, —OC(═O)— ＊ , 【Transformation 60】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （５） 【Chemistry 61】 (In the formula, Each R is H, —CH ３ and -CH ２ CH ２ C(═O)OH; A is a bond, —OC(═O)— ＊ , 【Transformation 62】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （６） 【Transformation 63】 (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)— ＊ , 【Chemistry 64】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （７） 【Transformation 65】 (In the formula, R is H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemical Formula 66】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （８） 【Transformation 67】 (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)— ＊ , 【Transformation 68】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （９） 【Transformation 69】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Transformation 70】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１０） 【Chemistry 71】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 72】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１１） 【Transformation 73】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 74】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１２） 【Chemistry 75】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Transformation 76】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１３） 【Chemical 77】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Transformation 78】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１４） 【Transformation 79】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 80】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) （１５） 【Chemistry 81】 (In the formula, A is a bond, —OC(═O)— ＊ , 【Chemistry 82】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor), or （１６） 【Chemistry 83】 (In the formula, Each R is independently H, —CH ３ or -CH ２ CH ２ C(═O)OH, A is a bond, —OC(═O)— ＊ , 【Chemical 84】 、-OC(=O)8(3H ３ )32 ２ 38 ２ 8(3) ３ )C(=O)- ＊ または-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 Independent of cycloalkyl and selected, and A's ＊ indicates the point of attachment to D, D is an Mcl-1 inhibitor) 37. Any one of claims 23 to 36, comprising or formed from a compound of The antibody-drug conjugate according to claim 1.

38. A is a bond and / or R is —CH ３ 38. Any one of claims 23 to 37, Item 1. The antibody-drug conjugate according to item 1.

