panRAS inhibitor antibody drug conjugate and method of use thereof

Abstract

Antibody-drug conjugates that bind to human tumor targets are disclosed. The antibody-drug conjugates include a panRAS inhibitor drug moiety. This disclosure further relates to methods and compositions for use in the treatment of cancer by administering the antibody-drug conjugates provided herein. Linker-drug conjugates containing a panRAS inhibitor drug moiety and methods for producing them are also disclosed.

Description

[Technical Field]

[0001] This disclosure relates to panRAS inhibitors and antibody-drug conjugates (ADCs) comprising antibodies or antigen-binding fragments thereof that bind to antigens expressed in tumors or other cancer cells, for example, antigens expressed in tumors or other cancer cells. This disclosure further relates to methods and compositions useful for the treatment and / or diagnosis of cancers suitable for expression and / or treatment by modulating panRAS expression and / or activity, as well as methods for producing such compositions. Linker-drug conjugates comprising a panRAS inhibitor drug portion and methods for producing the same are also disclosed. [Background technology]

[0002] Ras proteins (K-Ras, H-Ras, and N-Ras) play important roles in various human cancers and are therefore suitable targets for anti-cancer therapy. In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the Ras protein due to activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in Ras are frequently seen in human cancers. For example, an activating mutation at codon 12 in the Ras protein functions by inhibiting both the GTPase-activated protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of Ras mutant proteins into an "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codon 13 of Ras (e.g., G13D) and at codon 61 (e.g., Q61K) are also associated with oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts against Ras over the past several decades, further efforts are needed to identify more drugs for cancers driven by various Ras mutations. [Overview of the project]

[0004] In some embodiments, this disclosure provides novel antibody-drug conjugate (ADC) compounds that are partially bioactive against cancer cells. These compounds may slow, inhibit, and / or reverse tumor growth in mammals and / or may be useful in treating human cancer patients. More specifically, this disclosure relates in some embodiments to ADC compounds that can bind to and kill cancer cells. In some embodiments, the ADC compounds disclosed herein include a conjugate linker that binds a panRAS inhibitor to a full-length antibody or antigen-binding fragment. In some embodiments, the ADC compounds may also be internally transported into target cells after binding.

[0005] In some embodiments, the ADC compound may be represented by formula (1): Ab-(LD) p (1) In the formula, Ab is an antibody or its antigen-binding fragment; D is a panRAS inhibitor; L is a conjugate linker that covalently bonds Ab to D; p is an integer between 1 and 16. In some embodiments, Ab is an antibody or its antigen-binding fragment that targets cancer cells.

[0006] In some embodiments, for the ADC compound of formula (1), D is a panRAS inhibitor compound of formula (Ia) covalently bonded to the conjugate linker L: [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A D This is -N(H or CH3)C(O)-(CH2)-(where amino nitrogen is -C(R D10a )(R D10) bonded to the carbon atom of ), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; Y X is

Chemical formula

Chemical formula

Chemical formula

[0007] In some embodiments, p is an integer between 1 and 8. In some embodiments, p is an integer between 1 and 6. In some embodiments, p is an integer between 1 and 5. In some embodiments, p is an integer between 2 and 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0008] In some embodiments, the conjugate linker (L) comprises a bonding group, at least one spacer group, and at least one cleavable group. In some cases, the cleavable group comprises a pyrophosphate group and / or a self-sacrificing group. In certain embodiments, L comprises a bonding group; at least one bridging spacer group; and at least one cleavable group comprising a pyrophosphate group and / or a self-sacrificing group.

[0009] In some embodiments, the antibody-drug conjugate is the linker-drug (or "linker-payload") portion of formula (A) - (LD): [ka] Includes, in the formula, R 1 is a bonding group, L 1 E is a bridging spacer group, and E is a cleavable group.

[0010] In some embodiments, the cleavable group includes a pyrophosphate group. In some embodiments, the cleavable group is [ka] Includes.

[0011] In some embodiments, the crosslinking spacer group comprises a polyoxyethylene (PEG) group. In some cases, the PEG group may be selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some embodiments, the crosslinking spacer group may comprise -CO-CH2-CH2-PEG12-. In other embodiments, the crosslinking spacer group comprises a butanoyl, pentanoyl, hexanoyl, heptanyl, or octanoyl group. In some embodiments, the crosslinking spacer group comprises a hexanoyl group.

[0012] In some embodiments, the binding group is formed from at least one reactive group selected from maleimide groups, thiol groups, cyclooctin groups, and azide groups. For example, the maleimide group has the following structure: [ka] It may have.

[0013] The azide group has the structure: -N=N + =N - It may have.

[0014] The cyclooctin group is structured as follows: [ka] It may have, in the formula, [ka] This refers to binding to an antibody or its antigen-binding fragment.

[0015] In some cases, the cyclooctin group is structural: [ka] It has, in the formula, [ka] This refers to binding to an antibody or its antigen-binding fragment.

[0016] In some embodiments, the bonding group is [ka] The formula includes, [ka] This refers to binding to an antibody or its antigen-binding fragment.

[0017] In some embodiments, the antibody or its antigen-binding fragment is bound to a group selected from the following: [ka] By doing so, it is coupled to the conjugate linker (L), in the formula, [ka] This is binding to an antibody or its antigen-binding fragment, in the formula, [ka] This refers to bonding to the crosslinking spacer group. As used herein, the term “bonded” means being covalently bonded or covalently linked.

[0018] In some embodiments, the crosslinking spacer groups are bonded or covalently connected to the cleavable groups.

[0019] In some embodiments, the crosslinking spacer group is -CH2CH2-O-CH2CH2-CO-.

[0020] In some embodiments, the cleavable group is -pyrophosphate-CH2-CH2-NH2-.

[0021] In some embodiments, the cleavable group is bound or covalently linked to the panRAS inhibitor (D).

[0022] In some embodiments, the conjugate linker comprises a binding group, at least one crosslinking spacer group, a peptide group, and at least one cleavable group.

[0023] In some embodiments, the antibody-drug conjugate comprises a linker-drug moiety, -(LD), and formula (B): [ka] It is of the form, and in the formula, R 1 L1 is a binding group, Lp is a crosslinking spacer, Lp is a peptide group containing 1 to 6 amino acid residues, E is a cleavable group, L2 is a crosslinking spacer, m is 0 or 1; D is a panRAS inhibitor. In some cases, m is 1, and the crosslinking spacer is [ka] Includes.

[0024] In some connections, at least one bridging spacer contains a PEG group. In some cases, the PEG group is selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some cases, at least one crosslinking spacer is selected from *-C(O)-CH2-CH2-PEG1-**, *-C(O)-CH2-PEG3-**, *-C(O)-CH2-CH2-PEG12**, *-NH-CH2-CH2-PEG1-**, polyhydroxyalkyl group, *-C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-**, *-C(O)-CH2-CH2-PEG12-NH-C(O)CH2-CH2-**, where ** indicates a direct or indirect binding site of at least one crosslinking spacer to a binding group, and * indicates a direct or indirect binding site of at least one crosslinking spacer to a peptide group.

[0025] In some embodiments, L1 is selected from *-C(O)-CH2-CH2-PEG1-**, *-C(O)-CH2-PEG3-**, *-C(O)-CH2-CH2-PEG12**, *-NH-CH2-CH2-PEG1-**, and polyhydroxyalkyl groups, where ** is R 1 The direct or indirect connection points of L1 to Lp are indicated, and * indicates the direct or indirect connection points of L1 to Lp.

[0026] In some embodiments, m is 1 and L2 is -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-.

[0027] In some embodiments, the peptide group contains 1 to 12 amino acid residues. In some embodiments, each peptide group (Lp) contains 1 to 10 amino acid residues. In some embodiments, each peptide group (Lp) contains 1 to 8 amino acid residues. In some embodiments, each peptide group (Lp) contains 1 to 6 amino acid residues. In some embodiments, the peptide group contains 1 to 4 amino acid residues. In some embodiments, the peptide group contains 1 to 3 amino acid residues. In some embodiments, the peptide group contains 1 to 2 amino acid residues. In some cases, the amino acid residue is selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). For example, the peptide group may include Val-Cit, Val-Ala, Val-Lys, and / or sulfo-Ala-Val-Ala. In some embodiments, the peptide group (Lp) is [ka] It contains one amino acid residue linked to a base. In some embodiments, the peptide group (Lp) is a base: [ka] Includes.

[0028] In some cases, the peptide group includes a group selected from the following: [ka]

[0029] In some embodiments, the self-sacrificing group includes para-aminobenzylcarbamate, para-aminobenzylammonium, para-amino-(sulfo)benzylammonium, para-amino-(sulfo)benzylcarbamate, para-amino-(alkoxy-PEG-alkyl)benzylcarbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkylbenzylcarbamate, or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkylbenzylammonium.

[0030] In some embodiments, m is 1, and the bridging spacer is [ka] Includes.

[0031] In some embodiments, the linker-drug portion, -(LD) is formed from a compound selected from the following: [ka] [ka] [ka] [ka] [ka]

[0032] In some embodiments, the antibody-drug conjugate comprises a linker-drug group, -(LD), which is selected from the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] Includes, Here, [ka] This refers to binding to an antibody or its antigen-binding fragment.

[0033] In some embodiments, the antibody-drug conjugate comprises a linker-drug group, -(LD), which is of formula (C): [ka] It is of the form, and in the formula, R 1 L is a bonding group, and L1 is a bridging spacer; L p G1 is a peptide group containing 1 to 6 amino acids; D is a panRAS inhibitor; G1-L2-A is a self-sacrificing spacer; L2 is a bond, methylene, neopentylene or C2-C3 alkenylene; A is a bond, -OC(=O)-* [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(Ra)2C(Ra)2N(CH3)C(=O)-*, Here, each R a The elements are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl, where * in A indicates the bond site to D; L3 is the spacer portion; R 2 This is the hydrophilic part.

[0034] In some embodiments, the antibody-drug conjugate comprises a linker-drug moiety, -(L-D), which is of formula (D):

Chemical formula

Chemical formula

[0035] In some embodiments, L1 comprises

Chemical formula

[0036] In some embodiments, L1 is

Chemical formula

[0037] In some embodiments, L1 is [Chemical formula] where n is 1, the * of L1 indicates a direct or indirect bonding point to Lp, and the ** of L1 indicates a direct or indirect bonding point to R 1 .

[0038] In some embodiments, L1 is [Chemical formula] where n is 12, the * of L1 indicates a direct or indirect bonding point to Lp, and the ** of L1 indicates a direct or indirect bonding point to R 1 .

[0039] In some embodiments, L1 is [Chemical formula] where n is an integer from 1 to 12, the * of L1 indicates a direct or indirect bonding point to Lp, and the ** of L1 indicates a direct or indirect bonding point to R 1 .

[0040] In some embodiments, L1 comprises [Chemical formula] where the * of L1 indicates a direct or indirect bonding point to Lp, and the ** of L1 indicates a direct or indirect bonding point to R 1 .

[0041] 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 ARN 3 C(=O)(CH2) m -**; *-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**; *-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**; *-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**; *-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**; *-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**; *-C(=O)((CH2) m O) t(CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R 3 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -** is a bridging spacer, where * of L1 indicates a direct or indirect connection point to Lp, and ** of L1 indicates a direct or indirect connection point to R1, where X1 is [ka] And, Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.

[0042] In some embodiments, R 2 Polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1-3 [ka] C2-C6 alkyl groups substituted with -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1~4 The hydrophilic moiety comprises a C2-C6 alkyl group substituted with one or two substituents independently selected from the alkylene-P(O)(OCH2CH3)2 and -COOH groups. In some embodiments, R 2 teeth, [ka] (In the formula, n is an integer between 1 and 6.) [ka] That is the case.

[0043] In some embodiments, the hydrophilic portion is given by formula: [ka] Contains polyethylene glycol, In the formula, R is H, -CH3CH2CH2NHC(=O)ORa, -CH2CH2NHC(=O)R a , or -CH2CH2C(=O)OR a And R' is OH, -OCH3, CH2CH2NHC(=O)OR a -CH2CH2NHC(=O)R a , or -OCH2CH2C(=O)OR a The equation is such that m and n are both integers between 2 and 25 (for example, between 3 and 25).

[0044] In some embodiments, the hydrophilic portion is [ka] Includes.

[0045] In some embodiments, the hydrophilic portion is, for example, the following portion. [ka] (In the formula, n is an integer between 3 and 25, and R is H, -CH3, or -CH2CH2C (=O)OH) It contains polysarcosine.

[0046] In some embodiments, L3 is structure [ka] A spacer portion having, in the formula, W is -CH2-, -CH2O-, -CH2N(R b )C(=O)O-, -NHC(=O)C(Rb )2NHC(=O)O-, -NHC(=O)C(R b )2NH-, -NHC(=O)C(R b )2NHC(=O)-,-CH2N(XR 2 )C(=O)O-, -C(=O)N(XR 2 )-,-CH2N(XR 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH2NR b C(=O)-, -CH2NR b C(=O)NH-, -CH2NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, where each R b These are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; X is a bond, triazolyl, or -CH2-triazolyl-, where X is R 2 It will be joined to

[0047] In some embodiments, L3 is structure [ka] A spacer portion having, 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 bC(=O)NH-, -CH2NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, where each R b These are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; X is -CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-,-C 4~6 Cycloalkylene -OC(O)NHS(O)2NH-,-(CH2CH2O) n -C(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -, -CH2-triazolyl-C 1~4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -, or -C 4~6 Cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n - and each n is independently 1, 2, or 3, and X is R 2 It will be joined to

[0048] In some embodiments, the binding group is formed by a reaction involving at least one reactive group. In some cases, the binding group is formed by reacting a first reactive group that is bound to a conjugate linker with a second reactive group that is bound to an antibody or its antigen-binding fragment, or is an amino acid residue of the antibody or its antigen-binding fragment.

[0049] In some embodiments, at least one of the reactive groups includes: Thiol, Maleimide, Haloacetamide, Azid, Alkin, Cyclocotene, Triarylphosphine, Oxanorbornadiene, Cyclooctin, diaryltetrazine, Monoaryltetrazine, Norbornen, aldehyde, Hydroxylamine, Hydrazine, NH2-NH-C(=O)-, Ketones, Vinyl sulfone, Aziridine, amino acid residues, [ka] -ONH2, -NH2, [ka] ,-N3, [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, [ka] -C(O)NHNH2, [ka] (In the formula, Each R 3 The H and C1-C6 alkyl groups are independently selected; Each R 4 It is 2-pyridyl or 4-pyridyl; Each R 5 These are independently selected from H, C1-C6 alkyl, F, Cl, and -OH; Each R 6These are independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2, and -OH; Each R 7 H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 C substituted with alkoxy and -C(=O)OH 1~4 (Selected independently of alkyl).

[0050] In some embodiments, the first reactive group and the second reactive group include: Thiols and maleimides, Thiols and haloacetamides, Thiols and vinyl sulfones, Thiols and aziridines, Azid and Alkyne, Azide and cyclooctin, Azide and cyclooctene, Azide and triarylphosphine, Azide and oxanorbornadiene, diaryltetradine and cyclooctene, Monoaryltetrazine and norbornene, 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 [ka] amines and [ka] or CoA or CoA analogs and serine residues.

[0051] In some embodiments, the bonding group includes a group selected from the following: [ka] [ka] [ka] Amido; [ka] [ka] and disulfide (In the formula, R 32 H, C 1~4 It is an alkyl, phenyl, pyrimidine, or pyridine; R 35 H, C 1~6 Alkyl, phenyl, or C substituted with 1-3 -OH groups 1~4 It is alkyl; Each R 7 H and C are independent of each other. 1~6 Alkyl, fluoro, -C(=O)OH-substituted benzyloxy, -C(=O)OH-substituted benzyl, -C(=O)OH-substituted C 1~4 C substituted with alkoxy and -C(=O)OH 1~4 Selected from alkyl groups; R 37 These are independently selected from H, phenyl, and pyridine; q is 0, 1, 2, or 3; R 8 is H or methyl; and R 9 (wherein it is H, -CH3, or phenyl).

[0052] In some embodiments, each peptide group (Lp) contains 1 to 6 amino acid residues. In some embodiments, each peptide group (Lp) contains 1 to 4 amino acid residues. In some embodiments, the peptide group contains 1 to 3 amino acid residues. In some embodiments, the peptide group contains 1 to 2 amino acid residues. In some embodiments, the amino acid residues are selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). In some embodiments, the peptide group includes Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, sulfo-Ala-Val, and / or sulfo-Ala-Val-Ala. In some embodiments, Lp is selected from the following: [ka]

[0053] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, R is H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R aH is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0054] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, R is H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0055] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, R is H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0056] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Each R is independently selected from H, -CH3, and -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0057] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Each R is independently selected from H, -CH3, and -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0058] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Xa is -CH2-, -OCH2-, -NHCH2-, or -NRCH2-, and each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] is the binding to an antibody or its antigen-binding fragment; Xa, A, D, and R are as defined above. In some embodiments, Xa is -CH2- or -NHCH2-; A is the binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0059] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, R is H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0060] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Xb is -CH2-, -OCH2-, -NHCH2-, or -NRCH2-, and each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] is binding to an antibody or its antigen-binding fragment; Xb, A, D, and R are as defined above. In some embodiments, A is binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0061] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] It includes or is formed therefrom, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and A are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0062] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0063] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R aH is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0064] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0065] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0066] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0067] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, where each R a H is independently selected from C1-C6 alkyl and C3-C8 cycloalkyl groups, and * in A indicates a bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is binding to an antibody or its antigen-binding fragment; A and D are as defined above. In some embodiments, A is binding or -OC(=O)-*.

[0068] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a These are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl, and the * in A indicates the bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0069] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, Each R is independently H, -CH3, or -CH2CH2C(=O)OH; A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a These are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl, and the * in A indicates the bond site to D; D is a panRAS inhibitor. In some embodiments, the linker-drug group (LD) is as follows: [ka] Including, in the formula, [ka] A is a binding to an antibody or its antigen-binding fragment; A, D, and R are as defined above. In some embodiments, A is a binding or -OC(=O)-*; and R is -CH3 or -CH2CH2C(=O)OH.

[0070] In some embodiments, the linker-drug group-(LD) is a compound of the following formula: [ka] It includes or is formed therefrom, in the formula, A is a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a These are independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl, and the * in A indicates the bond site to D; D is a panRAS inhibitor.

[0071] In some embodiments, A is a bond.

[0072] In some embodiments, A is -OC(=O)-*.

[0073] In some embodiments, R is -CH3.

[0074] In some embodiments, R is -CH2CH2COOH.

[0075] In some embodiments, the antibody-drug conjugate comprises a linker-drug group, -(LD), which is formed from a compound selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0076] In some embodiments, the antibody-drug conjugate comprises a linker-drug group, -(LD), which is selected from the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Including, in the formula, [ka] This refers to binding to an antibody or its antigen-binding fragment.

[0077] In some embodiments, the panRAS inhibitor (D) is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for formula (Ia).

[0078] In some embodiments, the panRAS inhibitor (D) is a compound of formula (I): [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A D This is -N(H or CH3)C(O)-(CH2)-(where amino nitrogen is -C(R D10a )(R D10)- bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B D is -CH(R D9 )- or >C=CR D9 R D9’ (Here, carbon is -N(R) D11 The compounds are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; G D This includes arbitrarily substituted C1-C4 alkylenes, arbitrarily substituted C1-C4 alkenylenes, arbitrarily substituted C1-C4 heteroalkylenes, and -C(O)O-CH(R D6 )-(Here, -CH(R D6 )- is -C(R D7 R D8 )-(bonded),-C(O)NH-CH(R D6 )-(Here, -CH(R D6 )- is -C(R D7 R D8 A C1-C4 heteroalkylene or a 3-8 membered heteroarylene, which is optionally substituted (and bonded to) a C1-C4 heteroalkylene; L D It either does not exist or is a drug linker; W D This is hydrogen, cyano, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 3-8 member heteroaryl; X D1 These are arbitrarily substituted C1-C2 alkylenes, NRD , O, or S(O) nD and; X D2 is either O or NH; X D3 is N or CH; nD is 0, 1, or 2; R D This includes hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, and C(O)R. D’ , C(O)OR D’ , C(O)N(R D’ )2, S(O)R D’ S(O)2R D’ , or S(O)2N(R D’ )2; each R D’ These are independently H or optionally substituted C1-C4 alkyl groups; Y D1 is C, CH, or N; Y D2 , Y D3 , Y D4 , and Y D7 Independently, C or N; Y D5 is CH, CH2, or N; Y D6 is C(O), CH, CH2, or N; R D1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R D1 and R D2 These combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups; R D2This is either absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, or optionally substituted 5 or 6 member heteroaryl; R D3 It does not exist, or R D2 and R D3 These combine with the atoms to which they are bonded to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R D4 is either absent, or methyl optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens; R D5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens; R D6 is hydrogen or methyl; R D7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R D6 and R D7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R D8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R D7 and R D8 These combine with the carbon atoms to which they are bonded, resulting in C=CR D7’ R D8’;Forming C=N(OH), C=N(O-C1~C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups; R D7a and R D8a These can independently form a carbonyl group, either with hydrogen, a halo, an optionally substituted C1-C3 alkyl group, or in combination with the carbon atom to which they are bonded; R D7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R D8’ is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R D7’ and R D8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R D9 This is hydrogen, fluorine, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups; R D9 and L D These combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups; R D9’ is a hydrogen atom or optionally substituted C1-C6 alkyl group; R D10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxyl, or C1-C3 alkyl; R D10a is hydrogen or halogen; R D11is hydrogen or a C1-C3 alkyl group; R D16 This is either hydrogen or a C1-C3 alkyl group.

[0079] In some embodiments, the panRAS inhibitor (D) is a compound of formula (Ic): [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A D This is -N(H or CH3)C(O)-(CH2)-(where amino nitrogen is -CH(R D10 )- bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B D is -CH(R D9 )-(Here, carbon is -N(R D11 The compounds are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; L D It either does not exist or is a drug linker; W D This is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl; X D2 is either O or NH; X D3 is N or CH; R D This includes hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, and C(O)R. D’ , C(O)OR D’ , C(O)N(R D’ )2, S(O)R D’ S(O)2R D’ , or S(O)2N(R D ')2; Each R D’ These are independently H or optionally substituted C1-C4 alkyl groups; Y D1 is C, CH, or N; Y D2 , Y D3 , Y D4 , and Y D7 Independently, C or N; Y D5 and Y D6 It is independently CH or N; R D1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl; R D2 These are hydrogen, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-7 member heterocycloalkyls, optionally substituted 6 member aryls, and optionally substituted 5 or 6 member heteroaryls; R D3 It does not exist; or R D2 and R D3 These combine with the atoms to which they are bonded to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R D4is either absent, or methyl optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens; R D5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens; R D6 is hydrogen or methyl; R D7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R D6 and R D7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R D8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R D7 and R D8 These combine with the carbon atoms to which they are bonded, resulting in C=CR 7’ R 8’ ;Forming C=N(OH), C=N(O-C1~C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups; R D7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R D8’is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R D7’ and R D8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R D9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups; R D10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R D11 This is either hydrogen or a C1-C3 alkyl group.

[0080] In some embodiments, the panRAS inhibitor (D) is a compound of formula (If): [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, A D These are -N(H or CH3)C(O)-(CH2)- (where the amino nitrogen is bonded to the carbon atom of -CH2-), optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes; B D is -CH(R D9)-(where the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; L D It either does not exist or is a drug linker; W D This is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl; R D1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl; R D2 These are C1-C6 alkyl or 3-6 membered cycloalkyl groups; R D7 These are C1-C3 alkyl groups; R D8 is a C1-C3 alkyl group; and R D9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups.

[0081] In some embodiments, R D1 These are 5-10 member heteroaryl compounds.

[0082] In some embodiments, R D1 This is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0083] In some embodiments, panRAS inhibitor D is A D or R D1 It is coupled to a conjugate linker represented by L at its position.

[0084] In some embodiments, the panRAS inhibitor D is a compound of formula (Ig): [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, A D This is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B D is -CH(R D9 )-(where the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; L D It either does not exist or is a drug linker; W D This is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl; R D2 These are C1-C6 alkyl or 3-6 membered cycloalkyl groups; R D7 These are C1-C3 alkyl groups; R D8 These are C1-C3 alkyl groups; R D9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups; X De is N, CH, or CR D17 and; X Df is N or CH; R D12 is an optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; R D17 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-6 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups.

[0085] In some embodiments, A D This is a 6-membered arrine that has been arbitrarily substituted.

[0086] In some embodiments, A D These are arbitrarily substituted 5-6 member heteroarylenes.

[0087] In some embodiments, B D -CHR D9 - is

[0088] In some embodiments, R D9 These are optionally substituted C1-C6 alkyl groups or optionally substituted 3-6 member cycloalkyl groups.

[0089] In some embodiments, the drug linker in the panRAS inhibitor described in any one of the embodiments above has the structure of formula II: A D1 -( B D1 ) fD -(C D1 ) gD -( B D2 ) hD -(D D1 )-(B D3 ) iD -(C D2 ) jD -( B D4 ) kD -A D2 Formula II And in the formula, A D1 This is a bond between the drug linker and B; A D2 This is the bond between W and the drug linker; B D1 B D2 B D3 , and B D4 These are, independently, an arbitrarily substituted C1-C2 alkylene, an arbitrarily substituted C1-C3 heteroalkylene, O, S, and NR, respectively. DN Selected from; R DN This is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C1-C7 heteroalkyl; C D1 and C D2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; fD, gD, hD, iD, jD, and kD are each independently either 0 or 1; D D1 C1~C are arbitrarily substituted. 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C2-C 10 Polyethylene glycolene, or optionally substituted C1-C 10 Heteroalkylene, or A D1 -( B D1 ) fD -(C D1 ) gD -( B D2 ) hD -to-(B D3 ) iD -(C D2 ) Dj -( B D4 ) Dk -A D2 It is a chemical bond that connects to something.

[0090] In some embodiments, the drug linker has the structure of formula IIa: [ka] It has, in the formula, X Da It either does not exist or is N; R D14 is either absent, hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl; L D2 X is either nonexistent, -C(O)-, -SO2-, an arbitrarily substituted C1-C4 alkylene, or an arbitrarily substituted C1-C4 heteroalkylene, where X Da , R D14 , or L D2 At least one of these exists.

[0091] In some embodiments, the panRAS inhibitor described in any one of the embodiments above is W D It is hydrogen.

[0092] In some embodiments, the panRAS inhibitor described in any one of the embodiments above is W D These are C0-C4 alkyl groups, or optionally substituted 3-11 member heterocycloalkyl groups.

[0093] In some embodiments, panRAS inhibitor D is A D or R D17 It is coupled to a conjugate linker represented by L at its position.

[0094] In some embodiments, the panRAS inhibitor D is a compound of formula (Ih): [ka] or comprising a pharmaceutically acceptable salt thereof, in the formula, R D2 These are C1-C3 alkyl groups; R D7 These are C1-C3 alkyl groups; R D8 These are C1-C3 alkyl groups; R D9 These are C1-C6 alkyl groups; R D14 is hydrogen or C 1~ It is a C6 alkyl group, R D17 is an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl; W D These are optionally substituted 3- to 11-membered heterocycloalkyl groups.

[0095] In some embodiments, R D9 R is a C1-C3 alkyl group; D14 R is a C1-C3 alkyl group; D17 is an optionally substituted 3- to 6-membered heterocycloalkyl group; W D These are arbitrarily substituted 5-6 member heterocycloalkyl groups.

[0096] In some embodiments, panRAS inhibitor D is a compound represented by the following: [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the panRAS inhibitor D is a compound of formula (Ij): [ka] or a pharmaceutically acceptable salt thereof, where aD is 0 or 1. Definitions of other variables are provided in any one of the embodiments described above.

[0098] In some embodiments, the panRAS inhibitor D is a compound of formula (Ik): [ka] or a pharmaceutically acceptable salt thereof, where aD is 0 or 1. Definitions of other variables are provided in any one of the embodiments described above.

[0099] In some embodiments, the panRAS inhibitor D is a compound of formula (Im): [ka] or a pharmaceutically acceptable salt thereof, where aD is 0 or 1. Definitions of other variables are provided in any one of the embodiments described above.

[0100] In some embodiments, the panRAS inhibitor D is a compound of formula (In): [ka] or a pharmaceutically acceptable salt thereof, where aD is 0 or 1. Definitions of other variables are provided in any one of the embodiments described above.

[0101] In some embodiments, D represents a panRAS inhibitor covalently bonded to a conjugate linker L, where the panRAS inhibitor is selected from the compounds in Table A1 or their pharmaceutically acceptable salts.

[0102] [Table 1]

[0103] [Table 2]

[0104] In some embodiments, the panRAS inhibitor D comprises a formula selected from any one of the formulas in Table A2 or from pharmaceutically acceptable salts thereof.

[0105] [Table 3]

[0106] [Table 4]

[0107] During the ceremony, [ka] This represents binding to a conjugate linker.

[0108] In some embodiments, -(LD) is formed from a compound selected from Table B or its enantiomer, diastereoisomer, and / or pharmaceutically acceptable salt. In some embodiments, the maleimide group in the compounds of Table B [ka] It forms a covalent bond with the antibody or its antigen-binding fragment (Ab), [ka] The compound forms an ADC compound of formula (1) containing the part, where * indicates a bond site to Ab. For the compounds in Tables A1, A2, B and 1, depending on their charge, these compounds form one pharmaceutically acceptable monovalent anionic counterion M1 - It may contain a monovalent anionic counterion M1 - This can be selected from bromides, chlorides, iodides, acetates, trifluoroacetates, benzoates, mesylates, tosylates, triflates, formates, and the like. In some embodiments, a monovalent anionic counterion M1 - It is a trifluoroacetate or formate salt.

[0109] [Table 5]

[0110] [Table 6]

[0111] [Table 7]

[0112] [Table 8]

[0113] In some embodiments, the antibody-drug conjugate has a formula represented by one of the structures shown in Table 1.

[0114] [Table 9]

[0115] [Table 10]

[0116] [Table 11]

[0117] [Table 12]

[0118] * [ka] Or Ab: Any antibody or antigen-binding fragment thereof as described herein, for example, anti-EphA2 antibody, anti-B7-H3 antibody, or antigen-binding fragment thereof.

[0119] The ADC shown above is also expressed by the following formula: Ab-(LD) p (1) It can be expressed by, in the formula, Ab or [ka] p represents an antibody or its antigen-binding fragment covalently linked to the linker-payload (LD) shown above; 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. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0120] As used herein, “LD” refers to a linker-payload, linker-drug, or linker-compound disclosed herein; the term “L#-D#” is used to refer to a specific linker-drug disclosed herein, while the symbol “D#” is used to refer to a specific compound, including any enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharmaceutically acceptable salt, unless otherwise specified.

[0121] In some embodiments, for the ADCs shown in Table 1, Ab is an antibody or its antigen-binding fragment described herein. In some embodiments, for the ADCs shown in Table 1, Ab is an anti-EphA2 antibody or its antigen-binding fragment. In some embodiments, Ab is an anti-B7-H3 antibody or its antigen-binding fragment.

[0122] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on cancer cells. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276).

[0123] In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276).

[0124] In some embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody or antigen-binding fragment. In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) selected from the group consisting of: 1) Heavy chain CDR1 (HCDR1) consisting of sequence number 17, heavy chain CDR2 (HCDR2) consisting of sequence number 18, heavy chain CDR3 (HCDR3) consisting of sequence number 19; light chain CDR1 (LCDR1) consisting of sequence number 26, light chain CDR2 (LCDR2) consisting of sequence number 27, and light chain CDR3 (LCDR3) consisting of sequence number 28; 2) Heavy chain CDR1 (HCDR1) consisting of sequence number 20, heavy chain CDR2 (HCDR2) consisting of sequence number 21, heavy chain CDR3 (HCDR3) consisting of sequence number 19; light chain CDR1 (LCDR1) consisting of sequence number 29, light chain CDR2 (LCDR2) consisting of sequence number 30, and light chain CDR3 (LCDR3) consisting of sequence number 31; 3) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 22, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 23, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 24; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 32, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31; and 4) Heavy chain CDR1 (HCDR1) consisting of sequence number 25, heavy chain CDR2 (HCDR2) consisting of sequence number 21, heavy chain CDR3 (HCDR3) consisting of sequence number 19; light chain CDR1 (LCDR1) consisting of sequence number 29, light chain CDR2 (LCDR2) consisting of sequence number 30, and light chain CDR3 (LCDR3) consisting of sequence number 31.

[0125] In some embodiments, the anti-EphA2 antibody or antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 11 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-EphA2 antibody or antigen-binding fragment includes an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain includes cysteine ​​residues (C) at positions 152 and 375. In some embodiments, the antibody or antigen-binding fragment includes an Igκ light chain constant domain.

[0126] In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 3 and a light chain containing the amino acid sequence of SEQ ID NO: 5.

[0127] In some embodiments, the antibody or antigen-binding fragment is an anti-B7-H3 (CD276) antibody or antigen-binding fragment. In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs) selected from the group consisting of: 1) Heavy chain CDR1 (HCDR1) consisting of sequence number 33, heavy chain CDR2 (HCDR2) consisting of sequence number 34, heavy chain CDR3 (HCDR3) consisting of sequence number 35; light chain CDR1 (LCDR1) consisting of sequence number 42, light chain CDR2 (LCDR2) consisting of sequence number 43, and light chain CDR3 (LCDR3) consisting of sequence number 44; 2) Heavy chain CDR1 (HCDR1) consisting of sequence number 36, heavy chain CDR2 (HCDR2) consisting of sequence number 37, heavy chain CDR3 (HCDR3) consisting of sequence number 35; light chain CDR1 (LCDR1) consisting of sequence number 45, light chain CDR2 (LCDR2) consisting of sequence number 46, and light chain CDR3 (LCDR3) consisting of sequence number 47; 3) Heavy chain CDR1 (HCDR1) consisting of sequence number 38, heavy chain CDR2 (HCDR2) consisting of sequence number 39, heavy chain CDR3 (HCDR3) consisting of sequence number 40; light chain CDR1 (LCDR1) consisting of sequence number 48, light chain CDR2 (LCDR2) consisting of sequence number 43, and light chain CDR3 (LCDR3) consisting of sequence number 47; 4) Heavy chain CDR1 (HCDR1) consisting of sequence number 41, heavy chain CDR2 (HCDR2) consisting of sequence number 37, heavy chain CDR3 (HCDR3) consisting of sequence number 35; light chain CDR1 (LCDR1) consisting of sequence number 45, light chain CDR2 (LCDR2) consisting of sequence number 46, and light chain CDR3 (LCDR3) consisting of sequence number 47; 5) Heavy chain CDR1 (HCDR1) consisting of sequence number 49, heavy chain CDR2 (HCDR2) consisting of sequence number 50, heavy chain CDR3 (HCDR3) consisting of sequence number 51; light chain CDR1 (LCDR1) consisting of sequence number 58, light chain CDR2 (LCDR2) consisting of sequence number 59, and light chain CDR3 (LCDR3) consisting of sequence number 60; 6) Heavy chain CDR1 (HCDR1) consisting of sequence number 52, heavy chain CDR2 (HCDR2) consisting of sequence number 53, heavy chain CDR3 (HCDR3) consisting of sequence number 51; light chain CDR1 (LCDR1) consisting of sequence number 61, light chain CDR2 (LCDR2) consisting of sequence number 62, and light chain CDR3 (LCDR3) consisting of sequence number 63; 7) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 54, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 55, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 56; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 58, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 59, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63; and 8) Heavy chain CDR1 (HCDR1) consisting of sequence number 57, heavy chain CDR2 (HCDR2) consisting of sequence number 53, heavy chain CDR3 (HCDR3) consisting of sequence number 51; light chain CDR1 (LCDR1) consisting of sequence number 61, light chain CDR2 (LCDR2) consisting of sequence number 62, and light chain CDR3 (LCDR3) consisting of sequence number 63.

[0128] In some embodiments, the anti-B7-H3(CD276) antibody or antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment includes a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain includes cysteine ​​residues (C) at positions 152 and 375. In some embodiments, the antibody or antigen-binding fragment includes an Igκ light chain constant domain.

[0129] In some embodiments, the anti-B7-H3(CD276) antibody or antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 15 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment includes a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain includes cysteine ​​residues (C) at positions 152 and 375. In some embodiments, the antibody or antigen-binding fragment includes an Igκ light chain constant domain.

[0130] In some embodiments, the anti-B7-H3(CD276) antibody or antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 7 and a light chain containing the amino acid sequence of SEQ ID NO: 8.

[0131] In some embodiments, the anti-B7-H3(CD276) antibody or antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0132] In some embodiments, compositions comprising multiple copies of an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein) are also provided herein. In some embodiments, the average p of the antibody-drug conjugates in the composition is about 2 to about 4.

[0133] In some embodiments herein, pharmaceutical compositions are also provided, comprising an antibody-drug 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.

[0134] Furthermore, in several embodiments, therapeutic uses for the ADC compounds and compositions described herein are provided, for example, in the treatment of cancer. In some embodiments, the disclosure provides a method for treating cancer (e.g., cancer expressing an antigen that is targeted by an antibody or antigen-binding fragment of an ADC, such as EphA2 or B7-H3 (CD276)). In some embodiments, the disclosure provides a method for reducing or slowing the growth of a cancer cell population in a subject. In some embodiments, the disclosure provides a method for determining whether a subject having or suspected of having cancer would respond to treatment with the ADC compounds or compositions disclosed herein.

[0135] An exemplary embodiment is a method for treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2. CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA These include hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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, VEGFR-2, or vimentin.

[0136] In some embodiments, the target antigen is EphA2 or B7-H3 (CD276).

[0137] In some embodiments, the target antigen is EphA2.

[0138] In some embodiments, the target antigen is B7-H3(CD276).

[0139] In some embodiments, cancer is a tumor or hematological cancer. In some embodiments, cancer is breast cancer, including ER-positive breast cancer; multiple myeloma; plasmacytic myeloma; leukemia; lymphoma; sarcoma; gastric cancer or stomach cancer; acute myeloid leukemia; bladder cancer; brain tumor; bone marrow cancer; cervical cancer; chronic lymphocytic leukemia; colorectal cancer; pancreatic cancer; esophageal cancer; hepatocellular carcinoma; lymphoblastic leukemia, including acute lymphoblastic leukemia; follicular lymphoma; lymphoid tumor of T-cell or B-cell origin; metastatic castration-resistant prostate cancer; urothelial carcinoma of the bladder; melanoma; myeloid leukemia; myeloma; oral cancer; ovarian cancer; non-small cell lung cancer; prostate cancer; small cell lung cancer; splenic cancer; or head and neck cancer.

[0140] Another exemplary embodiment is a method for 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 antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP)IB, SPAP IC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, Prostate-Specific Membrane Antigen (PSMA), PSCA (Prostate Stem Cell Antigen Precursor), PRLR (Prolactin Receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate Cancer-Related Gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient Receptor Potential Cation Channel Subfamily M, Member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the tumor is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer. In some embodiments, administration of an antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0141] Another exemplary embodiment is a method for reducing or slowing the growth of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer cell population expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP)IB, SPAP IC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, Prostate-Specific Membrane Antigen (PSMA), PSCA (Prostate Stem Cell Antigen Precursor), PRLR (Prolactin Receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate Cancer-Related Gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient Receptor Potential Cation Channel Subfamily M, Member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the cancer cell population originates from a tumor or hematological malignancy. In some embodiments, the cancer cell population includes breast cancer, including ER-positive breast cancer; multiple myeloma; plasmacytic myeloma; leukemia; lymphoma; sarcoma; gastric cancer or stomach cancer; acute myeloid leukemia; bladder cancer; brain tumor; bone marrow cancer; cervical cancer; chronic lymphocytic leukemia; colorectal cancer; pancreatic cancer; esophageal cancer; hepatocellular carcinoma; lymphoblastic leukemia, including acute lymphoblastic leukemia; follicular lymphoma; lymphoid tumors of T-cell or B-cell origin; metastatic castration-resistant prostate cancer; urothelial carcinoma of the bladder; melanoma; myeloid leukemia; myeloma; oral cancer; ovarian cancer; non-small cell lung cancer; prostate cancer; small cell lung cancer; splenic cancer; or head and neck cancer.