39. D is a compound of formula (I): 【Chemical 85】 (In the formula, Ring D ０ is a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. is a methyl group, Ring E ０ 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. the law of nature, X ０２ is C-R ０２６ group or a nitrogen atom, 【Chemical 86】 means that the ring is aromatic, Y ０ is a nitrogen atom or C—R ０３ It is the basis, 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 groups, linear or is 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, hydroxy (C １ ~C ６ ) alkyl group, linear or branched (C １ ~C ６ ) alkoxy group, —S—(C １ ~ C ６ ) Alkyl group, cyano group, nitro group, -Cy ０８ , -(C ０ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -O-(C １ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -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 ０１ １ -C(O)-OR ０１１ ', -(C １ ~C ６ ) alkyl-NR ０１１ -C(O)-R ０ １１ ', -SO ２ -NR ０１１ R ０１１ ' or -SO ２ -(C １ ~C ６ ) alkyl the law of nature, R ０２ , R ０３ , R ０４ and R ０５ are independently hydrogen atoms, halogen atoms, and or branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) Arke a linear or branched alkyl group (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~ C ６ ) haloalkyl, hydroxy group, hydroxy (C １ ~C ６ ) alkyl groups, linear or is branched (C １ ~C ６ ) alkoxy group, —S—(C １ ~C ６ ) alkyl group, cyano group, nitro group Toro 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 , —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 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 aromatic rings containing 5 to 7 ring members. and optionally forming an aromatic or non-aromatic ring, which may optionally contain 1 to 10 carbon atoms selected from O, S and N. and 3 heteroatoms, wherein the resulting ring is not further substituted by halogen, linear or branched ( C １ ~C ６ ) alkyl, (C ０ ~C ６ ) alkyl-NR ０１１ R ０１１ ', -NR ０１３ R ０１３ ', -(C ０ ~C ６ ) Alkyl-Cy ０１ or oxo optionally substituted with one or two groups; 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 groups, linear or Branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) Hello Archie aryl, hydroxyl 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-(C １ ~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 ０１ １ -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 to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they 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, The resulting ring may be linear or branched (C １ ~C ６ ) alkyl group, —NR ０１３ R ０１３ ', -(C ０ ~C ６ ) Alkyl-Cy ０１ or optionally substituted with oxo And, W ０ is -CH ２ - group, -NH- group or oxygen atom, R ０８ is a hydrogen atom, a linear or branched (C １ ~C ８ ) alkyl group, —CHR ０ａ R ０ｂ group, aryl group, heteroaryl group, aryl (C １ ~C ６ ) alkyl group or hetero group Royall (C １ ~C ６ ) alkyl group, R ０９ is a hydrogen atom, a linear or branched (C １ ~C ６ ) alkyl groups, linear or branched Branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) alkynyl group, - Cy ０２ , -(C １ ~C ６ ) Alkyl-Cy ０２ , -(C ２ ~C ６ ) Alkenyl-Cy ０ ２ , -(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 ０１０ is a hydrogen atom, a linear or branched (C １ ~C ６ ) alkyl groups, linear or Branched (C ２ ~C ６ ) alkenyl group, linear or branched (C ２ ~C ６ ) an alkynyl group, Aryl (C １ ~C ６ ) alkyl group, (C １ ~C ６ ) cycloalkylalkyl groups, linear or or branched (C １ ~C ６ ) haloalkyl or -(C １ ~C ６ ) alkyl-O-Cy ０ ４ and Or pair (R ０９ , R ０１０ ) when fused to two adjacent carbon atoms, together with the carbon atom to which it is 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; R ０１１ and R ０１１ ' are independently a hydrogen atom, an optionally 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 5 to forming an aromatic or non-aromatic ring containing 7 ring members, which optionally includes the nitrogen atom and 1 to 3 heteroatoms selected from O, S, and N, wherein said N The atoms may be linear or branched (C １ ~C ６ ) one or two groups selected from alkyl groups wherein said linear or branched (C １ ~C ６ ) Carbon atom of alkyl group wherein one or more of are optionally deuterated; R ０１２ is -Cy ０５ , -Cy ０５ -(C ０ ~C ６ ) alkyl-O—(C ０ ~C ６ ) Alkyl-Cy ０６ , -Cy ０５ -(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 ) Alki Ru-O-(C ０ ~C ６ ) Alkyl-Cy ０９ , -Cy ０５ -(C ０ ~C ６ ) Alkyl-C y ０９ 、 -NH-C(O)-NH-R ０１１ , -Cy ０５ -(C ０ ~C ６ ) alkyl-NR ０１１ -(C ０ ~C ６ ) Alkyl-Cy ０９ , —C(O)—NR ０１１ R ０１１ ', -NR ０１ １ R ０１１ ’、-OR ０１１ 、-NR ０１１ -C(O)-R ０１１ ’、-O-(C １ ~C ６ ) alkyl-OR ０１１ , -SO ２ -R ０１１ , —C(O)—OR ０１１ and R ０１３ , R ０１３ ', R ０１４ and R ０１４ ' are independently hydrogen atoms, or is an optionally substituted linear or branched (C １ ~C ６ ) alkyl group, R ０ａ is a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, R ０ｂ is -O-C(O)-O-R ０ｃ group, -OC(O)-NR ０ｃ R ０ｃ 'Moto is -OP(O)(OR ０ｃ ) ２ It is the basis, R ０ｃ and R ０ｃ ' are independently a hydrogen atom, a linear or branched (C １ ~C ８ ) alkyl group, cycloalkyl group, (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl group or (C １ ~C ６ ) alkoxycarbonyl (C １ ~C ６ ) alkyl group, Or pair (R ０ｃ , R ０ｃ ') together with the nitrogen atom to which they are attached, form 5 to 7 which, in addition to the nitrogen atom, also contains oxygen and may contain 1 to 3 heteroatoms selected from nitrogen, wherein said nitrogen is linear or is branched (C １ ~C ６ ) optionally substituted with an alkyl group; Cy ０１ 、Cy ０２ 、Cy ０３ 、Cy ０４ 、Cy ０５ 、Cy ０６ 、Cy ０７ 、Cy ０８ and Cy ０１０ are each independently a cycloalkyl group, a heterocycloalkyl group, an aryl group, and aryl or heteroaryl groups, each of which is optionally substituted. the law of nature, Cy ０９ teeth 【Transformation 87】 and または|y ０９ は、﯁P()(R ０２０ ) ２ ? － * ＋ ) ２ ;-(CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ０２０ ; Hydro hydroxy (C １ ~C ６ ) alkyl; -(CH ２ ) ｒ０ -U ０ - (CH ２ ) ｓ０ - heterocycloalkyl; and -U ０ - (CH ２ ) ｑ０ -NR ０２１ R ０２１ 'Select from is a heteroaryl group substituted with a group 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 ) Alki -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; H 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 ０１ ８ -CHR ０１９ -O) ｑ０ -R ０２０ group; -(CH ２ ) ｐ０ -O-C(O)-NR ０２ ２ 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, -O-P(O)(OR ０２ ０ ) ２ Group: —O—P(O)(O － M ＋ ) ２ group; hydroxy group; hydroxy (C １ ~C ６ ) Alkyl group; -(CH 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 the law of nature, 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 5 to forming an aromatic or non-aromatic ring containing 7 ring members, which optionally includes the nitrogen atom and 1 to 3 heteroatoms selected from O, S and N, wherein The bonded ring is substituted with a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, if desired has been replaced by R ０２２ is (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl group, —(CH ２ ) ｐ０ -NR ０２４ R ０２４ ' group or -(CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ２０ It is the basis, R ０２３ is a hydrogen atom or (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl group the law of nature, Or pair (R ０２２ , R ０２３ ) together with the nitrogen atom to which they are attached, forming an aromatic or non-aromatic ring containing 8 ring members, which optionally includes the nitrogen atom and 1 to 5 heteroatoms selected from O, S and N, wherein The bonded ring may be a hydrogen atom, a linear or branched (C １ ~C ６ ) alkyl group or heterocyclic group optionally substituted with alkyl groups, R ０２４ and R ０２４ ' are independently a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, Or pair (R ０２４ , R ０２４ ') together with the nitrogen atom to which they are attached form 5 to forming an aromatic or non-aromatic ring consisting of seven ring members, which is attached to the nitrogen atom In addition, it may contain 1 to 3 heteroatoms selected from O, S and N, wherein The resulting ring can be substituted with a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, if necessary It is replaced by R ０２５ is a hydrogen atom, a hydroxy group or a hydroxy (C １ ~C ６ ) alkyl group the law of nature, R ０２６ is a hydrogen atom, a halogen atom, a linear or branched (C １ ~C ６ ) alkyl group or a cyano group, R ０２７ is a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl group, R ０２８ is an -O-P(O)(O － )(O － group, -O-P(O)(O － )(OR ０３ ０ ), a group of -O-P(O)(OR ０３０ )(OR ０３０ '), a group of -(CH ２ ), ｐ０ -O-S O ２ -O － group, -(CH ２ ) ｐ０ -SO ２ -O － group, -(CH ２ ) ｐ０ -O-SO ２ -O R ０３０ group, -Cy ０１０ , -(CH ２ ) ｐ０ -SO ２ -OR ０３０ group, -OC(O) -R ０２９ group, -OC(O)-OR ０２９ group or —O—C(O)—NR ０２９ R ０２ ９ 'Based on R ０２９ and R ０２９ ' are independently a hydrogen atom, a linear or branched (C １ ~ C ６ ) alkyl group or linear or branched amino (C １ ~C ６ ) alkyl group, R ０３０ and R ０３０ ' are independently a hydrogen atom, a linear or branched (C １ ~ C ６ ) alkyl group or aryl (C １ ~C ６ ) alkyl group, R ０３１ teeth 【Chemical 88】 wherein the ammonium is optionally present in zwitterionic form or or a monovalent anionic counterion, n ０ is an integer equal to 0 or 1, p ０ is an integer equal to 0, 1, 2, or 3, q ０ is an integer equal to 1, 2, 3, or 4, r ０ and s ０ are independently integers equal to 0 or 1; Here, at most, the R ０３ group, R ０９ group or R ０１２ One of the groups is present is covalently attached to said linker, where the valency of the atom is not exceeded by one or more substituents attached to it. or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate according to any one of claims 1 to 4.