[0142] In some embodiments, administration of an antibody-drug conjugate, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, administration of an antibody-drug conjugate, composition, or pharmaceutical composition slows the growth 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%.

[0143] Another exemplary embodiment is an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) for use in treating subjects having or suspected of having cancer. In some embodiments, cancer expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0144] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in treating a subject having or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0145] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in a method for producing a pharmacopoeia for the treatment of a subject having or suspected of having cancer. In some embodiments, cancer expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0146] Another exemplary embodiment is a method for determining whether a subject having or suspected of having cancer would respond to treatment with an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample derived from the subject; contacting the sample with the antibody-drug conjugate; and detecting the binding of the antibody-drug conjugate to cancer cells in the sample. In some embodiments, the cancer cells in the sample express the target antigen. In some embodiments, the cancer expresses the target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the target antigen is EphA2. In some embodiments, the target antigen is B7-H3 (CD276). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

[0147] Methods for producing the described ADC compounds and compositions are also disclosed. An exemplary embodiment is a method for producing an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a cleavable conjugate linker conjugated to or covalently bound to a panRAS inhibitor under conditions that enable conjugation. [Brief explanation of the drawing]

[0148] [Figure 1] This study demonstrates the in vitro activity of panRAS ADC, isotype ADC, and sotracib in multiple cancer cell lines (LU65, HPAC, H727, and SW1271). [Modes for carrying out the invention]

[0149] The compositions and methods disclosed may be more readily understood by reference to the following detailed description in conjunction with the accompanying drawings that form part of this disclosure.

[0150] Throughout this document, descriptions refer to compositions and methods of using the compositions. Where this disclosure describes or requests features or embodiments related to a composition, such features or embodiments also apply to methods of using the composition. Similarly, where this disclosure describes or requests features or embodiments related to methods of using a composition, such features or embodiments also apply to the composition.

[0151] Where a range of values ​​is expressed, it includes embodiments that use any specific value within that range. Furthermore, references to values ​​listed within a range include each value within that range. All ranges encompass and are combinable, including their endpoints. Where a value is expressed as an approximation by the preceding use of “about,” it is understood that a particular value forms another embodiment. References to a particular numerical value include at least that particular value unless explicitly indicated otherwise by the context. The use of “or” means “and / or” unless explicitly indicated otherwise by the specific context of its use. All references cited herein are incorporated by reference for any purpose. In the event of any conflict between the references and the specification, the specification shall prevail.

[0152] Unless otherwise indicated by the context of the description, for example, if there is no symbol indicating a specific linkage point, and a structure or structural fragment is depicted, it may be used on its own, may be bound to other components of the ADC, and may be done in any orientation, such as when the antibody or its antigen-binding fragment is bound to a chemical part such as a linker-drug at any suitable linkage point. However, if shown, the components of the ADC are bound in the orientation shown in the given formula. For example, if formula (1) is written as Ab-(LD)p, and the group "-(LD)" is, [ka] When described as such, the detailed structure of formula (1) is: [ka] That is, [ka] No.

[0153] For clarity, it should be understood that certain features of the compositions and methods disclosed herein, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the compositions and methods disclosed, described in the context of a single embodiment, may also be provided separately or in any subordinate combination.

[0154] When used throughout this specification, antibody-drug conjugates may be identified using the nomenclature convention in the general form of “target antigen / antibody-linker-payload”. For example, only when an antibody-drug conjugate is referred to as “target X-L0-P0”, such a conjugate will include an antibody that binds to target X, a conjugate linker indicated as L0, and a payload indicated as P0. Alternatively, when an antibody-drug conjugate is referred to as “anti-target X-L0-P0”, such a conjugate will include an antibody that binds to target X, a conjugate linker indicated as L0, and a payload indicated as P0. Another option is when an antibody-drug conjugate is referred to as “AbX-L0-P0”, such a conjugate will include an antibody indicated as AbX, a conjugate linker indicated as L0, and a payload indicated as P0. A control antibody-drug conjugate containing a nonspecific isotype control antibody may be referred to as “isotype control IgG1-L0-P0” or “IgG1-L0-P0”.

[0155] All formulas provided herein are intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotope-labeled compounds have the structure described by the formulas provided herein, except in which one or more atoms are substituted by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include: 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. Therefore, this disclosure includes, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 Please understand that this includes compounds that incorporate one or more of the aforementioned isotopes, including those that contain non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic tests. 14 (by C), reaction rate test (for example) 2 H or 3 It is useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays (by H), or in radiotherapy for patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT testing. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, by using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0156] definition Various terms relating to aspects of this specification are used throughout this specification and the claims. Unless otherwise specified, such terms shall have the given common meaning in the art. Other specifically defined terms shall be construed in a manner consistent with the definitions provided herein.

[0157] As used herein, the singular forms “a,” “an,” and “it” include the plural form unless explicitly stated otherwise in the context. The terms “comprising,” “having,” “being of,” “including,” and “containing,” as in “being of a chemical formula,” should be considered open terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Furthermore, whenever “comprising” or another non-restrictive term is used in an embodiment, it should be understood that the same embodiment may be more strictly claimed using the intermediate term “essentially consisting of” or the restrictive term “consisting of.”

[0158] When used in the context of numbers and ranges, the terms “about” or “approximately” refer to values ​​or ranges that approximate or are close to the listed values ​​or ranges, as will be apparent to those skilled in the art from the teachings contained herein, so that the embodiments can be carried out as intended. In some embodiments, “about” means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of a quantity. In one embodiment, the term “about” refers to a set of numbers that are more than 10% or less than 10% of a particular number. In another embodiment, the term “about” refers to a set of numbers that are more than 5% or less than 5% of a particular number. In yet another embodiment, the term “about” refers to a set of numbers that are more than 1% or less than 1% of a particular number.

[0159] The terms “antibody-drug conjugate,” “antibody conjugate,” “conjugate,” “immune conjugate,” and “ADC” are used interchangeably and refer to one or more therapeutic compounds (e.g., panRAS inhibitors) conjugated to one or more antibodies or antigen-binding fragments. In some embodiments, ADC is a compound with the general formula: Ab-(LD) pDefined by (Formula 1), where Ab = antibody or antigen-binding fragment (e.g., anti-EphA2 antibody or anti-B7-H3 antibody, or its antigen-binding fragment), L = conjugate linker portion, D = drug portion (e.g., panRAS inhibitor drug portion), and p = number of drug portions per antibody or antigen-binding fragment. In an ADC containing a panRAS inhibitor drug portion, "p" refers to the number of panRAS inhibitor compounds linked to the antibody or antigen-binding fragment.

[0160] The term “antibody” is used in its broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination thereof, via at least one antigen recognition site within the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and can be of natural or recombinant origin. An “intact” antibody is a glycoprotein typically containing at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region contains three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain: CL. The VH and VL regions can be further subdivided into highly variable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs aligned from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or to various cells of the immune system (e.g., effector cells) and factors containing the first component (C1q) of the classical complement system. Antibodies can be monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, or chimeric antibodies. Antibodies may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Antibodies may be intact antibodies or their antigen-binding fragments.

[0161] In some embodiments, the antibodies or antibody fragments disclosed herein include modified or manipulated amino acid residues, such as one or more cysteine ​​residues, as sites for conjugation to a drug moiety (Junutula JR, et al., Nat Biotechnol 2008, 26:925-932). In one embodiment, the disclosure provides a modified antibody or antibody fragment comprising the substitution of one or more amino acids with cysteine ​​at the sites described herein. The sites for cysteine ​​substitution are located in a constant region of the antibody or antibody fragment and are therefore applicable to a variety of antibodies or antibody fragments, and the sites are selected to result in a stable and uniform conjugate. The modified antibody or fragment may have one, two or more cysteine ​​substitutions, and these substitutions may be used in combination with other modification and conjugation methods as described herein. Methods for inserting cysteine ​​at specific locations in antibodies are known in the art; see, for example, Lyons et al, (1990) Protein Eng., 3:703-708, International Publication No. 2011 / 005481, International Publication No. 2014 / 124316, and International Publication No. 2015 / 138615. In a particular embodiment, the modified antibody comprises the substitution of one or more amino acids by cysteine ​​in its constant region selected from positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 191, 195, 197, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, ​​390, 392, 398, 400, and 422 in the antibody's heavy chain, the positions being numbered according to the EU system.In some embodiments, the modified antibody or antibody fragment comprises a cysteine ​​substitution of one or more amino acids in its constant region, selected from positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of the light chain of the antibody or antibody fragment, the positions numbered according to the EU system, and the light chain is a human kappa light chain. In certain embodiments, the modified antibody or antibody fragment comprises a combination of cysteine ​​substitutions of two or more amino acids in its constant region, the combination comprising substitutions at position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, or position 107 of the antibody light chain, the positions numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment includes a cysteine ​​substitution of one amino acid in its constant region, the substitution being at position 375, 152, or 360 of the antibody heavy chain, position 107, 165, or 159 of the antibody light chain, the positions numbered according to the EU system, and the light chain is a kappa chain. In certain embodiments, the modified antibody or antibody fragment includes a combination of two cysteine ​​substitutions of amino acids in its constant region, the combination including substitutions at position 375 and 152 of the antibody heavy chain, the positions numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment includes a cysteine ​​substitution of one amino acid at position 360 of the antibody heavy chain, the positions numbered according to the EU system. In other specific embodiments, the modified antibody or antibody fragment comprises a cysteine ​​substitution of one amino acid at position 107 of the antibody light chain, the position numbered according to the EU system, and the light chain is a kappa chain.

[0162] The terms “antibody fragment,” “antigen-binding fragment,” or “functional antibody fragment,” as used herein, refer to at least a portion of an antibody that retains the ability to specifically interact with an epitope of an antigen (e.g., EphA2 or B7-H3 (CD276)) (e.g., by binding, steric hindrance, stabilization / destabilization, or spatial distribution). Antigen-binding fragments may also retain the ability to internalize into antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immunoeffector activity. Terms such as antibody, antibody fragment, and antigen-binding fragment are intended to encompass the use of antibody-derived binding domains in the context of larger macromolecules such as ADCs. Fragments of full-length antibodies have been shown to perform the antigen-binding function of a 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 fragments consisting of VH and CH1 domains, linear antibodies, single-domain antibodies such as sdAb (either VL or VH), camel VHH domains, and bivalent fragments containing two Fab fragments linked by disulfide crosslinking at the hinge region. These fragments form multispecific antibodies and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bis-scFv (e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):1126-36). Antigen-binding fragments can also be implanted onto polypeptide-based scaffolds, such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, which describes fibronectin polypeptide minibodies).The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment containing a light chain variable region and at least one antigen-binding fragment containing a heavy chain variable region, wherein the light chain and heavy chain variable regions are linked in close proximity via, for example, a synthetic linker, such as a short mobile polypeptide linker, and the scFv can be expressed as a single-chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. Unless otherwise specified, the scFv may have the VL and VH variable regions in either order relative to, for example, the N-terminus and C-terminus of the polypeptide, and the scFv may comprise VL-linker-VH or VH-linker-VL. Antigen-binding fragments are obtained using conventional methods known to those skilled in the art, and the binding fragments are selected for usefulness (e.g., binding affinity, internal migration) in the same manner as intact antibodies. Antigen-binding fragments can be prepared, for example, by cleavage of intact proteins, such as by proteases or chemical cleavage.

[0163] As used herein, the term “complementarity-determining region” or “CDR” refers to a sequence of amino acids within an antibody variable region that confers antigen specificity and binding affinity. For example, typically, three CDRs are present in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3), and three CDRs are present in each light chain variable region (LCDR1, LCDR2, and LCDR3). The exact amino acid sequence boundaries of a given CDR can be determined using one of several well-known schemes, including those described in Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al. (1997) J Mol Biol. 273(4):927-48 (“Chothia” numbering scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77) (“IMGT” numbering scheme); or a combination thereof. In a combination of Kabat and Chothia numbering schemes relating to a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, the CDR corresponds to amino acid residues defined as part of a Kabat CDR, along with amino acid residues defined as part of a Chothia CDR. As used herein, a CDR defined according to the “Chothia” numbering scheme may also be referred to as a “hypervariable loop.”

[0164] In some embodiments, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1) (e.g., insertion after position 35), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) (e.g., insertion after position 27), 50-56 (LCDR2), and 89-97 (LCDR3). In some embodiments, under Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1) (e.g., insertion after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, in some embodiments, the CDR includes, for example, amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. In some embodiments, under IMGT, the CDR amino acid residues in VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the CDR region of the antibody can be determined using a program called IMGT / DomainGap Align.

[0165] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting the population are identical except for naturally occurring variants that may exist in small amounts. Monoclonal antibodies are highly specific and directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically contain multiple antibodies directed against (or specific to) different epitopes. The modifier “monoclonal” indicates a characteristic of the antibody that it is obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with this disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495 or by the recombinant DNA method (see, e.g., U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J Mol Biol. 222:581-97. This term also includes formulations of antibody molecules in single-molecule compositions. Monoclonal antibody compositions exhibit single-binding specificity and affinity for specific epitopes.

[0166] The monoclonal antibodies described herein may be non-human, human, or humanized. The term "specifically" includes "chimeric" antibodies in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody of a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to an antibody of a different species or belonging to a different antibody class or subclass, and to a corresponding sequence in a fragment of such antibody, insofar as they specifically bind to a target antigen and / or exhibit the desired biological activity.

[0167] The term "human antibody," as used herein, refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human. This term includes antibodies in which both the framework region and the CDR region have a variable region derived from a human sequence. Furthermore, if the antibody contains a constant region, the constant region is also such a human sequence, e.g., a human germline sequence or a variant of a human germline sequence, or e.g., Knappik, et al. ((2000) J Mol Biol. 296(1):57-86). The structure and position of the immunoglobulin variable domain, e.g., the CDR, may be defined using well-known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia and / or ImMunoGenTics (IMGT) numbering. The human antibodies of the present invention may contain amino acid residues not encoded by a human sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo, or conservative substitutions to enhance stability or production). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted onto a human framework sequence.

[0168] As used herein, the term “recombinant human antibody” means a human antibody produced, expressed, produced, or isolated by recombinant means, including antibodies isolated from transgenic or chromosomally transfected animals (e.g., mice) with respect to human immunoglobulin genes, antibodies isolated from hybridomas produced therefrom, antibodies isolated from host cells transformed to express human antibodies, for example from transfectomas, antibodies isolated from recombinant combinatorial human antibody libraries, and antibodies produced, expressed, produced, or isolated by any other means including splicing all or part of the sequence of a human immunoglobulin gene with another DNA sequence. Such recombinant human antibodies have a framework region and a CDR region that are variable regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, if transgenic animals for human Ig sequences are used), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, but which may not be naturally present in the human antibody germline repertoire in vivo.

[0169] As used herein, the term "chimeric antibody" refers to an antibody whose immunoglobulin molecule's amino acid sequence originates from two or more species. In some examples, both the heavy and light chain variable regions correspond to the variable regions of an antibody from one species having desired specificity, affinity, and activity, while the constant region is homologous to an antibody from another species (e.g., human) that minimizes the immune response in the latter species.

[0170] As used herein, the term “humanized antibody” refers to a form of antibody containing sequences derived from both non-human (e.g., mouse) and human antibodies. Such antibodies are a type of chimeric antibody containing minimal sequences derived from non-human immunoglobulins. Generally, a humanized antibody will contain substantially all of at least one, typically two, variable domains, where all or substantially all high-frequency variable loops correspond to those of a non-human immunoglobulin, and all or substantially all framework (FR) regions are from human immunoglobulin sequences. A humanized antibody will optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Humanized antibodies may be further modified by substitution of any residue in the Fv framework region and / or substituted non-human residues to refine and optimize antibody specificity, affinity, and / or activity.

[0171] The term “Fc region,” as used herein, refers to a polypeptide comprising at least a portion of the CH3, CH2, and hinge regions of the constant domain of the antibody. Optionally, the Fc region may include the CH4 domain present in some antibody classes. The Fc region may include the entire hinge region of the constant domain of the antibody. In some embodiments, the antibody or antigen-binding fragment includes the Fc region and CH1 region of the antibody. In some embodiments, the antibody or antigen-binding fragment includes the CH3 region of the Fc region of the antibody. In some embodiments, the antibody or antigen-binding fragment includes the Fc region, CH1 region, and kappa / lambda region derived from the constant domain of the antibody. In some embodiments, the antibody or antigen-binding fragment includes a constant domain, e.g., a heavy chain constant domain and / or a light chain constant domain. In some embodiments, such a constant domain is modified compared to the wild-type constant domain. That is, the polypeptide may include changes or modifications to one or more of the three heavy chain constant domains (CH1, CH2, or CH3) and / or light chain constant domain domains (CL). Examples of modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such changes may optimize effector function, half-life, etc.

[0172] When used herein in relation to antibodies or antigen-binding fragments, “internal migration” refers to an antibody or antigen-binding fragment that, upon binding to a cell, is taken up into an internal compartment, preferably into a degradable compartment within the cell, via the cellular lipid bilayer (i.e., “internal migration”). For example, an internal migration anti-EphA2 antibody is one that can be taken up into the cell after binding to EphA2 on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein is an internal migration antibody or antigen-binding fragment that targets a cell surface antigen (e.g., EphA2 or B7-H3 (CD276)) (i.e., the ADC migrates across the cell membrane after antigen binding). In some embodiments, the internal migration antibody or antigen-binding fragment binds to a receptor on the cell surface. An internal migration antibody or antigen-binding fragment that targets a receptor on the cell membrane may induce receptor-mediated endocytosis. In some embodiments, the internal migration antibody or antigen-binding fragment is taken up into the cell via receptor-mediated endocytosis.

[0173] When used herein in relation to antibodies or antigen-binding fragments, "non-transferable" refers to an antibody or antigen-binding fragment that remains on the cell surface upon binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein is an antibody or antigen-binding fragment that targets a cell surface antigen and does not transfer internally (i.e., the ADC remains on the cell surface and does not transfer across the cell membrane after antigen binding). In some embodiments, the non-transferable antibody or antigen-binding fragment binds to a receptor or other cell surface antigen that does not transfer internally. Examples of non-transferable cell surface antigens include, but are not limited to, CA125 and CEA, and antibodies that bind to non-transferable antigen targets are also known in the art (see, for example, Bast et al. (1981) J Clin Invest. 68(5):1331-7; Scholler and Urban (2007) Biomark Med. 1(4):513-23; and Boudousq et al. (2013) PLoS One 8(7):e69613).

[0174] The terms “EPH receptor A2,” “ephrin type A receptor 2,” and “EphA2” are used interchangeably herein and refer to any native form of human EphA2. This term encompasses full-length human EphA2 (e.g., NCBI reference sequence: NP_004422.2; SEQ ID NO: 1) and any form of human EphA2 that may arise from cell processing. This term includes, but is not limited to, splice variants, allele variants, and isoforms that retain one or more biological functions of human EphA2, and also encompasses functional variants or fragments of human EphA2 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). EphA2 can be isolated from humans or produced by recombinant synthesis or other synthetic methods.

[0175] The terms “anti-EphA2 antibody” or “antibody that binds to EphA2” refer, as used herein, to any form of antibody or antigen-binding fragment that binds to EphA2, for example, specifically. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, insofar as they bind to EphA2, for example, specifically. Exemplary EphA2 binding sequences, including exemplary anti-EphA2 antibody sequences, provided in International Publication No. 2007 / 030642, are incorporated herein by reference. In some embodiments, the anti-EphA2 antibodies used in the ADCs disclosed herein are internally migrated antibodies or internally migrated antigen-binding fragments. 1C1 (International Publication No. 2007 / 030642) is an example of an exemplary anti-EphA2 antibody.

[0176] The terms “B7 homology 3 protein,” “B7-H3,” and “CD276” are used interchangeably herein and refer to any native form of human B7-H3 or CD276. This term encompasses full-length human B7-H3(CD276) (e.g., NCBI reference sequence: NP_001019907.1) and any form of human B7-H3(CD276) that may arise from cell processing. This term includes, but is not limited to, splice variants, allele variants, and isoforms that retain one or more biological functions of human B7-H3(CD276), and also includes functional variants or fragments of human B7-H3(CD276) (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). B7-H3(CD276) can be isolated from humans or produced by recombinant or synthetic methods.

[0177] The terms “anti-B7-H3 antibody” or “antibody that binds to B7-H3(CD276)” refer, as used herein, to any form of antibody or antigen-binding fragment that binds to B7-H3(CD276), for example, specifically. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, insofar as they bind to B7-H3(CD276), for example, specifically. Exemplary B7-H3 binding sequences, including exemplary anti-B7-H3(CD276) antibody sequences, provided in International Publication No. 2017214322 and International Publication No. 2012147713, are incorporated herein by reference. ABBV-155 and DS-5573a are examples of exemplary anti-B7-H3(CD276) antibodies.

[0178] As used herein, the term "binding specificity" refers to the ability of an individual antibody or antigen-binding fragment to preferentially react with one antigenic determinant over different antigenic determinants. The degree of specificity indicates the extent to which the antibody or fragment preferentially binds to one antigenic determinant over different antigenic determinants. Also as used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., anti-EphA2 antibody or anti-B7-H3 antibody) and a target antigen (e.g., EphA2 or B7-H3 (CD276)) in heterogeneous populations of proteins and other biologics. An antibody may be tested for binding specificity by comparing its binding to a suitable antigen with its binding to an inappropriate antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to a suitable antigen with an affinity at least 2, 5, 7, or 10 times higher than that to an inappropriate antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is one that binds only to a target antigen (e.g., EphA2 or B7-H3 (CD276)) but does not bind to (or shows minimal binding to) other antigens. In some embodiments, the antibody or antigen-binding fragment that specifically binds to the target antigen (e.g., EphA2 or B7-H3 (CD276)) is 1 × 10⁻¹⁶ -6 Less than M, 1 x 10 -7 Less than M, 1 x 10 -8 Less than M, 1 x 10 -9 Less than M, 1 x 10 -10 Less than M, 1 x 10 -11 Less than M, 1 x 10 -12 Less than M, or 1 × 10 -13 Less than M K D It uses K D The concentration is 1 pM to 500 pM. In some embodiments, K D These ranges are 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0179] The term "affinity," as used herein, refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Without being bound by theory, within each antigenic site, the variable regions of the antibody "arm" interact with the antigen at numerous sites via weak non-covalent forces; typically, the stronger the interaction, the stronger the affinity. Antibody binding affinity is the sum of the attractive and repulsive forces acting between the antigenic determinant and the antibody binding site.

[0180] The term "k" on " or "k a This refers to the binding rate constant for the association of an antibody with an antigen to form an antibody / antigen complex. This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0181] The term "k" off " or "k d This refers to the dissociation rate constant for the dissociation of antibodies from an antibody / antigen complex. This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0182] The term “K D " refers to the equilibrium dissociation constant of a specific antibody-antigen interaction. D is, k a / k d This rate is calculated by [method / method]. This rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0183] The term "epitope" refers to a portion of an antigen that can be recognized and specifically bound to an antibody (or antigen-binding fragment). Epitope determinants generally consist of chemically active surface groups of molecules such as amino acids or carbohydrate or sugar side chains, and can have specific three-dimensional structural and charge properties. When the antigen is a polypeptide, the epitope can be formed from continuous or discontinuous amino acids juxtaposed by the three-dimensional folding of the polypeptide. Epitopes can be "linear" or "concrete." Concrete epitopes and linear epitopes are distinguished by the fact that binding to the former is lost in the presence of a denaturing solvent, while binding to the latter is not. Epitopes bound by antibodies (or antigen-binding fragments) can be identified using any epitope mapping techniques known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, and monitoring the binding of antibodies to antigen fragments or mutated variants, or monitoring the solvent accessibility of different parts of the antibody and antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, protein-limited hydrolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) BioDrugs 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev Proteomics 2:745-56).

[0184] Competitive binding and epitope binning can also be used to identify antibodies that share the same or overlapping epitopes. Competitive binding can be evaluated using cross-blocking assays, such as those described in “Antibodies, A Laboratory Manual,” Cold Spring Harbor Laboratory, Harlow and Lane (1st edition 1988, 2nd edition 2014). In some embodiments, competitive binding is identified when the test antibody or binding protein reduces the binding of a reference antibody or binding protein to a target antigen such as EphA2 or B7-H3 (CD276) (e.g., a binding protein containing a CDR and / or variable domain selected from those identified in Tables 3-5) by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or any percentage in between) and / or vice versa in a cross-blocking assay. In some embodiments, competitive binding may result from shared or similar (e.g., partially overlapping) epitopes, or from steric hindrance to the antibody or binding protein binding to a neighboring epitope (see, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66)). In some embodiments, competitive binding may be used to select groups of binding proteins that share similar epitopes. For example, binding proteins that compete for binding may be "binned" as a group of binding proteins that have overlapping or neighboring epitopes, while non-competitive ones are placed in separate groups of binding proteins that do not have overlapping or neighboring epitopes.

[0185] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably to refer to polymers of amino acid residues. This term encompasses amino acid polymers, which are artificial chemical mimics of corresponding naturally occurring amino acids, as well as amino acid polymers containing two or more amino acids linked together by peptide bonds, which are both naturally occurring and non-naturally occurring amino acid polymers. This term includes, among other things, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. This term also includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof. Unless otherwise specified, a particular polypeptide sequence implicitly includes its conservatively modified variants.

[0186] "Recombinant" proteins refer to proteins (e.g., antibodies) produced using recombination techniques, such as those involving the expression of recombinant nucleic acids.

[0187] An "isolated" protein refers to a protein that is not accompanied by at least some of the materials that normally associate with it in its native state. For example, a naturally occurring polynucleotide or polypeptide present in an organism is not isolated, but the same polynucleotide or polypeptide separated from some or all of the materials coexisting in the organism is isolated. This definition includes the production of antibodies in the wide variety of organisms and / or host cells known in the art.

[0188] "Isolated antibody," as used herein, is an antibody identified and isolated from one or more (e.g., the majority) components of its original environment, for example, the hybridoma cell culture or different cell culture used for its production. In some embodiments, the isolation is carried out to sufficiently remove components that, otherwise, might impair the suitability of the antibody for the desired application (e.g., for therapeutic use). Methods for preparing isolated antibodies are known in the Art and not limited to, but include protein A chromatography, anion exchange chromatography, cation exchange chromatography, virus-retaining filtration, and ultrafiltration.

[0189] As used herein, the term “variant” refers to a nucleic acid sequence or amino acid sequence that differs from a reference nucleic acid sequence or amino acid sequence, but retains one or more biological properties of the reference sequence. A variant may contain one or more amino acid substitutions, deletions, and / or insertions (or corresponding substitutions, deletions, and / or insertions of codons) with respect to the reference sequence. Changes in a nucleic acid variant do not necessarily alter the amino acid sequence of the peptide encoded by the reference nucleic acid sequence, but may result in amino acid substitutions, additions, deletions, fusions, and / or shortenings. In some embodiments, the nucleic acid variants disclosed herein encode either an amino acid sequence identical to that encoded by the unmodified nucleic acid or a modified amino acid sequence that retains one or more functional properties of the unmodified amino acid sequence. Changes in the sequence of a peptide variant are usually limited or conserved, and as a result, the sequences of the unmodified peptide and the variant are very similar overall and identical in many regions. In some embodiments, the peptide variant retains one or more functional properties of the unmodified peptide sequence. Variant and unmodified peptides may differ in their amino acid sequence due to one or more substitutions, additions, or deletions in any combination.

[0190] Nucleic acid or peptide variants may be naturally occurring variants or variants not known to exist naturally. Nucleic acid and peptide variants may be prepared by mutagenesis techniques, direct synthesis, or other techniques known in the art. Variants do not necessarily require physical manipulation of the reference sequence. As long as the sequence contains different nucleic acids or amino acids compared to the reference sequence, it is considered a “variant” regardless of the method of synthesis. In some embodiments, variants have high sequence identity (i.e., 60% or more nucleic acid or amino acid sequence identity) compared to the reference sequence. In some embodiments, peptide variants include polypeptides having amino acid substitutions, deletions, and / or insertions, insofar as the polypeptide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% amino acid sequence identity with the reference sequence or the corresponding segment of the reference sequence (e.g., a functional fragment), e.g., the variant also retaining one or more functions of the reference sequence. In some embodiments, the nucleic acid variant includes polynucleotides having amino acid substitutions, deletions, and / or insertions, insofar as the polynucleotide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% nucleic acid sequence identity with the reference sequence or the corresponding segment of the reference sequence (e.g., a functional fragment).

[0191] The term “conservatively modified variant” applies to both amino acid sequences and nucleic acid sequences. With respect to nucleic acid sequences, a conservatively modified variant refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Therefore, at any position where alanine is specified by the codon, the codon can be modified to any of the corresponding codons described without modifying the encoded polypeptide. Such nucleic acid variations are a type of conservatively modified variant called a “silent variation.” Any nucleic acid sequence encoding a polypeptide described herein also describes any possible silent variations of that nucleic acid. Those skilled in the art will recognize that each codon within a nucleic acid (except AUG, which is typically the codon for methionine only, and TGG, which is typically the codon for tryptophan only) can be modified to produce a functionally identical molecule. Therefore, within each sequence described, each silent variation of the nucleic acid encoding the polypeptide is implied. In polypeptide sequences, a “conservatively modified variant” includes individual substitutions, deletions, or additions to the polypeptide sequence that result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art.

[0192] The term "conservative sequence modification," as used herein, refers to an amino acid modification that does not significantly affect or alter the binding properties of an antibody or antigen-binding fragment containing an amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into antibodies or antigen-binding fragments by standard techniques known in the art, such as site-directed mutagenesis and PCR-induced mutagenesis. A conservative amino acid substitution is a substitution in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains are defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with non-charged side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), amino acids with β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, in some embodiments, one or more amino acid residues in an antibody can be replaced with other amino acid residues from the same side chain family, and the modified antibody can be tested using the functional assays described herein.

[0193] The terms “homologous” or “identical,” as used herein, refer to the identity of subunit sequences between two polymer molecules, for example, between two nucleic acid molecules, for example, between two DNA molecules or two RNA molecules or two polypeptide molecules. Two molecules are homologous or identical in that position if the positions of subunits in both are occupied by subunits of the same monomer, for example, if the positions in each of two DNA molecules are occupied by adenine. The homology between two sequences is a linear function of the number of matching or homologous positions. For example, two sequences are 50% homologous if half of the positions in two sequences (e.g., 5 positions out of 10 subunits in a polymer) are matching or homologous; two sequences are 90% homologous if 90% of the positions (e.g., 9 out of 10) are matching or homologous.

[0194] The "sequence identity" percentage can be determined by comparing two optimally aligned sequences across a comparison window, where the amino acid sequence fragments within the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to a reference sequence (without additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions where identical amino acid residues exist in both sequences, obtaining the number of matching positions, dividing that number by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the sequence identity percentage. The result is the identity percentage of the target sequence to the query sequence. The identity percentage between two sequences is a function of the number of identical positions shared by these sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap. Generally, the amino acid identity or homology between the proteins disclosed herein and their variants, including variants of target antigens (such as EphA2 or B7-H3 (CD276)) and variants of antibody variable domains (including individual variant CDRs), is at least 80%, for example, at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, nearly 100%, or 100% identity or homology with the sequences shown herein.

[0195] Sequence comparison and determination of identity percentage between two sequences can be achieved using mathematical algorithms. In some embodiments, the identity percentage between two amino acid sequences is determined using Needleman and Wunsch ((1970) J.Mol. (48):444-53) (an algorithm incorporated into the GAP program of the GCG software package, using either the Blosum62 matrix or the PAM250 matrix, and gap weightings of 16, 14, 12, 10, 8, 6, or 4 and length weightings of 1, 2, 3, 4, 5, or 6). In some embodiments, the identity percentage between two nucleotide sequences is determined using the NWSgapdna.CMP matrix and the GAP program in the GCG software package, using gap weightings of 40, 50, 60, 70, or 80 and length weightings of 1, 2, 3, 4, 5, or 6. An exemplary set of parameters is the Blosum 62 scoring matrix with a gap penalty of 12, a gap length penalty of 4, and a frameshift gap penalty of 5. The percentage of identity between two amino acid or nucleotide sequences can also be determined using the Meyers and Miller ((1989) CABIOS 4:11-17) algorithm, which is incorporated into the ALIGN program (version 2.0), using the PAM120 weighted residue table, the gap length penalty of 12, and the gap penalty of 4.

[0196] The term “agent” is used herein to mean a compound, a mixture of compounds, a biomolecule, an extract made from a biomaterial, or a combination of two or more thereof. The term “therapeutic agent” or “drug” means an agent that is capable of modulating a biological process and / or is bioactive. The panRAS inhibitors and ADCs containing them described herein are exemplary therapeutic agents.

[0197] The terms “chemotherapeutic agent” or “anticancer agent” are used herein to refer to all agents that are effective in treating cancer (regardless of their mechanism of action). Inhibition of metastasis or angiogenesis is often a characteristic of chemotherapeutic agents. Chemotherapy agents include antibodies, biomolecules, and small molecules, and include panRAS inhibitors and ADCs containing them as described herein. Chemotherapy agents may be cytotoxic agents or cell division inhibitors. The term “cell division inhibitor” refers to an agent that inhibits or suppresses cell proliferation and / or cell manipulation. The term “cytotoxic agent” refers to a substance that causes cell death, primarily by interfering with the expression activity and / or function of cells.

[0198] The terms “rat sarcoma virus (Ras)” or “panRAS,” as used herein, refer to any native form of the human Ras protein family (e.g., K-Ras (including splice mutations KRAS4A and KRAS4B), H-Ras, and N-Ras). This term encompasses full-length human K-Ras (Kristen rat sarcoma virus) (e.g., UniProt reference sequence: P01116; SEQ ID NO: 64), H-Ras (Harvey rat sarcoma virus) (e.g., UniProt reference sequence: P01112; SEQ ID NO: 65), N-Ras (neuroblastoma rat sarcoma virus) (e.g., UniProt reference sequence: P01111; SEQ ID NO: 66), and any form of human Ras that may arise from cell processing. This term includes, but is not limited to, splice variants, allele variants, and isoforms of the human Ras protein that retain one or more biological functions, and also includes functional variants or fragments of the human Ras protein (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). The Ras protein can be isolated from humans or produced by recombinant or synthetic means. Exemplary Ras protein amino acid sequences are listed in Table C below.

[0199] [Table 13]

[0200] The terms “inhibit,” “inhibit,” or “to inhibit,” as used herein, mean to reduce biological activity or process by a measurable amount, and may include, but do not require, complete interference or inhibition. In some embodiments, “inhibit” means reducing the expression and / or activity of panRAS and / or one or more upstream modulators or downstream targets thereof.

[0201] The term “panRAS inhibitor,” as used herein, refers to a drug capable of reducing the expression and / or activity of panRAS (e.g., K-Ras (including splice mutations KRAS4A and KRAS4B), H-Ras, and N-Ras) and / or one or more upstream modulators or downstream targets thereof. Exemplary panRAS modulators (including exemplary inhibitors of panRAS) are described in International Publication No. 2021 / 091956 or International Publication No. 2022 / 060836 as exemplary panRAS modulators, which may be included as drug portions in the disclosed ADCs, and are incorporated herein by reference, respectively.

[0202] As used herein, "panRAS inhibitor drug moiety," "panRAS inhibitor," etc., refer to a panRAS inhibitor compound or a component of a composition that provides a structure for binding to an ADC that essentially retains the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, the panRAS inhibitor drug moiety is component (D) in the ADC of formula (1).

[0203] As used herein, the term “cancer” refers to the presence of cellular processing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic ability, rapid growth and growth rate, and / or specific morphological features. While cancer cells often exist in the form of tumors or masses, such cells may exist alone within a subject or circulate in the bloodstream as independent cells, such as leukemia or lymphoma cells. The term “cancer” encompasses all types of cancer and cancer metastases, including hematological cancers, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Hematological cancers may include B-cell malignancies, cancers of the blood (leukemia), plasma cell cancers (myeloma, e.g., multiple myeloma), or cancers of the lymph nodes (lymphoma). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemia may include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL). The terms "acute lymphoblastic leukemia" and "acute lymphoblastic leukemia" may be used interchangeably to describe ALL. Lymphoma may include Hodgkin lymphoma, non-Hodgkin lymphoma, and others. Other hematological cancers may include myelodysplastic syndromes (MDS). Solid tumors may include cancers such as adenocarcinoma, breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumors of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0204] As used herein, the term “tumor” refers to any mass of tissue resulting from excessive cell proliferation or growth, whether benign or malignant, including precancerous lesions. In some embodiments, tumors are breast cancer, including ER-positive breast cancer; multiple myeloma; plasmacytic myeloma; leukemia; lymphoma; sarcoma; gastric or stomach cancer; acute myeloid leukemia; bladder cancer; brain tumor; bone marrow cancer; cervical cancer; chronic lymphocytic leukemia; colorectal cancer; pancreatic cancer; esophageal cancer; hepatocellular carcinoma; lymphoblastic leukemia, including acute lymphoblastic leukemia; follicular lymphoma; lymphoid tumor of T-cell or B-cell origin; metastatic castration-resistant prostate cancer; urothelial carcinoma of the bladder; melanoma; myeloid leukemia; myeloma; oral cancer; ovarian cancer; non-small cell lung cancer; prostate cancer; small cell lung cancer; splenic cancer; or head and neck cancer.

[0205] The terms “tumor cells” and “cancer cells” may be used interchangeably herein and refer to individual cells or an entire population of cells derived from a tumor or cancer, including both non-tumorogenic cells and cancer stem cells. The terms “tumor cells” and “cancer cells” would be modified by the term “non-tumorogenic” if they refer only to those cells that lack the ability to regenerate and differentiate in order to distinguish them from those cells derived from cancer stem cells.

[0206] The terms “target-negative,” “target antigen-negative,” or “antigen-negative,” as used herein, refer to the absence of target antigen expression by cells or tissues. The terms “target-positive,” “target antigen-positive,” or “antigen-positive,” refer to the presence of target antigen expression. For example, cells or cell lines that do not express a target antigen may be described as target-negative, while cells or cell lines that express a target antigen may be described as target-positive.

[0207] The terms “subject” and “patient” are used interchangeably herein to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is human.

[0208] As used herein, the term “subjects requiring treatment” refers to subjects who would benefit biologically, medically, or in terms of quality of life from treatment (for example, treatment with one or more of the exemplary ADC compounds described herein).

[0209] As used herein, the terms “to treat,” “to treat,” or “treatment” mean any improvement of any outcome of a disease, disorder, or condition, such as an extension of survival, a reduction in morbidity, and / or a reduction in side effects resulting from an alternative treatment modality. In some embodiments, treatment includes delaying or relieving a disease, disorder, or condition (i.e., delaying, stopping, or reducing the onset of at least one of the disease or its clinical symptoms). In some embodiments, treatment includes delaying, mitigating, or relieving at least one physical parameter of a disease, disorder, or condition, including those that may not be identifiable by the patient. In some embodiments, treatment includes modulating a disease, disorder, or condition either or both physically (e.g., stabilization of identifiable symptoms) and / or physiologically (e.g., stabilization of physical parameters). In some embodiments, treatment includes administering the described ADC compound or composition to a subject, e.g., a patient, in order to obtain the therapeutic benefits enumerated herein. Treatment may cure, alleviate, delay, prevent, mitigate, alter, correct, remission, reduce, improve, or influence a disease, disorder or condition (e.g., cancer), its symptoms, or a predisposition to the disease, disorder or condition (e.g., cancer). In some embodiments, in addition to treating subjects having a disease, disorder or condition, the compositions disclosed herein may also be provided prophylactically to prevent or reduce the likelihood of developing such disease, disorder or condition.