40. Cy ０１ 、Cy ０２ 、Cy ０３ 、Cy ０４ 、Cy ０５ 、Cy ０６ 、Cy ０７ 、Cy ０８ and Cy ０１０ are each independently a cycloalkyl group, a heterocycloalkyl group, an alkyl group, an aryl or heteroaryl group, each of which is halo; -(C １ ~C ６ ) Alkoxy; -(C １ ~C ６ ) haloalkyl; -(C １ ~C ６ ) haloalkoxy; -(C H ２ ) ｐ０ -O-SO ２ -OR ０３０ ;-(CH ２ ) ｐ０ -SO ２ -OR ０３０ ;-O- P(O)(OR ０２０ ) ２ ;-O-P(O)(O － M ＋ ) ２ ;-CH ２ -P(O)(OR ０２０ ） ２ ； - (CH ２ ) ｐ０ -O-(CHR ０１８ -CHR ０１９ -O) ｑ０ -R ０２０ Hydroxy C; Hydroxy (C １ ~C ６ ) alkyl; -(CH ２ ) ｒ０ -U ０ - (CH ２ ) ｓ０ -He or -U ０ - (CH ２ ) ｑ０ -NR ０２１ R ０２１ Selected from 40. The antibody-drug of claim 39, optionally substituted with one or more groups selected from the group consisting of: Conjugates.