[0210] As used herein, the terms “prevent,” “prevent,” or “prevention” relating to any disease, disorder, or condition mean preventive measures for the disease, disorder, or condition; or delaying the onset or progression of the disease, disorder, or condition.

[0211] As used herein, “pharmaceutical composition” refers to a composition, e.g., an ADC compound or a formulation of a composition, in addition to at least one other (and optionally two or more other) components suitable for administration to a subject, such as a pharmaceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical compositions provided herein exist in a form that enables administration and subsequently provides the intended biological activity of the active ingredient and / or achieves a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that are unacceptably toxic to the subject to which the formulation will be administered.

[0212] As used herein, the terms “pharmaceutically acceptable carrier” and “physiologically acceptable carrier,” which may be used interchangeably, refer to carriers or diluents that do not cause significant irritation to the subject and do not inhibit the biological activity and properties of the administered ADC compound or composition and / or any additional therapeutic agent in the composition. A pharmaceutically acceptable carrier may be used to enhance or stabilize a composition, or to facilitate the preparation of the composition. A pharmaceutically acceptable carrier may include, as is well known to those skilled in the art, solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption retarders, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, colorants, etc., and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed., Mack Printing Company, 1990, pp. 1289–1329). Unless any conventional carrier is unsuitable for the active ingredient, its use in therapeutic or pharmaceutical compositions is intended. The carrier may be selected to minimize adverse side effects and / or degradation of the active ingredient in the subject. Adjuvants may also be included in any of these formulations.

[0213] As used herein, the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the active ingredient. Formulations for parenteral administration may contain excipients such as sterile water or saline solution, polyalkylene glycols such as polyethylene glycol, vegetable oils, or naphthalene hydrogenation. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, such as polysorbate 20.

[0214] The term "pharmaceutically acceptable salt," as used herein, refers to a salt that does not impair the biological activity and properties of the compounds of the present invention 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) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine. For example, see Haynes et al., “Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database,” J. Pharmaceutical Sciences, vol. 94, no. 10 (2005), and Berge et al., “Pharmaceutical Salts,” J. Pharmaceutical Sciences, vol. 66, no. 1 (1977), which are incorporated herein by reference.

[0215] In some embodiments, depending on their charge, the antibody-drug conjugate (ADC), conjugate linker, payload, and linker-payload described herein are monovalent anionic counterions M1 - It may contain any suitable anionic counterion. In certain embodiments, the monovalent anionic counterion is a pharmaceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M1 - This can be selected from bromides, chlorides, iodides, acetates, trifluoroacetates, benzoates, mesylates, tosylates, triflates, formates, and the like. In some embodiments, a monovalent anionic counterion M1 - It is a trifluoroacetate or formate salt.

[0216] As used herein, the term “therapeutic dose” refers to the amount of a compound, e.g., an ADC compound or composition described herein, that produces a desired therapeutic outcome (i.e., reduction or inhibition of enzyme or protein activity, improvement of symptoms, alleviation of symptoms or conditions, delay of disease progression, reduction of tumor size, inhibition of tumor growth, or prevention of metastasis). In some embodiments, the therapeutic dose does not induce or cause any undesirable side effects. In some embodiments, the therapeutic dose induces or causes side effects, but is only an amount acceptable to the clinician treating the patient in light of their condition. In some embodiments, the therapeutic dose is effective in terms of detectable death, reduction and / or inhibition of cancer cell proliferation or spread, tumor size or number, and / or other measures of cancer level, stage, progression, and / or severity. The term also applies to doses that will induce a specific response in target cells, e.g., reduction, slowing, or inhibition of cell proliferation. The therapeutic dose can be determined by administering a low dose first, and then gradually increasing the dose until the desired effect is achieved. The therapeutically effective dose may also vary depending on the intended application (in vitro or in vivo), which can be readily determined by those skilled in the art, or on the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, and the mode of administration. The specific dose may vary, for example, on the specific pharmaceutical composition, the subject and their age and pre-existing health condition or risks related to their health condition, the subsequent administration regimen, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system through which it is carried. In the case of cancer, a therapeutically effective dose of ADC may reduce the number of cancer cells, shrink tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0217] As used herein, the term “preventive effective dose” refers to the amount of a compound disclosed herein, e.g., an ADC compound or composition described herein, that is effective in the dosage and duration required to achieve the desired preventive outcome. Typically, a preventive dose is less than a therapeutic effective dose, as preventive doses are used in a subject before or early in the course of the disease. In some embodiments, a preventive effective dose can prevent the onset of disease symptoms, including those associated with cancer.

[0218] The term "p," "drug load," "drug:antibody ratio," "drug-to-antibody ratio," or "DAR" refers to the number of -LD portions per antibody or antigen-binding fragment, i.e., the drug load, or the number of drug portions per antibody or antigen-binding fragment (Ab) in the ADC of formula (1). In an ADC containing a panRAS inhibitor drug portion, "p" refers to the number of panRAS inhibitor compounds linked to the antibody or antigen-binding fragment. For example, if two panRAS inhibitor compounds are linked to the antibody or antigen-binding fragment, p=2. In a composition containing multiple copies of the ADC of formula (1), "average p" refers to the average number of -LD portions per antibody or antigen-binding fragment, also called the "average drug load."

[0219] Antibody-drug conjugates The antibody-drug conjugate (ADC) compounds disclosed herein include those having anticancer activity. In particular, the ADC compounds comprise an antibody or antigen-binding fragment conjugated (i.e., covalently linked by a conjugate linker) to a drug moiety (e.g., a panRAS inhibitor), and the drug moiety, when not conjugated to the antibody or antigen-binding fragment, has cytotoxic or cell division inhibitory effects. In some embodiments, the drug moiety, when not conjugated to the antibody or antigen-binding fragment, can reduce the expression and / or activity of panRAS and / or one or more upstream modulators or downstream targets. By targeting panRAS expression and / or activity without being constrained by theory, in some embodiments, the ADCs disclosed herein may provide potent anticancer agents. Also, without being constrained by theory, by conjugating the drug moiety to an antibody that binds to an antigen associated with expression in tumor cells or cancer, the ADC may provide improved activity, good cytotoxic specificity, and / or reduced off-target death compared to the drug moiety administered alone.

[0220] Accordingly, in some embodiments, the components of the ADC are selected to (i) retain one or more therapeutic properties exhibited by the antibody and drug moieties in isolation; (ii) maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) optimize drug load and drug-to-antibody ratio; (iv) enable delivery of the drug moiety, e.g., intracellular delivery, via suitable binding to the antibody or antigen-binding fragment; (v) maintain ADC stability as an intact conjugate until transport or delivery to the target site; (vi) minimize aggregation of the ADC before or after administration; (vii) enable the therapeutic effect of the drug moiety, e.g., cytotoxic effect, after cleavage or other release mechanism in the cellular environment; (viii) exhibit in vivo anticancer therapeutic efficacy equivalent to or better than that of the antibody and drug moieties in isolation; (ix) minimize off-target cell death by the drug moiety; and / or (x) exhibit desirable pharmacokinetic and pharmacokinetic properties, formulation suitability, and toxicological / immunological profile. Each of these characteristics may provide an improved ADC for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0221] The ADC compounds of this disclosure can selectively deliver effective doses of cytotoxic agents or cell division inhibitors to cancer cells or tumor tissue. In some embodiments, the cytotoxic and / or cell division inhibitory activity of the ADCs depends on the expression of the target antigen in the cells. In some embodiments, the disclosed ADCs are particularly effective in killing cancer cells expressing the target antigen while minimizing off-target death. In some embodiments, the disclosed ADCs do not exhibit cytotoxic and / or cell division inhibitory effects on cancer cells that do not express the target antigen.

[0222] In certain embodiments, ADC compounds are provided herein that comprise an antibody or an antigen-binding fragment thereof (Ab), a panRAS inhibitor drug moiety (D), and a conjugate linker moiety (L) covalently binding Ab to D. In some embodiments herein, ADC compounds are provided that comprise an antibody or an antigen-binding fragment thereof (Ab), a panRAS inhibitor drug moiety (D), and a conjugate linker moiety (L) covalently binding Ab to D, targeting cancer cells. In some embodiments, the antibody or antigen-binding fragment can bind to a tumor-associated antigen (e.g., EphA2 or B7-H3 (CD276)) with, for example, high specificity and high affinity. In some embodiments, the antibody or antigen-binding fragment is internally transported into the target cell upon binding, for example, into a degradable compartment within the cell. In some embodiments, the ADC internally transports to the target cell upon binding, undergoes degradation, and releases the panRAS inhibitor drug moiety to kill the cancer cells. The panRAS inhibitor drug moiety may be released from the antibody and / or conjugate linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0223] An example ADC is given by equation (1): Ab-(LD) p (1) It is represented as follows, where Ab = antibody or antigen-binding fragment, L = conjugate linker portion, D = panRAS inhibitor drug portion, and p = number of panRAS inhibitor drug portions per antibody or antigen-binding fragment.

[0224] antibody The antibody or antigen-binding fragment (Ab) of formula (1) includes, within its range, any antibody or antigen-binding fragment that specifically binds to a target antigen on a cell. 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, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2 (NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142 (F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA These include hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3. In some embodiments, the antibody or antigen-binding fragment (Ab) of formula (1) includes, within its range, any antibody or antigen-binding fragment that specifically binds to a target antigen on cancer cells. In some embodiments, the cells or cancer cells express EphA2. In some embodiments, the target antigen EphA2 has the amino acid sequence listed in Table 6.

[0225] In some embodiments, the target antigen B7-H3 (CD276) has the amino acid sequence shown in Table 6.

[0226] The antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) has a dissociation constant (K) of ≤1 mM, ≤100 nM, or ≤10 nM, or any amount in between, as measured by BIAcore® analysis, for example. D ) can bind to the target antigen. In some embodiments, K D The concentration is 1 pM to 500 pM. In some embodiments, K D These ranges are 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0227] In some embodiments, the antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) is a tetrachain antibody (also referred to as immunoglobulin or full-length or intact antibody) comprising two heavy chains and two light chains. In some embodiments, the antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) is an antigen-binding fragment of an immunoglobulin. In some embodiments, the antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) is an antigen-binding fragment of an immunoglobulin that binds to a target cancer antigen and / or retains the ability to provide at least one function of the immunoglobulin.

[0228] In some embodiments, the antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) is an internally translocating antibody or its internally translocating antigen-binding fragment. In some embodiments, the internally translocating antibody (e.g., anti-EphA2 or anti-B7-H3 antibody) or its internally translocating antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antigen-binding fragment) is expressed on the surface of cells and binds to a target cancer antigen that enters the cell upon binding. In some embodiments, the panRAS inhibitor drug portion of the ADC is released from the antibody or antigen-binding fragment (e.g., anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) of the ADC after the ADC has entered the cell and is present in cells expressing the target cancer antigen (i.e., after the ADC has been internally translocated), for example by cleavage, degradation of the antibody or antigen-binding fragment, or any other suitable release mechanism.

[0229] In some embodiments, the antibody (e.g., anti-EphA2 antibody or anti-B7-H3 antibody) contains mutations that mediate or do not mediate reduced antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cell-mediated cytotoxicity (CDC). In some embodiments, these mutations are known as Fc-silencing, Fc-silent, or Fc-silencing mutations. In some embodiments, amino acid residues L234 and L235 in the constant region of IgG1 are replaced with A234 and A235 (also known as "LALA"). In some embodiments, amino acid residue N297 in the constant region of IgG1 is replaced with A297 (also known as "N297A"). In some embodiments, amino acid residues D265 and P329 in the constant region of IgG1 are replaced with A265 and A329 (also known as "DAPA"). Other antibody Fc-silencing mutations may also be used. In some embodiments, Fc silencing mutations are used in combination (e.g., D265A, N297A, and P329A, also known as "DANAPA").

[0230] In addition to exemplary antigen targets, the amino acid sequences of the exemplary antibodies of this disclosure are shown in Tables 2-6.

[0231] [Table 14]

[0232] [Table 15]

[0233] [Table 16]

[0234] [Table 17]

[0235] [Table 18]

[0236] [Table 19]

[0237] [Table 20]

[0238] [Table 21]

[0239] [Table 22]

[0240] [Table 23]

[0241] In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein may comprise any set of heavy and light chain variable domains listed in the table above or a set of six CDRs derived from any set of heavy and light chain variable domains listed in the table above. In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein may comprise the ADC having the ability to bind to its target cancer antigen (e.g., 1 × 10⁻⁶). -8 Less than M K D Insofar as it retains one or more functional properties of the ADCs disclosed herein (e.g., the ability to move internally, an antigen target, such as the ability to bind to an antigen expressed on a tumor or other cancer cell), it may include conservatively modified and / or amino acid sequences homologous to those listed in the table above.

[0242] In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein further comprises human heavy and light chain constant domains or fragments thereof. For example, the antibody or antigen-binding fragment of the ADC described may comprise a human IgG heavy chain constant domain (such as IgG1) and a human kappa or lambda light chain constant domain. In some embodiments, the antibody or antigen-binding fragment of the ADC described comprises a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain along with a human Ig kappa light chain constant domain.

[0243] In some embodiments, the target cancer antigen for ADC is EphA2.

[0244] In some embodiments, the anti-EphA2 antibody or antigen-binding fragment of the ADC disclosed herein further comprises human heavy and light chain constant domains or fragments thereof. For example, the described anti-EphA2 antibody or antigen-binding fragment of the ADC may comprise a human IgG heavy chain constant domain (such as IgG1) and a human kappa or lambda light chain constant domain. In some embodiments, the described anti-EphA2 antibody or antigen-binding fragment of the ADC comprises a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain along with a human Ig kappa light chain constant domain.

[0245] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 17, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 18, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 26, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 28.

[0246] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 20, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 21, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 29, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 30, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31.

[0247] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 22, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 23, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 24; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 32, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31.

[0248] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 25, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 21, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 29, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 30, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31.

[0249] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 17), HCDR2 (SEQ ID NO: 18), HCDR3 (SEQ ID NO: 19); LCDR1 (SEQ ID NO: 26), LCDR2 (SEQ ID NO: 27), and LCDR3 (SEQ ID NO: 28).

[0250] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 20), HCDR2 (SEQ ID NO: 21), HCDR3 (SEQ ID NO: 19); LCDR1 (SEQ ID NO: 29), LCDR2 (SEQ ID NO: 30), and LCDR3 (SEQ ID NO: 31).

[0251] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 22), HCDR2 (SEQ ID NO: 23), HCDR3 (SEQ ID NO: 24); LCDR1 (SEQ ID NO: 32), LCDR2 (SEQ ID NO: 27), and LCDR3 (SEQ ID NO: 31).

[0252] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 25), HCDR2 (SEQ ID NO: 21), HCDR3 (SEQ ID NO: 19); LCDR1 (SEQ ID NO: 29), LCDR2 (SEQ ID NO: 30), and LCDR3 (SEQ ID NO: 31).

[0253] In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment includes the heavy chain variable region amino acid sequence of SEQ ID NO: 11 and the light chain variable region amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment includes a light chain variable sequence that is at least 95% identical to the heavy chain variable region amino acid sequence of SEQ ID NO: 11 and the light chain variable region amino acid sequence of SEQ ID NO: 12, or a sequence that is at least 95% identical to the disclosed sequence. In some embodiments, the anti-EphA2 antibody or its antigen-binding fragment has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 11 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 12.

[0254] In some embodiments, the anti-EphA2 antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 3 or a sequence identical to SEQ ID NO: 3 by at least 95%, and the light-chain amino acid sequence of SEQ ID NO: 5 or a sequence identical to SEQ ID NO: 5 by at least 95%. In some embodiments, the anti-EphA2 antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 3 and the light-chain amino acid sequence of SEQ ID NO: 5 or a sequence identical to the disclosed sequence by at least 95%. In some embodiments, the anti-EphA2 antibody has a heavy-chain amino acid sequence that is identical to SEQ ID NO: 3 by at least 96%, at least 97%, at least 98%, or at least 99%, and a light-chain amino acid sequence that is identical to SEQ ID NO: 5 by at least 96%, at least 97%, at least 98%, or at least 99%.

[0255] In some embodiments, the target cancer antigen for ADC is B7-H3(CD276).

[0256] In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment of the ADC disclosed herein further comprises human heavy and light chain constant domains or fragments thereof. For example, the described anti-B7-H3 (CD276) antibody or antigen-binding fragment of the ADC may comprise a human IgG heavy chain constant domain (such as IgG1) and a human kappa or lambda light chain constant domain. In some embodiments, the described anti-B7-H3 (CD276) antibody or antigen-binding fragment of the ADC comprises a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain along with a human Ig kappa light chain constant domain.

[0257] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 33, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 34, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 42, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44.

[0258] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 36, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 37, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 45, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 46, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47.

[0259] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 38, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 39, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 40; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 48, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47.

[0260] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 41, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 37, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 45, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 46, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47.

[0261] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35); LCDR1 (SEQ ID NO: 42), LCDR2 (SEQ ID NO: 43), and LCDR3 (SEQ ID NO: 44) with 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions.

[0262] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 36), HCDR2 (SEQ ID NO: 37), HCDR3 (SEQ ID NO: 35); LCDR1 (SEQ ID NO: 45), LCDR2 (SEQ ID NO: 46), and LCDR3 (SEQ ID NO: 47).

[0263] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 38), HCDR2 (SEQ ID NO: 39), HCDR3 (SEQ ID NO: 40); LCDR1 (SEQ ID NO: 48), LCDR2 (SEQ ID NO: 43), and LCDR3 (SEQ ID NO: 47).

[0264] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 41), HCDR2 (SEQ ID NO: 37), HCDR3 (SEQ ID NO: 35); LCDR1 (SEQ ID NO: 45), LCDR2 (SEQ ID NO: 46), and LCDR3 (SEQ ID NO: 47).

[0265] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 49, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 50, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 58, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 59, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 60.

[0266] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 52, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 53, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 61, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 62, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63.

[0267] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 54, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 55, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 56; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 58, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 59, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63.

[0268] In some embodiments, the anti-B7-H3 (CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 57, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 53, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 61, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 62, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63.

[0269] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 49), HCDR2 (SEQ ID NO: 50), HCDR3 (SEQ ID NO: 51); LCDR1 (SEQ ID NO: 58), LCDR2 (SEQ ID NO: 59), and LCDR3 (SEQ ID NO: 60).

[0270] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 52), HCDR2 (SEQ ID NO: 53), HCDR3 (SEQ ID NO: 51); LCDR1 (SEQ ID NO: 61), LCDR2 (SEQ ID NO: 62), and LCDR3 (SEQ ID NO: 63).

[0271] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 54), HCDR2 (SEQ ID NO: 55), HCDR3 (SEQ ID NO: 56); LCDR1 (SEQ ID NO: 58), LCDR2 (SEQ ID NO: 59), and LCDR3 (SEQ ID NO: 63).

[0272] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, or the CDRs comprise 1, 2, 3, 4, 5, or 6 or fewer amino acid additions, deletions, or substitutions of HCDR1 (SEQ ID NO: 57), HCDR2 (SEQ ID NO: 53), HCDR3 (SEQ ID NO: 51); LCDR1 (SEQ ID NO: 61), LCDR2 (SEQ ID NO: 62), and LCDR3 (SEQ ID NO: 63).

[0273] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment includes a light chain variable region containing the heavy chain variable region amino acid sequence of SEQ ID NO: 13 and the light chain variable region amino acid sequence of SEQ ID NO: 14, or a sequence that is at least 95% identical to the disclosed sequence. In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 13 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 14.

[0274] In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 15 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment includes a light chain variable region containing the heavy chain variable region amino acid sequence of SEQ ID NO: 15 and the light chain variable region amino acid sequence of SEQ ID NO: 16, or a sequence that is at least 95% identical to the disclosed sequence. In some embodiments, the anti-B7-H3(CD276) antibody or its antigen-binding fragment has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 15 and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 16.

[0275] In some embodiments, the anti-B7-H3(CD276) antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 7 or a sequence identical to SEQ ID NO: 7 by at least 95%, and the light-chain amino acid sequence of SEQ ID NO: 8 or a sequence identical to SEQ ID NO: 8 by at least 95%. In some embodiments, the anti-B7-H3(CD276) antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 7 and the light-chain amino acid sequence of SEQ ID NO: 8 or a sequence identical to the disclosed sequence by at least 95%. In some embodiments, the anti-B7-H3(CD276) antibody has a heavy-chain amino acid sequence that is identical to SEQ ID NO: 7 by at least 96%, at least 97%, at least 98%, or at least 99%, and a light-chain amino acid sequence that is identical to SEQ ID NO: 8 by at least 96%, at least 97%, at least 98%, or at least 99%.

[0276] In some embodiments, the anti-B7-H3(CD276) antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 9 or a sequence identical to SEQ ID NO: 9 by at least 95%, and the light-chain amino acid sequence of SEQ ID NO: 10 or a sequence identical to SEQ ID NO: 10 by at least 95%. In some embodiments, the anti-B7-H3(CD276) antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 9 and the light-chain amino acid sequence of SEQ ID NO: 10 or a sequence identical to the disclosed sequence by at least 95%. In some embodiments, the anti-B7-H3(CD276) antibody has a heavy-chain amino acid sequence that is identical to SEQ ID NO: 9 by at least 96%, at least 97%, at least 98%, or at least 99%, and a light-chain amino acid sequence that is identical to SEQ ID NO: 10 by at least 96%, at least 97%, at least 98%, or at least 99%.

[0277] Residues in two or more polypeptides are said to "correspond" if they occupy similar positions in the polypeptide structure. Similar positions in two or more polypeptides can be determined by aligning polypeptide sequences based on amino acid sequence or structural similarity. Those skilled in the art understand that it may be necessary to introduce gaps in either sequence to produce a satisfactory alignment.

[0278] In some embodiments, amino acid substitutions are of a single residue. Insertions are typically of the magnitude of about 1 to 20 amino acid residues, but considerably larger insertions may be acceptable as long as biological function is preserved (e.g., binding to the target antigen). Deletions are typically in the range of about 1 to 20 amino acid residues, but in some cases deletions can be much larger. Substitutions, deletions, insertions, or any combination thereof may be used to arrive at the final derivative or variant. Generally, these changes are made to a small number of amino acids to minimize molecular changes, particularly changes in the immunogenicity and specificity of the antigen-binding protein. However, larger changes may be acceptable in certain circumstances. Conservative substitutions can be made according to the following diagrams, shown as Table 7.

[0279] [Table 24]

[0280] In some embodiments, when a variant antibody sequence is used in an ADC, the variant will typically exhibit the same qualitative biological activity and induce the same immune response. However, the variant may also be selected to modify the characteristics of the antigen-binding protein as needed. Alternatively, the variant may be designed to alter the biological activity of the antigen-binding protein. For example, glycosylation sites may be modified or removed.

[0281] Various antibodies can be used with the ADCs used herein against target cancer cells. As shown below, the linker-payloads in the ADCs disclosed herein are remarkably effective against different tumor antigen-targeted antibodies. Suitable antigens that are expressed on cancer cells but not on healthy cells, or expressed on cancer cells at higher levels than healthy cells, are known in the art as well as antibodies directed against them. Further antibodies against these antigen targets can be prepared by those skilled in the art. These antibodies can be used with the conjugate linkers and panRAS inhibitor payloads disclosed herein. In some embodiments, the antibody or antigen-binding fragment target EphA2 or B7-H3 (CD276) provided particularly improved drug-to-antibody ratio, aggregation levels, stability (i.e., in vitro and in vivo stability), tumor targeting (i.e., cytotoxicity, titer), minimized off-target killing, and / or therapeutic efficacy. Improved therapeutic efficacy can be measured in vitro or in vivo and may include a reduction in tumor growth rate and / or tumor volume.

[0282] In some embodiments, alternative antibodies against the same target or antibodies against different antigen targets are used to provide at least some of the above-mentioned desirable functional properties (e.g., improved stability, improved tumor targeting, improved therapeutic efficacy, etc.). In some embodiments, some or all of these desirable functional properties are observed when the disclosed conjugate linker and panRAS inhibitor payload are conjugated to an alternative EphA2 or B7-H3 (CD276) targeted antibody or antigen-binding fragment. In some other embodiments, some or all of these desirable functional properties are observed when the disclosed conjugate linker and panRAS inhibitor payload are conjugated to an EphA2 targeted antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets EphA2. In other embodiments, some or all of these desirable functional properties are observed when the disclosed conjugate linker and panRAS inhibitor payload are conjugated to a B7-H3 (CD276) targeted antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment targets B7-H3(CD276).

[0283] Conjugate Linker In some embodiments, the conjugate linker in the ADC is stable extracellularly in a manner sufficient to be therapeutically effective. In some embodiments, the conjugate linker is stable extracellularly so that the ADC remains intact when present under extracellular conditions (e.g., before transport or delivery into cells). As used in the context of ADCs, the term "intact" means that the antibody or antigen-binding fragment remains bound to the drug moiety (e.g., a panRAS inhibitor).

[0284] As used herein, “stable” in the context of a conjugate linker or an ADC containing a conjugate linker means that 20% or less, about 15% or less, about 10% or less, about 5% or less, about 3% or less, or about 1% or less (or any percentage in between) of the conjugate linker in a sample of the ADC is cleaved when the ADC is present under extracellular conditions (or otherwise not intact in the case of the entire ADC). In some embodiments, the conjugate linkers and / or ADCs disclosed herein are more stable than alternative conjugate linkers and / or ADCs having alternative conjugate linkers and / or panRAS inhibitor payloads. In some embodiments, the ADCs disclosed herein may remain intact for more than about 48 hours, more than 60 hours, more than about 72 hours, more than about 84 hours, or more than about 96 hours.

[0285] Whether a conjugate linker is stable outside the cell can be determined, for example, by exposing the ADC to plasma for a predetermined period (e.g., 2, 4, 6, 8, 16, 24, 48, or 72 hours) and subsequently quantifying the amount of free drug portion present in the plasma. Stability may give the ADC time to localize to target cancer cells and prevent premature release of the drug portion, which could reduce the therapeutic index of the ADC by indiscriminately damaging both normal and cancerous tissue. In some embodiments, the conjugate linker is stable outside the target cell and, upon entering the cell, releases the drug portion from the ADC, allowing the drug to bind to its target. Therefore, an effective conjugate linker (i) maintains the specific binding properties of the antibody or antigen-binding fragment; (ii) enables the delivery of the drug moiety, e.g., intracellular delivery, via stable binding to the antibody or antigen-binding fragment; (iii) remains stable and intact until the ADC is transported to or delivered to its target site; and (iv) enables the therapeutic effect of the drug moiety, e.g., cytotoxic effect, after cleavage or alternative release mechanism.

[0286] Conjugate linkers can affect the physicochemical properties of ADCs. Since many cytotoxic agents are naturally hydrophobic, linking them to antibodies with additional hydrophobic moieties can lead to aggregation. ADC aggregates are insoluble and often limit the achievable drug load on the antibody, which can negatively impact the potency of the ADC. Protein aggregates in biologics are also generally associated with increased immunogenicity. As shown below, the conjugate linkers disclosed herein result in ADCs with low aggregation levels and desirable levels of drug load.

[0287] Conjugate linkers can be either "cleavable" or "incleavable" (Ducry and Stump (2010) Bioconjugate Chem. 21:5-13). Cleavable conjugate linkers are designed to release a drug moiety (e.g., a panRAS inhibitor) when exposed to certain environmental factors, for example, when internalized into target cells, while incleavable conjugate linkers generally rely on the degradation of the antibody or antigen-binding fragment itself.

[0288] As used herein, the term "alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing no unsaturation. As used herein, the term "C1-C6 alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation, having 1 to 6 carbon atoms, and bonded to the remainder of the molecule by single bonds. Non-limiting examples of "C1-C6 alkyl" groups include methyl (C1 alkyl), ethyl (C2 alkyl), 1-methylethyl (C3 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), n-butyl (C4 alkyl), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), n-pentyl (C5 alkyl), isopentyl (C5 alkyl), neopentyl (C5 alkyl), and hexyl (C6 alkyl).

[0289] As used herein, the term “alkenyl” refers to a radical group of a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms and containing at least one double bond. As used herein, the term “C2-C6 alkenyl” refers to a radical group of a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms and containing at least one double bond having 2 to 6 carbon atoms and being bonded to the remainder of the molecule by single bonds. Non-restrictive examples of the "C2-C6 alkenyl" group include ethenyl (C2 alkenyl), propa-1-enyl (C3 alkenyl), buta-1-enyl (C4 alkenyl), penta-1-enyl (C5 alkenyl), penta-4-enyl (C5 alkenyl), penta-1,4-dienyl (C5 alkenyl), hexa-1-enyl (C6 alkenyl), hexa-2-enyl (C6 alkenyl), hexa-3-enyl (C6 alkenyl), hexa-1,4-dienyl (C6 alkenyl), hexa-1,5-dienyl (C6 alkenyl), and hexa-2,4-dienyl (C6 alkenyl). As used herein, the term "C2-C3 alkenyl" refers to a radical group of a linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, containing at least one double bond and having 2-3 carbon atoms, with the remainder of the molecule bonded by a single bond. Non-limiting examples of "C2-C3 alkenyl" groups include ethenyl (C2 alkenyl) and propa-1-enyl (C3 alkenyl).

[0290] As used herein, the term "alkylene" refers to a divalent linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing no unsaturation. As used herein, the term "C1-C6 alkylene" refers to a divalent linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing no unsaturation, and having 1 to 6 carbon atoms. Non-limiting examples of the "C1-C6 alkylene" group include methylene (C1 alkylene), ethylene (C2 alkylene), 1-methylethylene (C3 alkylene), n-propylene (C3 alkylene), isopropylene (C3 alkylene), n-butylene (C4 alkylene), isobutylene (C4 alkylene), sec-butylene (C4 alkylene), tert-butylene (C4 alkylene), n-pentylene (C5 alkylene), isopentylene (C5 alkylene), neopentylene (C5 alkylene), and hexylene (C6 alkylene).

[0291] As used herein, the term "alkenylene" refers to a divalent linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing at least one double bond. As used herein, the term "C2-C6 alkenylene" refers to a divalent linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one double bond and having 2 to 6 carbon atoms. Non-limiting examples of the "C2-C6 alkenylene" group include etenylene (C2 alkenylene), propa-1-enylene (C3 alkenylene), buta-1-enylene (C4 alkenylene), penta-1-enylene (C5 alkenylene), penta-4-enylene (C5 alkenylene), penta-1,4-dienylene (C5 alkenylene), hexa-1-enylene (C6 alkenylene), hexa-2-enylene (C6 alkenylene), hexa-3-enylene (C6 alkenylene), hexa-1,4-dienylene (C6 alkenylene), hexa-1,5-dienylene (C6 alkenylene), and hexa-2,4-dienylene (C6 alkenylene). As used herein, the term "C2-C6 alkenylene" refers to a radical group of a divalent linear or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, containing at least one double bond, and having 2-3 carbon atoms. Non-limiting examples of "C2-C3 alkenylene" groups include ethenylene (C2 alkenylene) and propa-1-enylene (C3 alkenylene).

[0292] As used herein, the term "cycloalkyl" refers to a non-aromatic, monocyclic, condensed bicyclic, condensed tricyclic, or bridged polycyclic ring system. In some embodiments, cycloalkyl is a monocyclic or bicyclic saturated carbocyclic group containing 3 to 10 ring members, which may include condensed, bridged, or spirocyclic systems. Non-limiting examples of condensed bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and adamantanil. Non-limiting examples of monocyclic C3-C8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0293] The terms heteroarylene, cycloalkylene, and heterocycloalkylene refer to divalent heteroaryl, cycloalkyl, and heterocycloalkyl compounds.

[0294] As used herein, the term "haloalkyl" refers to a linear or branched alkyl chain in which one or more halogen groups replace hydrogen atoms along the hydrocarbon chain. Examples of halogen groups suitable for substitution in haloalkyl groups include fluorine, bromine, chlorine, and iodine. A haloalkyl group may include substitution of hydrogen atoms in the alkyl chain with multiple halogen groups, and the halogen groups may be bonded to the same carbon or another carbon in the alkyl chain.

[0295] As used herein, alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted linear or branched (C1-C6) alkyl groups, optionally substituted linear or branched (C2-C6) alkenyl groups, optionally substituted linear or branched (C2-C6) alkynyl groups, optionally substituted linear or branched (C1-C6) alkoxy groups, optionally substituted (C1-C6) alkyl-S-, hydroxy, oxo (or N-oxide (as appropriate)), It can be optionally substituted with 1 to 4 groups selected from nitro, cyano, -C(O)-OR0', -OC(O)-R0', -C(O)-NR0'R0'', -NR0'R0'', -(C=NR0')-OR0'', linear or branched (C1-C6) haloalkyl, trifluoromethoxy, or halogen (wherein R0' and R0'' are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, and one or more carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated).

[0296] The terms "polyethylene," "polyethylene glycol," or "PEG," as used herein, refer to a linear, branched, or star-shaped configuration composed of (OCH2CH2) groups. In certain embodiments, the polyethylene or PEG group is -(OCH2CH2) t *-, where t is 1-40 or 4-40, "-" indicates a terminal directed toward a self-sacrificing spacer, "*-" indicates a bond point to the terminal group R', and R' is OH, OCH3 or OCH2CH2C(=O)OH. In other embodiments, the polyethylene or PEG group is -(CH2CH2O) t *- is a compound where t is 1 to 40 or 4 to 40, "-" indicates a terminal directed toward a self-sacrificing spacer, "*-" indicates a bond point to the terminal group R'', and R'' is H, CH3, or CH2CH2C(=O)OH. For example, the term "PEG12" as used herein means that t is 12.

[0297] As used herein, the term "polyalkylene glycol" means (O(CH2) m ) n This refers to a linear, branched, or star-shaped configuration composed of groups. In certain embodiments, the polyethylene or PEG group is -(O(CH2) m ) t *-, where m is 1 to 10, t is 1 to 40 or 4 to 40, "-" indicates the end directed toward the self-sacrificing spacer, "*-" indicates the bond point to the terminal group R', and R' is OH, OCH3 or OCH2CH2C(=O)OH. In other embodiments, the polyethylene or PEG group is -((CH2) m O) t *- is the expression where m is 1 to 10, t is 1 to 40 or 4 to 40, "-" indicates the end directed toward the self-sacrificing spacer, "*-" indicates the bond point to the terminal group R'', and R'' is H, CH3 or CH2CH2C(=O)OH.

[0298] As used herein, the term "reactive group" refers to a functional group of an antibody, an antibody fragment, or a functional group capable of forming a covalent bond with another reactive group bound to an antibody or antibody fragment. Non-limiting examples of such functional groups include the reactive groups provided herein in Table 8.

[0299] The terms “binding group” or “coupling group,” as used herein, refer to the divalent portion that links a crosslinking spacer to an antibody or fragment thereof. A binding or coupling group is a divalent portion formed on the antibody or fragment thereof by a reaction between a reactive group and a functional group. Non-limiting examples of such divalent portions include the divalent chemical portions shown in Tables 8 and 9 provided herein.

[0300] As used herein, the term “crosslinking spacer” refers to one or more conjugate linker components that covalently bond together to form a divalent moiety, which either link a divalent peptide spacer to a reactive group, a divalent peptide spacer to a coupling group, or a binding group to at least one cleavable group. In certain embodiments, the “crosslinking spacer” includes a carboxyl group bonded to the N-terminus of a divalent peptide spacer via an amide bond.

[0301] As used herein, the term “spacer portion” refers to one or more conjugate linker components that covalently bond together to form a portion connecting a self-sacrificing spacer to a hydrophilic portion.

[0302] As used herein, the term “divalent peptide spacer” refers to a divalent conjugate linker comprising one or more amino acid residues that covalently bond together to form a portion that links a crosslinking spacer to a self-sacrificing spacer. One or more amino acid residues may be amino acid residues selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolicine (Pyl), homoserine, homocysteine, and desmethylpyrrolicine.

[0303] In certain embodiments, the "divalent peptide spacer" is a combination of 2 to 4 amino acid residues, where each residue is independently 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), or threonine (Thr). ), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolicin (Pyl), homoserine, homocysteine, and desmethylpyrrolicin, for example, -ValCit*;-CitVal*;-AlaAla*;-AlaCit*;-CitAla*;-AsnCit*;-CitAsn*;-CitCit*;-ValGlu*;-GluVal*;-SerCit*;-CitSer*;-LysCit*;-CitLys* ;-AspCit*;-CitAsp*;-AlaVal*;-ValAla*;-PheAla*;-AlaPhe*;-PheLys*;-LysPhe*;-ValLys*;-LysVal*;-AlaLys*;-LysAla*;-PheCit*;-CitPh e*;-LeuCit*;-CitLeu*;-IleCit*;-CitIle*;-PheArg*;-ArgPhe*;-CitTrp*;-TrpCit*;-PhePheLys*;-LysPhePhe*;-DPhePheLys*;-DLysPhePhe* The amino acid residues are selected from -GlyPheLys*;-LysPheGly*;-GlyPheLeuGly-[SEQ ID NO: 67];-GlyLeuPheGly-[SEQ ID NO: 68];-AlaLeuAlaLeu-[SEQ ID NO: 69], -GlyGlyGly*;-GlyGlyGlyGly-[SEQ ID NO: 70];-GlyPheValGly-[SEQ ID NO: 71]; and -GlyValPheGly-[SEQ ID NO: 72], where "-" indicates a binding site to a crosslinking spacer and "*" indicates a binding site to a self-sacrificing spacer.

[0304] As used herein, the term "conjugate linker component" refers to a chemical part that is part of a conjugate linker. An example of a conjugate linker component is an alkylene group: -(CH2) n -(Can be either linear or branched (in this example, n is 1 to 18)); Alkenylene group; Alkynylene group; Alkenyl group; Alkynyl group; Ethylene group unit: -OCH2CH2- or -CH2CH2O-; Polyethylene glycol unit: (-CH2CH2O-) x (In this example, x is between 2 and 20); -O-; -S-; Carbonyl: -C(=O); Ester: C(=O)-O or OC(=O); Carbonate: -OC(=O)O-; Amine: -NH-; Tertiary amine; Amide: -C(=O)-NH-, -NH-C(=O)- or -C(=O)N(C 1~6 Alkyl; Carbamate: -OC(=O)NH- or -NHC(=O)O; Urea: -NHC(=O)NH; Sulfonamide: -S(O)2NH- or -NHS(O)2; Ether: -CH2O- or -OCH2-; Alkylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, sugar, phosphate and phosphonate); Alkenylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, sugar, phosphate and phosphonate; Alkynylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, sugar, phosphate and phosphonate; C1-C121 10Alkylenes; ring systems having two available bonding sites, such as phenyl (including 1,2-1,3- and 1,4-disubstituted phenyls), C5-C6 heteroaryls, C3-C8 cycloalkyls (including 1,1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and 1,4-disubstituted cyclohexyl), and divalent rings selected from C4-C8 heterocycloalkyls; alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (Hi) s), residues of amino acids selected from isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolicin (Pyl), homoserine, homocysteine, and desmethylpyrrolicin; two or more amino acids A combination of residues (where each residue is independently alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Ci t), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolicin (Pyl), homoserine, homocysteine, and desmethylpyrrolicin, e.g., Val-Cit;Cit-Val;Ala-Ala;Ala-Cit;Cit-Ala;Asn-Cit;Cit-Asn;Cit-Cit;Val-Glu;Glu-Val;Ser-Cit;Cit-Ser;Lys-Cit;Cit-Lys;Asp-Cit;Cit-Asp;Ala-Val;Val-Ala;Phe-Lys;Lys-Phe;Val-Lys;Examples include amino acid residues selected from Lys-Val;Ala-Lys;Lys-Ala;Phe-Cit;Cit-Phe;Leu-Cit;Cit-Leu;Ile-Cit;Cit-Ile;Phe-Arg;Arg-Phe;Cit-Trp; and Trp-Cit), as well as self-sacrificing spacers, where the self-sacrificing spacer comprises one or more protecting (trigger) groups sensitive to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage.