41. D is a compound of formula (II): 【Chemical 89】 (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 groups, linear or branched 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 , -NR ０１１ R ０１１ ' and R ０２ , R ０３ and R ０４ are each independently a hydrogen atom, a halogen atom, a linear or is branched (C １ ~C ６ ) alkyl group, linear or branched (C ２ ~C ６ ) alkenyl groups, Linear or branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) Ha alkyl, 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 ’、-N R 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 ) are the carbons to which they are attached. Together with the atoms, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which may optionally optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is Linear or branched (C １ ~C ６ ) alkyl, —NR ０１３ R ０１３ ', -(C ０ ~C ６ ) Alkyl-Cy ０１ and oxo, 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 groups, linear or Branched (C ２ ~C ６ ) alkynyl group, linear or branched (C １ ~C ６ ) Hello Archie aryl, hydroxyl 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 to two adjacent carbon atoms, Together with the carbon atoms to which they are attached, they 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, wherein the resulting ring is linear or branched (C １ ~C ６ ) alkyl group, —NR ０１３ R ０１３ ', -(C ０ ~C ６ ) Alkyl-Cy ０１ and oxo, optionally are substituted accordingly, R ０８ is a hydrogen atom, a linear or branched (C １ ~C ８ ) alkyl groups, aryl groups, 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 ０ ３ , a halogen atom, a cyano group, —C(O)—R ０１４ , —C(O)—NR ０１４ R ０１４ ' and R ０１１ and R ０１１ ' are independently a hydrogen atom, an optionally 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 5 to forming an aromatic or non-aromatic ring containing 7 ring members, which optionally includes the nitrogen atom and 1 to 3 heteroatoms selected from O, S, and N, wherein said N The atoms may be linear or branched (C １ ~C ６ ) optionally substituted with an alkyl group, Here, the linear or branched (C １ ~C ６ ) one or more of the carbon atoms of the alkyl group The numbers are deuterated as needed, R ０１２ is -Cy ０５ , -Cy ０５ -(C ０ ~C ６ ) Alkyl-Cy ０６ , -Cy ０ ５ -(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 ) Alki -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 ０１３ , R ０１３ ', R ０１４ and R ０１４ ' are independently hydrogen atoms, or is an optionally substituted linear or branched (C １ ~C ６ ) alkyl group, Cy ０１ , Cy ０２ , Cy ０３ , Cy ０５ , Cy ０６ , Cy ０７ and Cy ０８ are mutual independently a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group alkyl groups, each of which is optionally substituted; Cy ０９ teeth 【Chemistry 90】 and Here, R ０１５ , R ０１６ and R ０１７ is as defined for formula (I) 、 R ０３１ teeth 【Chemistry 91】 where R ０２７ and R ０２８ is as defined for formula (I), Here, at most, the R ０３ group, R ０９ group or R ０１２ One of the groups is present covalently attached to said linker, or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate according to any one of claims 1 to 4.