[0305] Non-limited examples of these self-sacrificing spacers include: [ka] These were cited, and in the formula, PG is a protecting (inducing) group; X a is O, NH, or S; X b is O, NH, NCH3, or S; X c is either O or NH; Y a is CH2, CH2O, or CH2NH; Y b is CH2, O, or NH; Y c It is a bond, CH2, O, or NH; LG is a leaving group such as the drug moiety (D) of the linker-drug group of the present invention.

[0306] Further non-limiting examples of these self-sacrificing spacers are described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0307] In addition, conjugate linker components can be chemical moieties readily formed by reactions between two reactive groups. Non-limiting examples of such chemical moieties are shown in Table 8.

[0308] [Table 25]

[0309] [Table 26]

[0310] [Table 27]

[0311] [Table 28]

[0312] [Table 29]

[0313] [Table 30]

[0314] In the formula, R in Table 8 32 H, C 1~4 Alkyl, phenyl, pyrimidine, or pyridine; R in Table 8 35 H, C 1~6 Alkyl, phenyl, or C substituted with 1-3 -OH groups 1~4 It is alkyl; each R in Table 8 7 H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 C substituted with alkoxy and -C(=O)OH 1~4 Selected independently of alkyl groups; R in Table 8 37 is independently selected from H, phenyl, and pyridine; q in Table 8 is 0, 1, 2, or 3; R in Table 88 and R 13 is H or methyl; and R in Table 8 9 and R 14 is H, -CH3, or phenyl; R in Table 8 is H or any preferred substituent; and R in Table 8 50 H is H.

[0315] In addition, the conjugate linker components may be the groups listed in Table 9 below.

[0316] [Table 31]

[0317] [Table 32]

[0318] [Table 33]

[0319] When used in this specification, if a substructure of a compound is shown in the illustration, a dashed line indicates ( [ka] ) indicates the bonding site of the substructure to the rest of the molecule.

[0320] As used herein, the terms “self-sacrificing spacer” and “self-sacrificing group” refer to a moiety containing one or more trigger groups (TGs) which are activated by acid-inducible cleavage, peptide-inducible cleavage, esterase-inducible cleavage, glycosidase-inducible cleavage, phosphodiesterase-inducible cleavage, phosphatase-inducible cleavage, protease-inducible cleavage, lipase-inducible cleavage, or disulfide bond cleavage, after which the protecting group is removed, which generates a decomposition reaction cascade resulting in the transient sequential release of the leaving group. Such reaction cascades may be, but are not limited to, 1,4-, 1,6-, or 1,8-elimination reactions.

[0321] A non-limiting example of a self-sacrificing spacer or base is: [ka] These are some examples, and these bases can be arbitrarily substituted. Here, TG is a trigger base; X a is O, NH, or S; X b is O, NH, NCH3, or S; X c is either O or NH; Y a is CH2, CH2O, or CH2NH; Y b is CH2, O, or NH; Y c It is a bond, CH2, O, or NH; LG is a leaving group such as the drug moiety (D) of the linker-drug group of the present invention.

[0322] An additional, non-restrictive example of a self-sacrificing spacer is described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0323] In certain embodiments, the self-sacrificing spacer is structured [ka] It is a part that has, Here, Lp is an enzymatically cleavable divalent peptide spacer, and A, D, L3 and R 2 This is defined herein.

[0324] In a preferred embodiment, the self-sacrificing spacer is structured [ka] It is a part that has, Here, Lp is an enzymatically cleavable divalent peptide spacer, and D, L3 and R 2 D is as defined herein. In some embodiments, D is a quaternary tertiary amine-containing panRAS inhibitor.

[0325] In another preferred embodiment, the self-sacrificing spacer is structured [ka] It is a part that has, Here, Lp is an enzymatically cleavable divalent peptide spacer, and D, L3 and R 2 This is defined herein.

[0326] As used herein, the term "hydrophilic portion" refers to a portion having hydrophilic properties that increases the water solubility of drug portion (D) when it is bonded to the conjugate linker group of the present invention. Examples of such hydrophilic groups include polyethylene glycol, polyalkylene glycol, sugars, oligosaccharides, polypeptides, and 1 to 3 [ka] Examples include, but are not limited to, C2-C6 alkyl groups substituted with a specific group.

[0327] Drug portion In some embodiments, an intermediate that is a precursor of the conjugate linker moiety is reacted with a drug moiety (e.g., a panRAS inhibitor) under appropriate conditions. In some embodiments, a reactive group is used on the drug and / or intermediate or conjugate linker. Subsequently, the product of the reaction between the drug and intermediate, or a derivatized drug (drug + conjugate linker), is reacted with an antibody or antigen-binding fragment under conditions that promote conjugation of the drug and intermediate or derivatized drug with an antibody or antigen-binding fragment. Alternatively, the intermediate or conjugate linker may be reacted first with the antibody or antigen-binding fragment or a derivatized antibody or antigen-binding fragment, and then with the drug or derivatized drug.

[0328] Several different reactions are available for the covalent bonding of a drug moiety and / or conjugate linker moiety to an antibody or antigen-binding fragment. This is often achieved by the reaction of one or more amino acid residues of the antibody or antigen-binding fragment, including the amine group of lysine, the free carboxylic acid groups of glutamic acid and aspartic acid, the sulfhydryl group of cysteine, and various parts of aromatic amino acids. For example, nonspecific covalent bonding can be attempted using the carbodiimide reaction to link a carboxyl (or amino) group on the drug moiety to an amino (or carboxy) group on the antibody or antigen-binding fragment. Furthermore, bifunctional agents such as dialdehydes or imide esters can also be used to link an amino group on the drug moiety to an amino group on the antibody or antigen-binding fragment. Schiff base reactions are also available for the binding of drugs (e.g., panRAS inhibitors) to binders. This method involves periodic acid oxidation of a drug containing a glycol or hydroxyl group, thus forming an aldehyde that is subsequently reacted with the binder. Bonding occurs via the formation of the amino group of the binder with the Schiff base. Isothiocyanates can also be used as coupling agents for covalently binding a drug to a binder. Other techniques are known to those skilled in the art and are within the scope of this disclosure. Examples of drug moieties that can be produced using various chemicals known in the art and linked to antibody or antigen-binding fragments include panRAS inhibitors, for example, the panRAS inhibitors described and illustrated herein.

[0329] A suitable drug portion may include compounds of formula (Ia), (I), (Ic), (If), (Ig), (Ih), (Ij), (Ik), (Im), or (In), or their enantiomers, diastereoisomers, and / or addition salts with pharmaceutically acceptable acids or bases. Furthermore, the drug portion may include any of the panRAS inhibitors (D) described herein.

[0330] In some embodiments, the drug portion (D) includes a formula selected from Table A2.

[0331] In some embodiments, the drug portion (D) includes, for example, panRAS inhibitors known in the art, disclosed in International Publication No. 2021 / 091956 or International Publication No. 2022 / 060836, which are incorporated herein by reference in their entirety.

[0332] In some embodiments, the drug portion (D) comprises a panRAS inhibitor selected from the following: [ka]

[0333] In some embodiments, the linker-drug (or "linker-payload") portion (LD) may comprise the compounds in Table B or any enantiomer, diastereoisomer, deuterated derivative, and / or pharmaceutically acceptable salts of any of the above.

[0334] Definitions of terms in the drug section Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms are substituted with isotopes of different atoms, such as hydrogen substituted with deuterium). Unless otherwise indicated or evident from the context, the structures shown may represent any such isomeric or isotopic forms individually or in combination.

[0335] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, including enantiomers and diastereomers, are intended.

[0336] Compounds of the Disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by decomposition of racemic mixtures or stereoselective synthesis, are known in the Art. Many geometric isomers of olefins, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are conceivable in the Disclosure. The cis and trans geometric isomers of the compounds of the Disclosure are described and can be isolated as mixtures of isomers or as separated isomers.

[0337] In some embodiments, one or more compounds shown herein may exist in different tautomers. As is evident from the context, unless explicitly excluded, references to such compounds encompass all such tautomers. In some embodiments, tautomers arise from the exchange of a single bond with an adjacent double bond and the resulting transfer of a proton. In certain embodiments, the tautomer form may be a prototropic tautomer, which is an isomer protonated state having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomers are ketone-enol pairs, amide-imido acid pairs, lactam-lactim pairs, amide-imido acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in the heterocyclic system, e.g., 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. In some embodiments, the tautomers may be in equilibrium or sterically fixed into one form by appropriate substitution. In certain embodiments, the tautomers arise from acetal interconversion.

[0338] Furthermore, unless otherwise specified, the structures shown herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I is an example. Isotope-labeled compounds (e.g., 3 H and 14 (labeled with 1C) may be useful in tissue distribution assays of compounds or substrates. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes may be useful due to their ease of preparation and detectability. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H) may result in certain therapeutic benefits derived from higher metabolic stability (e.g., increased in vivo half-life or reduced required dose). In some embodiments, one or more hydrogen atoms are, 2 H or 3 Substituted with H, or one or more carbon atoms, 13 C- or 14 C is replaced with concentrated carbon. 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as fluorine are useful for positron emission tomography (PET) scans to investigate the receptor occupancy rate of substrates.

[0339] The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by following a procedure similar to that disclosed for the compounds of the present invention described herein, by replacing unlabeled reagents with isotope-labeled reagents.

[0340] As is known in the art, many chemical substances can exist in various different solid forms (e.g., polymorphs, hydrates, solvates), such as amorphous or crystalline forms. In some embodiments, the compounds of the present invention may be used in any such form, including any solid form. In some embodiments, the compounds described or shown herein may be provided or used in hydrate or solvate form.

[0341] In various places in this specification, substituents of the compounds of this disclosure are disclosed in groups or ranges. This disclosure is particularly intended to include any individual partial combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is particularly intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions in which substituents are disclosed in groups or ranges, this disclosure is intended to include individual compounds and groups of compounds (e.g., genera and sub-genera) including any individual partial combination of members at each position, unless otherwise indicated.

[0342] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, where X is optionally substituted” (e.g., “alkyl, where the alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. As described herein, a particular compound of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally,” means that one or more hydrogens at a given moiety are replaced with preferred substituents, e.g., any substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have preferred substituents at each of its substituted positions, and if two or more positions in any given structure can be replaced with two or more substituents selected from the specified group, the substituents may be the same or different at all positions. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations envisioned in this disclosure preferably result in the formation of stable or chemically feasible compounds. As used herein, the term “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their generation, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0343] Suitable monovalent substituents on the replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium; halogen; -(CH2) 0~4 R°;-(CH2) 0~4 OR°;-O(CH2) 0~4 R o ;-O-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 CH(OR°)2;-(CH2) 0~4 SR°;-(CH2) 0~4 Ph(can be substituted with R°); R° can be substituted with -(CH2) 0~4 O(CH2) 0~1Can be substituted with Ph;R° -CH=CHPh;R° -(CH2) 0~4 O(CH2) 0~1 -Pyridyl; 4-8 member saturated or unsaturated heterocycloalkyl (e.g., pyridyl); 3-8 member saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R°)2;-(CH2) 0~4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0~4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0~4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0~4 C(O)R°;-C(S)R°;-(CH2) 0~4 C(O)OR°;-(CH2) 0~4 -C(O)-N(R°)2;-(CH2) 0~4 -C(O)-N(R°)-S(O)2-R°;-C(NCN)NR°2;-(CH2) 0~4 C(O)SR°;-(CH2) 0~4 C(O)OsiR°3;-(CH2) 0~4 OC(O)R°;-OC(O)(CH2)0~4SR°;-SC(S)SR°;-(CH2) 0~4 SC(O)R°;-(CH2) 0~4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0~4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0~4 SSR°;-(CH2) 0~4 S(O)2R°;-(CH2) 0~4 S(O)2OR°;-(CH2) 0~4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0~4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NOR°)NR°2;-C(NH)NR°2;-P( O)2R°;-P(O)R°2;-P(O)(OR°)2;-OP(O)R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°, -SiR°3;-(C 1~4 Linear or branched alkylene)ON(R°)2; or -(C 1~4 The linear or branched alkylene can be C(O)ON(R°)2, where each R° can be substituted as defined below, independently of hydrogen, -C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R° together with their intervening atoms to form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0344] Preferred divalent substituents on the saturated carbon atom of the "arbitrarily substituted" group are: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2))2-3S-, where R * Each independent occurrence is selected from an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from hydrogen, C1-6 aliphatic (which may be substituted as defined below), or nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to an adjacent substituted carbon of the "optionally substituted" group is -O(CR *2) Contains 2-3O-, where R * Each independent appearance is hydrogen, C 1~6 Selected from aliphatic (which may be substituted as defined below) or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0345] R * Suitable substituents on the aliphatic group are halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1~4 It is an aliphatic, -CH2Ph, -O(CH2)0~1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0346] A suitable substituent for the substitutable nitrogen of the "optionally substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † This includes; where each R † C can be substituted independently of hydrogen, as defined below. 1~6An aliphatic, unsubstituted Oph, or unsubstituted 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, R † The two independent occurrences, together with their intervening atoms, form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0347] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1~4 The R† ring is a 5-6 member saturated, partially unsaturated, or aryl ring having an aliphatic, -CH2Ph, -O(CH2)0-1Ph, or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R† include =O and =S.

[0348] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0349] The term "alkoxy" as used herein means -O-C1~C 20 This refers to an alkyl group, where the alkoxy group is bonded to the rest of the compound via an oxygen atom.

[0350] The term "alkyl," as used herein, refers to a saturated, linear, or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., linear); in some embodiments, the alkyl group is branched. Examples of alkyl groups, but not limited to, include methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0351] The term “heteroalkyl,” as used herein, refers to an alkyl group as defined herein, in which at least one carbon atom is substituted with a heteroatom (e.g., an O, N, or S atom). The heteroatom may be located in the middle or at the end of the group.

[0352] The term "alkylene," as used herein, refers to a saturated divalent hydrocarbon group derived from a linear or branched saturated hydrocarbon by the removal of two hydrogen atoms, exemplified by methylene, ethylene, isopropylene, and the like. The term "Cx~Cy alkylene" refers to an alkylene group having x~y carbon atoms. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1~C6, C1~C 10 , C2~C 20 , C2~C6, C2~C 10 , or C2~C 20 Alkylene). In some embodiments, the alkylene may be further substituted with one, two, three, or four substituents as defined herein.

[0353] The term "alkenyl," as used herein, unless otherwise specified, refers to a monovalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. The term "alkenylene," as used herein, unless otherwise specified, refers to a divalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds.

[0354] As used herein, the term "alkynyl" refers to a monovalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbon atoms) containing a carbon-carbon triple bond, exemplified by ethynyl and 1-propynyl.

[0355] The term "amino" as used herein is -N(R † )2, for example, represents -NH2 and -N(CH3)2.

[0356] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more amino moieties.

[0357] As used herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), where the amino acid is bonded to a parent molecule by a side chain, an amino group, or an acid group (e.g., a side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, the amino acid has the general structure H2N-C(H)(R A* )-COOH, where R A*is any chemically feasible substituent as described herein. In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; and in some embodiments, the amino acid is an L-amino acid. "Standard amino acids" refers to 20 standard L-amino acids commonly found in natural peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolicine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0358] The term "aryl," as used herein, refers to a monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, where the ring bonded to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenantrenyl, and anthracenyl. Unless otherwise specified, an aryl ring may be bonded to its pendant group with any heteroatom or carbocyclic atom that results in a stable structure, and any of the ring atoms may be optionally substituted. In some embodiments, aryl refers to a phenyl, naphthyl, biphenyl, or indenyl group.

[0359] The term "C0" as used herein represents a bond. For example, the term -N(C(O)-(C0~C5alkylene-H)- contains -N(C(O)-(C0alkylene-H)-, which can also be represented by -N(C(O)-H)-.

[0360] The terms "carbocyclic" and "carbocyclyl," as used herein, refer to monovalent, optionally substituted C3-C3 compounds that may be crosslinked, condensed, or spirocyclic. 12 This refers to monocyclic, bicyclic, or tricyclic ring structures, where all rings are formed from carbon atoms and at least one ring is non-aromatic.

[0361] Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, and dekalinyl. Unless otherwise specified, carbocyclic structures can be bonded to their pendant groups with any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted.

[0362] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0363] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH or its aprotonated counterpart.

[0364] As used herein, the term "cyano" refers to the -CN group.

[0365] As used herein, the term "diastereomer" refers to stereoisomers that are not mirror images of each other and cannot be superimposed on each other.

[0366] As used herein, the term “enantiomer” means each individual optically active form of the compound of the present invention having at least 80% (i.e., at least 90% of one enantiomer and 10% or less of the other enantiomer), preferably at least 90%, more preferably at least 98%, of optical purity or enantiomer excess (as determined by methods standard in the art).

[0367] As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more identical or different halogen moieties.

[0368] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0369] As used herein, the term “heteroalkyl” refers to an alkyl group as defined herein, in which at least one carbon atom is substituted with a heteroatom (e.g., an O, N, or S atom). The heteroatom may be located in the middle or at the end of the group.

[0370] The term "heteroaryl," as used herein, refers to a monovalent, monocyclic, or polycyclic ring structure containing at least one fully aromatic ring: that is, they contain 4n+2 π electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O, or S within the aromatic ring. Exemplary unsubstituted heteroaryl groups are those with 1 to 12 carbon atoms (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9). The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is condensed with one or more aryl or carbocyclic rings, e.g., a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindylol. Unless otherwise specified, a heteroaryl ring can be bonded to its pendant group with any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents. In some embodiments, the heteroaryl refers to any monocyclic or bicyclic group having at least one aromatic moiety and comprising 5 to 10 ring members containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen (including quaternary nitrogen).

[0371] The term "heterocycloalkyl," as used herein, refers to a monocyclic, bicyclic, or polycyclic ring system that may be crosslinked, condensed, or spirocyclic, where at least one ring is non-aromatic, and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six-membered and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups have 1 to 12 carbon atoms (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9).

[0372] The term "heterocycloalkyl" also refers to a heterocyclic compound having a bridging polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent ring members of a monocyclic ring, such as a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups, in which any of the above heterocyclic groups is condensed with one or more aromatic rings, carbocyclic rings, heteroaromatic rings, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or loridine ring.

[0373] Examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthilidinyl. Unless otherwise specified, heterocycloalkyl rings can be bonded to their pendant group with any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted.

[0374] As used herein, the term "hydroxy" refers to the -OH group.

[0375] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0376] The term "isomer," as used herein, means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. Compounds of the present invention may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers) or diastereomers (i.e., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures shown herein, and by extension the compounds of the present invention, encompass all corresponding stereoisomers, i.e., sterically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as both enantiomers and stereoisomer mixtures, e.g., racemates. Mixtures of enantiomers and stereoisomers of the compounds of the present invention can typically be decomposed into their constituent enantiomers or stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from sterically or enantiomerally pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0377] As used herein, the term “drug linker” means that the resulting compound is capable of achieving an IC50 of 2 μM or less in the Ras-RAF disruption assay protocol provided herein, with a portion B in the compound of Formula I. D to part W D This refers to the divalent organic part that is linked to it.

[0378] The purpose of this biochemical assay is to measure the ability of the test compound to promote the formation of a triple complex between the nucleotide loading Ras isoform and cyclophyllin A; the resulting triple complex is BRAF RBD It disrupts binding to the construct and inhibits Ras signaling via RAF effectors.

[0379] In an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, untagged cyclophyllin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF were added. RBD These compounds are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds are present in the plate wells as a 10-point 3-fold dilution series starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, the mixture of anti-His Eu-W1024 and anti-GST allophycocyanin is then added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reactants are incubated for a further 1.5 hours. The TR-FRET signal is read using a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote the disruption of the Ras:RAF complex are identified as those that cause a decrease in the TR-FRET ratio compared to the DMSO control well.