42. D is of formula (III): 【Chemistry 92】 (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 【Chemistry 93】 and Here, R ０１１ and R ０１１ ' are independently a hydrogen atom, an optionally 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 5 forming an aromatic or non-aromatic ring containing up to 7 ring members, which optionally includes the nitrogen atom; In addition to the alkyl group, the alkyl group contains 1 to 3 heteroatoms selected from O, S and N, wherein The N atom is a hydrogen atom or a linear or branched (C １ ~C ６ ) alkyl groups may be substituted with one or two 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, 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 -C y 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 has been replaced as necessary, Cy ０９ teeth 【Chemical 94】 and R ０１５ , R ０１６ and R ０１７ is as defined for formula (I), Here, at most, the R ０３ group, R ０９ group or R ０１２ One of the groups is present covalently attached to said linker, or enantiomers, diastereoisomers, atropisomers, deuterated derivatives of and / or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate according to any one of claims 1 to 4.

43. R ０１ is methyl or ethyl. 。

44. R ０３ -O-CH ２ -CH ２ -NR ０１１ R ０１１ '(in the formula, R ０１１ and R ０１ １ ' are hydrogen atoms or linear or branched ( C １ ~C ６ ) alkyl group) which forms a piperazinyl group which may be substituted with a group The antibody-drug conjugate of claim 42.

45. R ０３ But the formula: 【Chemical 95】 (In the formula, R ０２７ is a hydrogen atom, and R ０２８ Ha-(CH ２ ) ｐ０ -SO ２ -OR ０３ ０ (based on 43. The antibody-drug conjugate of claim 42, comprising:

46. R ０３ But the formula: 【Chemistry 96】 (In the formula, 【Chemistry 97】 is the bond to the linker) 43. The antibody-drug conjugate of claim 42, comprising:

47. R ０９ Cy ０２ The antibody-drug conjugate of claim 42, wherein

48. Cy ０２ is an optionally substituted aryl group. Object conjugates.

49. Cy ０５ containing a heteroaryl group selected from pyrazolyl and pyrimidinyl groups. The antibody-drug conjugate of claim 42.

50. Cy ０５ The antibody-drug conjugate of claim 42, wherein is a pyrimidinyl group.

51. The L is selected from L to R of formula (I), (II) or (III). ０３ By covalent bonding up to and / or said L is bonded to D, and / or said L is bonded to L of formula (I), (II) or (III) ) R ０９ 51. Any one of claims 1 to 50, wherein the hydroxyl group is covalently linked to D by a bond up to The antibody-drug conjugate according to claim 1.

52. (1) D is 【Chem.98】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (2) D is 【Chem.99】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (3) D is 【Chemistry 100】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (4) D is 【Chemistry 101】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (5) D is 【Chemical Engineering 102】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (6) D is 【Chemistry 103】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (7) D is 【Chemical 104】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (8) D is 【Chemistry 105】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (9) D is 【Chemistry 106】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (10) D is 【Chemistry 107】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (11) D is 【Chemistry 108】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (12) D is 【Chemistry 109】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (13) D is 【Chemical 110】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (14) D is 【Chemistry 111】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (15) D is 【Chemistry 112】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. (16) D is 【Chemistry 113】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing; (17) D is 【Chemistry 114】 or enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or or a pharmaceutically acceptable salt of any of the foregoing. The antibody-drug conjugate according to claim 1.

53. -(LD) is a compound in Table A or an enantiomer, diastereoisomer, atropine isomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing. The antibody-drug conjugate of any one of claims 1 to 42,

54. 6. The method of claim 1, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

4. The antibody-drug conjugate according to any one of claims 3 to 3.

55. (i) the target antigen is BCMA, CD33, HER2, CD38, CD48, or CD7 9b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT 3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD7 1, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin 4, TROP2, LIV1, CD46, or GPNMB; (ii) the target antigen is BCMA, CD33, PCAD, HER2, CD38, CD 46, CD48, or CD79b; or (iii) the target antigen is BCMA, CD33, CD48, PCAD, or HER2 55. The antibody-drug conjugate of claim 54, wherein:

56. the antibody or antigen-binding fragment is an anti-BCMA antibody or antigen-binding fragment. Item 56. The antibody-drug conjugate of any one of items 1 to 55.

57. the antibody or antigen-binding fragment (a) SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3) and three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences of: SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2) and SEQ ID NO: 20 (LC and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences of: (b) the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2; The antibody-drug conjugate of claim 56.

58. (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG and optionally the IgG1 heavy chain constant domain comprises an IgG1 heavy chain constant domain at positions 152 and 153. and a cysteine ​​residue (C) at position 375, or , containing cysteine ​​residues (C) at positions 156 and 379; and / or (b) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; 58. The antibody-drug conjugate of claim 56 or 57.

59. the antibody or antigen-binding fragment is an anti-CD33 antibody or antigen-binding fragment. Item 59. The antibody-drug conjugate of any one of items 1 to 58.

60. (a) the antibody or antigen-binding fragment is selected from the group consisting of SEQ ID NO: 21 (HCDR1), SEQ ID NO: 22 (HCDR2) and SEQ ID NO: 23 (HCDR3) Sex-determining region (HCDR), SEQ ID NO: 24 (LCDR1), SEQ ID NO: 25 (LCDR2) and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequence of SEQ ID NO: 26 (LCDR3). CDRs), 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. The antibody-drug conjugate of claim 59.

61. (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG 1 heavy chain constant domain, and optionally the IgG1 heavy chain constant domain comprises containing glutamine (Q), and / or (b) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; The antibody-drug conjugate of claim 59 or 60.

62. The antibody or antigen-binding fragment is an anti-PCAD antibody or antigen-binding fragment. Item 56. The antibody-drug conjugate of any one of items 1 to 55.

63. (a) the antibody or antigen-binding fragment is selected from the group consisting of SEQ ID NO: 33 (HCDR1), SEQ ID NO: 34 (HCDR2) and SEQ ID NO: 35 (HCDR3) Sex-determining region (HCDR), SEQ ID NO: 36 (LCDR1), SEQ ID NO: 37 (LCDR2) and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequence of SEQ ID NO: 38 (LCDR3). CDRs), 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. The antibody-drug conjugate of claim 62.

64. The antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment. Item 56. The antibody-drug conjugate of any one of items 1 to 55.

65. (a) the antibody or antigen-binding fragment is selected from the group consisting of SEQ ID NO: 39 (HCDR1), SEQ ID NO: 40 (HCDR2) and SEQ ID NO: 41 (HCDR3) Sex-determining region (HCDR), SEQ ID NO: 42 (LCDR1), SEQ ID NO: 43 (LCDR2) and three light chain complementarity determining regions (LCDRs) comprising the amino acid sequence of SEQ ID NO: 44 (LCDR3). CDRs), 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. The antibody-drug conjugate of claim 64.

66. (a) the antibody or antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG 1 heavy chain constant domain, and optionally the IgG1 heavy chain constant domain comprises glutamine (Q), or the IgG1 heavy chain constant domain contains serine (S) at position 297 and / or (b) the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain; 66. The antibody-drug conjugate of claim 64 or 65.

67. The antibody or antigen-binding fragment is an anti-CD38 antibody or antigen-binding fragment; an anti-CD4 anti-CD48 antibody or antigen-binding fragment; or anti-CD 79b antibody or antigen-binding fragment thereof. Body-drug conjugates.

68. 68. A method for treating a pulmonary arthritis, comprising administering to a patient a therapeutically effective amount of a drug comprising administering to said ... wherein the average p of said antibody-drug conjugates in said composition is from about 2 to about 16, for example, from about 2 to about 8, for example, from about 2 to about 4.

69. The antibody-drug conjugate of any one of claims 1 to 67 or claim 68 A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

70. 1. A method of treating a subject having or suspected of having cancer, comprising administering to said subject a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 67, A method comprising administering the composition of claim 68 or the pharmaceutical composition of claim 69. Law.

71. 71. The method of claim 70, wherein the cancer expresses a target antigen.

72. The cancer is a tumor or a blood cancer, and optionally the cancer is breast cancer, multiple myeloma, or ovarian cancer. Myeloma, plasma cell myeloma, leukemia, lymphoma, stomach cancer, acute myeloid leukemia, bladder cancer, Brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular Cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin tumors, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic phospholipid 72. The method according to claim 70 or 71, wherein the cancer is myeloma, ... The method described.

73. 1. A method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of The antibody-drug conjugate of any one of claims 1 to 67, or the antibody-drug conjugate of claim 68 or the pharmaceutical composition of claim 69.

74. 74. The method of claim 73, wherein the tumor expresses a target antigen.

75. 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 75. The method of claim 73 or 74, wherein the cancer is cancer or splenic cancer.

76. administration of the antibody-drug conjugate, composition or pharmaceutical composition to inhibit the growth of the tumor Increase the number of reproductions 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% reduction or inhibition 76. The method of any one of claims 73 to 75,

77. 1. A method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to said subject a therapeutic an effective amount of the antibody-drug conjugate of any one of claims 1 to 67; 8 or the pharmaceutical composition of claim 69.

78. 78. The method of claim 77, wherein the cancer cell population expresses a target antigen.

79. The cancer cell population is derived from a tumor or a blood cancer, and optionally the cancer cell population is , breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia Blood cancer, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, Esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell origin lymphoid malignancies, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer Claims arising from lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer 79. The method of claim 77 or 78.

80. The administration of the antibody-drug conjugate, composition or pharmaceutical composition is %, 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% %, by at least about 95%, or by at least about 99%, or slows the expansion of the cancer cell population method.

81. 68. A subject having or suspected of having cancer is treated with any one of claims 1 to 67. the antibody-drug conjugate of claim 68, the composition of claim 69, or The method of determining whether a subject will respond to treatment with the pharmaceutical composition comprises: providing a biological sample; contacting said sample with said antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample. Methods including:

82. 82. The method of claim 81, wherein the cancer cells in the sample express a target antigen.

83. 83. The method of claim 81 or claim 82, wherein the cancer expresses a target antigen.

84. The cancer is a tumor or a blood cancer, and optionally the cancer is breast cancer, multiple bone marrow cancer, or Myeloma, plasma cell myeloma, leukemia, lymphoma, stomach cancer, acute myeloid leukemia, bladder cancer, brain Cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin tumors, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphoma 84. The method according to claim 81, wherein the cancer is myeloma, ... The method according to any one of claims 1 to 5.

85. 85. Any of claims 82 to 84, wherein the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample. The method according to any one of claims 1 to 4.

86. (i) the target antigen is BCMA, CD33, HER2, CD38, CD48, or CD7 9b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT 3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD7 1, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin 4, TROP2, LIV1, CD46, or GPNMB; (ii) the target antigen BCMA, CD33, PCAD, HER2, CD38, CD46, CD48 or or (iii) BCMA, CD33, CD48, PCAD or HER2, a method according to any one of claims 70 to 85.

87. A method for producing an antibody-drug conjugate according to any one of claims 1 to 67. and a cleavable cleavable nucleotide linked to the MCL1 inhibitor under conditions that allow conjugation. The method comprises reacting an antibody or antigen-binding fragment with a suitable linker.

88. and administering at least one additional therapeutic agent to said subject in need thereof. Preferably, the one additional therapeutic agent is a Bcl-2 inhibitor, more preferably claim 7, wherein one additional therapeutic agent is venetoclax, compound A1, or compound A2.

87. The method of any one of claims 0 to 86.

89. The following structure: 【Chemical Engineering 115-1】 【Chemistry 115-2】 【Chemistry 115-3】 or a salt thereof (e.g., a pharmaceutically acceptable salt thereof).

90. A compound according to claim 1, which is used as a synthetic intermediate for preparing an antibody-drug conjugate of formula (1).

90. The compound of claim 89 for use in

91. 90. A compound or pharmaceutically acceptable salt thereof according to claim 89 for use as a pro-apoptotic agent. and its addition salts with acceptable acids or bases.

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