[0380] In some embodiments, the drug linker contains 20 or fewer linear atoms. In some embodiments, the drug linker contains 15 or fewer linear atoms. In some embodiments, the drug linker contains 10 or fewer linear atoms. In some embodiments, the drug linker has a molecular weight of less than 500 g / mol. In some embodiments, the drug linker has a molecular weight of less than 400 g / mol. In some embodiments, the drug linker has a molecular weight of less than 300 g / mol. In some embodiments, the drug linker has a molecular weight of less than 200 g / mol. In some embodiments, the drug linker has a molecular weight of less than 100 g / mol. In some embodiments, the drug linker has a molecular weight of less than 50 g / mol.

[0381] The term "stereoisomer," as used herein, refers to all possible different isomers and conformations that a compound (for example, a compound of any of the formulas described herein) may take, in particular all possible stereochemical and conformational isomers, all diastereomers, enantiomers or atropisomers of the basic molecular structure. Some of the compounds of the present invention may exist in different tautomers, all of which are included within the scope of the present invention.

[0382] The term "sulfonyl" or "sulfonyl" as used herein refers to the -S(O)2- group.

[0383] As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0384] Drug load The drug load is represented by p, also referred to herein as the drug-to-antibody ratio (DAR). The drug load may range from 1 to 16 drug parts per antibody or antigen-binding fragment. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p is an integer from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 4.

[0385] Drug loading may be limited by the number of binding sites on the antibody or antigen-binding fragment. In some embodiments, the conjugate linker portion (L) of the ADC binds to the antibody or antigen-binding fragment via a chemically active group on one or more amino acid residues on the antibody or antigen-binding fragment. For example, the conjugate linker may bind to the antibody or antigen-binding fragment via a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., at the N or C terminus, to the epsilon-amino group of one or more lysine residues, to the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteine ​​residues). The sites to which the conjugate linker binds may be native residues in the amino acid sequence of the antibody or antigen-binding fragment, or they may be introduced into the antibody or antigen-binding fragment, for example, by DNA recombination technology (e.g., by introducing cysteine ​​residues into the amino acid sequence) or by protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis).

[0386] In some embodiments, the number of drug moieties that can be conjugated to an antibody or antigen-binding fragment is limited by the number of free cysteine ​​residues. For example, if the conjugate is a cysteinethiol group, the antibody may have only one or a few cysteinethiol groups, or only one or a few sufficiently reactive thiol groups to which the conjugate linker can be bound. Generally, antibodies do not contain many free and reactive cysteinethiol groups that can be linked to drug moieties. In fact, most cysteinethiol residues in an antibody are involved in either interchain or intrachain disulfide bonds. Therefore, conjugation to cysteine ​​requires at least partial reduction of the antibody in some embodiments. Excessive binding of the conjugate linker—toxin—to the antibody can destabilize the antibody by reducing cysteine ​​residues available to form disulfide bonds. Therefore, the optimal drug:antibody ratio should increase the potency of the ADC without destabilizing the antibody or antigen-binding fragment (by increasing the number of conjugated drug moieties per antibody). In some embodiments, the optimal ratio may be 2, 4, 6, or 8.

[0387] In some embodiments, the antibody or antigen-binding fragment is exposed to reducing conditions prior to conjugation to produce one or more free cysteine ​​residues. In some embodiments, the antibody may be reacted with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) under partial or total reducing conditions to produce reactive cysteinethiol groups. Unpaired cysteine ​​can be produced via partial reduction with a limited molar equivalent of TCEP, which can reduce the interchain disulfide bonds linking the light and heavy chains (one pair per HL pair formation) and the two heavy chains in the hinge region (two pairs per HH pair formation in the case of human IgG1), while leaving the intrachain disulfide bonds unchanged (Stefano et al. (2013) Methods Mol Biol. 1045:145-71). In embodiments, the disulfide bonds in the antibody are electrochemically reduced, for example, by utilizing a working electrode to apply alternating reduction and oxidation potentials. This method may enable online coupling of disulfide bond reduction to analytical devices (e.g., electrochemical detection devices, NMR spectrometers, or mass spectrometers) or chemical separation devices (e.g., liquid chromatography (e.g., HPLC) or electrophoresis devices (see, for example, U.S. Patent Application Publication No. 2014 / 0069822)). In some embodiments, the antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups on amino acid residues such as cysteine.

[0388] The drug loading of an ADC can be controlled in various ways, for example, by (i) limiting the molar excess of the drug-linker intermediate or conjugate linker reagent relative to the antibody; (ii) limiting the conjugation reaction time or temperature; (iii) reducing conditions for partial or limited cysteine ​​thiol modification; and / or (iv) manipulating the amino acid sequence of the antibody by integration techniques so that the number and position of cysteine ​​residues are modified to control the number and / or position of linker-drug bindings.

[0389] In some embodiments, free cysteine ​​residues are introduced into the amino acid sequence of an antibody or antigen-binding fragment. For example, a cysteine-manipulated antibody may be prepared, in which one or more amino acids of the parent antibody are replaced with cysteine ​​amino acids. Any form of antibody can be manipulated in this way, i.e., mutated. For example, a parent Fab antibody fragment may be manipulated to form a cysteine-manipulated Fab referred to as "thioFab". Similarly, a parent monoclonal antibody may be manipulated to form "thioMab". A single-site mutation produces a single manipulated cysteine ​​residue in thioFab, while a single-site mutation produces two manipulated cysteine ​​residues in thioMab due to the dimeric nature of the IgG antibody. DNA encoding amino acid sequence variants of the parent polypeptide can be prepared by various methods known in the art (see, for example, the methods described in International Publication No. 2006 / 034488). These methods include, but are not limited to, site-directed (or oligonucleotide-mediated) mutagenesis, PCR mutagenesis, and preparation by cassette mutagenesis of previously prepared DNA encoding polypeptides. Variants of recombinant antibodies can also be constructed by restriction fragment manipulation or overlap extension PCR with synthetic oligonucleotides. Examples of ADCs of formula (1) include, but are not limited to, antibodies having 1, 2, 3, or 4 manipulated cysteine ​​amino acids (Lyon et al. (2012) Methods Enzymol. 502:123-38). In some embodiments, one or more free cysteine ​​residues are already present in the antibody or antigen-binding fragment without the use of engineering, in which case the existing free cysteine ​​residues can be used to conjugate the antibody or antigen-binding fragment to the drug portion.

[0390] After reacting two or more nucleophilic groups with a double linker intermediate or a conjugate linker partial reagent, the mixture is reacted with a drug partial reagent in a reaction mixture containing multiple copies of an antibody or antigen-binding fragment and a conjugate linker partial. The resulting product may be a mixture of ADC compounds having a distribution of one or more drug moieties bound to each copy of the antibody or antigen-binding fragment in the mixture. In some embodiments, the drug load in the mixture of ADCs obtained from the conjugation reaction is in the range of 1 to 16 bound drug moieties per antibody or antigen-binding fragment. The average number of drug moieties per antibody or antigen-binding fragment (i.e., average drug load, or average p) can be calculated by any conventional method known in the art, such as mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC-MS)) and / or high-performance liquid chromatography (e.g., HIC-HPLC). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is determined by liquid chromatography-mass spectrometry (LC-MS). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is approximately 1.5 to 3.5, 2.5 to 4.5, 3.5 to 5.5, 4.5 to 6.5, 5.5 to 7.5, 6.5 to 8.5, or 7.5 to 9.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is approximately 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, 2 to 8, or 4 to 8.

[0391] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 2. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 2.

[0392] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 4. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 4.

[0393] In some embodiments, the term “approximately” means plus or minus 20%, 15%, 10%, 5%, or 1% when used with respect to the average number of drug portions per antibody or antigen-binding fragment. In one embodiment, the term “approximately” refers to a range of numbers that are more than 10% or less than 10% of a particular number. In another embodiment, the term “approximately” refers to a range of numbers that are more than 5% or less than 5% of a particular number. In yet another embodiment, the term “approximately” refers to a range of numbers that are more than 1% or less than 1% of a particular number.

[0394] Individual ADC compounds or "species" can be identified in the mixture by mass spectrometry and separated, for example, by ULC or HPLC, or by hydrophobic interaction chromatography (HIC-HPLC). In some embodiments, homogeneous or nearly homogeneous ADC products with a single loading value can be isolated from the conjugation mixture, for example, by electrophoresis or chromatography.

[0395] In some embodiments, a higher drug load (e.g., p > 16) may cause aggregation, insolubility, toxicity, or loss of cell permeability of a particular antibody-drug conjugate. A higher drug load may also negatively affect the pharmacokinetics (e.g., clearance) of a particular ADC. In some embodiments, a lower drug load (e.g., p < 2) may reduce the potency of a particular ADC against target-expressing cells. In some embodiments, the drug load for the ADCs of this disclosure ranges from about 2 to about 16, about 2 to about 10, about 2 to about 8; about 2 to about 6; about 2 to about 5; about 3 to about 5; about 2 to about 4; or about 4 to about 8.

[0396] In some embodiments, a drug load and / or average drug load of about 2 is achieved, for example, by partial reduction of intrachain disulfides on the antibody or antigen-binding fragment, providing favorable properties. In some embodiments, a drug load and / or average drug load of about 4, or about 6, or about 8 is achieved, for example, by partial reduction of intrachain disulfides on the antibody or antigen-binding fragment, providing favorable properties. In some embodiments, a drug load and / or average drug load of less than about 2 may result in unacceptably high levels of unconjugated antibody species, which may compete with the ADC for binding to the target antigen and / or provide reduced therapeutic efficacy. In some embodiments, a drug load and / or average drug load of more than about 16 may result in unacceptably high levels of product heterogeneity and / or ADC aggregation. A drug load and / or average drug load of more than about 16 may also affect the stability of the ADC due to the loss of one or more chemical bonds necessary to stabilize the antibody or antigen-binding fragment.

[0397] This disclosure includes methods for producing the described ADCs. Briefly, an ADC comprises an antibody or antigen-binding fragment (e.g., an anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment), a drug moiety (e.g., a panRAS inhibitor), and a conjugate linker that binds the drug moiety and the antibody or antigen-binding fragment. In some embodiments, the ADC may be prepared using a conjugate linker having a reactive functional group for covalent bonding to the drug moiety and the antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is functionalized to prepare a functional group that is reactive with the conjugate linker or drug-linker intermediate. For example, in some embodiments, a cysteinethiol in the antibody or antigen-binding fragment can form a bond with a reactive functional group of the conjugate linker or drug-linker intermediate for producing the ADC. In some embodiments, the antibody or antigen-binding fragment is prepared from reactive glutamine specifically functionalized with an amine containing a bacterial transglutaminase (BTG)-cyclooctin BCN (N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-in-9-ylmethyloxycarbonyl]-1,8-diamino-3,6-dioxaoctane) moiety. In some embodiments, site-specific conjugation of the antibody or antigen-binding fragment of the conjugate linker or drug-linker intermediate to the BCN moiety is carried out, for example, as described and illustrated herein. The preparation of ADCs can be achieved by techniques known to those skilled in the art.

[0398] In some embodiments, ADCs are produced by sequentially contacting an antibody or antigen-binding fragment (e.g., an anti-EphA2 or anti-B7-H3 antibody or antigen-binding fragment) with a conjugate linker and a drug moiety (e.g., a panRAS inhibitor), resulting in the antibody or antigen-binding fragment being first covalently linked to the conjugate linker, followed by the reaction of a pre-formed antibody-linker intermediate with the drug moiety. The antibody-linker intermediate may or may not be purified before contact with the drug moiety. In other embodiments, ADCs are produced by contacting an antibody or antigen-binding fragment with a pre-formed linker-drug compound by reacting the conjugate linker with the drug moiety. The pre-formed linker-drug compound may or may not be purified before contact with the antibody or antigen-binding fragment. In other embodiments, the antibody or antigen-binding fragment comes into contact with a conjugate linker and a drug moiety in a single reaction mixture, allowing for the simultaneous formation of covalent bonds between the antibody or antigen-binding fragment and the conjugate linker, and between the conjugate linker and the drug moiety. Methods for producing ADCs may include a reaction in which the antibody or antigen-binding fragment comes into contact with the antibody or antigen-binding fragment before the addition of the conjugate linker to the reaction mixture, and the reverse reaction. In some embodiments, ADCs are produced by reacting the antibody or antigen-binding fragment with a conjugate linker bound to a drug moiety, such as a panRAS inhibitor, under conditions that allow for conjugation.

[0399] ADCs prepared according to the above method may be subjected to a purification step. The purification step may include any biochemical method known in the art for purifying proteins, or any combination thereof. These include, but are not limited to, tangential flow filtration (TFF), affinity chromatography, ion exchange chromatography, chromatography based on any charge or isoelectric point, mixed-mode chromatography, e.g., CHT (ceramic hydroxyapatite), hydrophobic interaction chromatography, size exclusion chromatography, dialysis, filtration, selective precipitation, or any combination thereof.

[0400] Therapeutic use and composition This specification discloses compositions described herein, e.g., the disclosed ADC compounds and methods of using the compositions in treating a subject for a disorder, e.g., cancer. The compositions, e.g., ADCs, may be administered alone or in combination with at least one additional inactive and / or active agent, e.g., at least one additional therapeutic agent, and may be administered in any pharmaceutically acceptable formulation, dosage, and administration regimen. Therapeutic efficacy may be evaluated with respect to indicators of toxicity and efficacy and adjusted accordingly. Measures of efficacy include, but are not limited to, cell division inhibitory and / or cytotoxic effects observed in vitro or in vivo, reduction of tumor volume, inhibition of tumor growth, and / or extension of survival.

[0401] Methods are known to determine whether ADCs exert cell division inhibitory and / or cytotoxic effects on cells. For example, the cytotoxic or cell division inhibitory activity of ADCs can be measured, for example, by exposing mammals expressing the target antigen of ADCs in cell culture medium; culturing cells for a period of about 6 hours to about 6 days; and measuring cell viability (e.g., using CellTiter-Glo® (CTG) or MTT cell viability assays). Cell-based in vitro assays can be used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) by ADCs.

[0402] To determine cytotoxicity, necrosis or apoptosis (programmed cell death) may be measured. Necrosis is usually achieved by increased cell membrane permeability, cell swelling, and cell membrane rupture. Apoptosis can be quantified, for example, by measuring DNA fragmentation. Commercial photometric methods are available for the quantitative in vitro determination of DNA fragmentation. Examples of such assays, including TUNEL (which detects the incorporation of labeled nucleotides in fragmented DNA) and ELISA-based assays, are described in Biochemica (1999) 2:34-7 (Roche Molecular Biochemicals).

[0403] Apoptosis can also be determined by measuring morphological changes within cells. For example, loss of cell membrane integrity, as well as necrosis, can be determined by measuring the uptake of certain dyes (e.g., fluorescent dyes such as acridine orange or ethidium bromide). Methods for measuring the number of apoptotic cells are described by Duke and Cohen, Current Protocols in Immunology (Coligan et al., eds. (1992) pp. 3.17.1-3.17.16). Cells can also be labeled with DNA dyes (e.g., acridine orange, ethidium bromide, or propidium iodide), and cells can be observed for chromatin condensation and periphery along the internal nuclear membrane. In some embodiments, apoptosis can also be determined by screening for caspase activity. In some embodiments, the Caspase-Glo® assay can be used to measure the activity of caspase-3 and caspase-7. In some embodiments, the assay provides a luminescent caspase-3 / 7 substrate in a reagent optimized for caspase activity, luciferase activity, and cell lysis. In some embodiments, the addition of the Caspase-Glo® 3 / 7 reagent in a “add-mix-measure” format may result in cell lysis, followed by caspase cleavage of the substrate and the generation of a “proliferative” luminescence signal produced by luciferase. In some embodiments, the luminescence may be proportional to the amount of caspase activity present and may serve as an indicator of apoptosis. Other morphological changes that can be measured to determine apoptosis include, for example, intracellular condensation, membrane vesicle formation, and cell shrinkage. Determining any of these effects on cancer cells indicates that ADC may be useful in the treatment of cancer.

[0404] Cell viability can be measured by determining the uptake of dyes in cells, such as neutral red, trypan blue, crystal violet, or ALAMAR® blue (see, for example, Page et al. (1993) Intl J Oncology 3:473-6). In such assays, cells are incubated in a culture medium containing the dye, the cells are washed, and the remaining dye, reflecting the cellular uptake of the dye, is measured spectrophotometrically.

[0405] Cell viability can also be measured, for example, by quantifying ATP, an indicator of metabolically active cells. In some embodiments, the in vitro potency and / or cell viability of a prepared ADC or panRAS inhibitor compound can be evaluated using the CellTiter-Glo® (CTG) cell viability assay as described in the examples provided herein. In this assay, in some embodiments, a single reagent (CellTiter-Glo® reagent) is added directly to cells cultured in serum-supplemented medium. The addition of the reagent results in cell lysis and the generation of a luminescence signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture.

[0406] Cell viability can also be measured, for example, by measuring the reduction of tetrazolium salts. In some embodiments, the in vitro potency and / or cell viability of the prepared ADC or panRAS inhibitor compound can be evaluated using an MTT cell viability assay as described in the examples provided herein. In this assay, in some embodiments, yellow tetrazolium MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) is reduced by metabolically active cells, partially by the action of a dehydrogenase enzyme, to produce reduced equivalents such as NADH and NADPH. The resulting purple formazan in the cells is then solubilized and can be quantified by spectrophotometric means.

[0407] In certain embodiments, the Disclosure features a method for killing, inhibiting, or modulating the proliferation of cancer cells or tissues by disrupting the expression and / or activity of panRAS (e.g., K-Ras (including splice mutations KRAS4A and KRAS4B), H-Ras, and N-Ras) and / or one or more upstream modulators or downstream targets thereof. The method may be used in any subject for which disruption of panRAS (e.g., K-Ras (including splice mutations KRAS4A and KRAS4B), H-Ras, and N-Ras) expression and / or activity provides a therapeutic effect. Subjects who may benefit from disrupting panRAS (e.g., K-Ras (including splice mutations KRAS4A and KRAS4B), H-Ras, and N-Ras) expression and / or activity include, but are not limited to, subjects who have or are at risk of having cancer, such as tumors or hematological malignancies. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0408] In some embodiments, the disclosed ADC may be administered to any cells or tissues expressing EphA2, such as EphA2-expressing cancer cells or tissues. Exemplary embodiments include methods for killing EphA2-expressing cancer cells or tissues. The methods may be used with any cells or tissues expressing EphA2, such as cancerous cells or metastatic lesions. Non-limiting examples of EphA2-expressing cancers include breast cancer, non-small cell lung cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric or stomach cancer, bladder cancer, and colorectal cancer.

[0409] In some embodiments, the disclosed ADC may be administered to any cells or tissues expressing B7-H3(CD276), such as B7-H3(CD276)-expressing cancer cells or tissues. Exemplary embodiments include a method for killing B7-H3(CD276)-expressing cancer cells or tissues. The method may be used with any cells or tissues expressing B7-H3(CD276), such as cancerous cells or metastatic lesions. Non-limiting examples of B7-H3(CD276)-expressing cancers include colorectal cancer, pancreatic cancer, lymphoma, non-small cell lung cancer, small cell lung cancer, breast cancer including ER-positive breast cancer, metastatic castration-resistant prostate cancer, melanoma, urothelial carcinoma of the bladder, head and neck cancer, and leukemia (e.g., acute myeloid leukemia).

[0410] An exemplary method involves contacting cells with an effective amount, i.e., an amount sufficient to kill the cells, as described herein. The method may be used in a culture, for example, in vitro, in vivo, ex vivo, or in situ. For example, cells expressing EphA2 (e.g., cells recovered by biopsy of tumors or metastatic lesions; cells derived from established cancer cell lines; or recombinant cells) may be cultured in vitro in a culture medium, and the contact step may be influenced by adding the ADC to the culture medium. The method will, in particular, cause the death of EphA2-expressing cells, including cancer cells expressing EphA2. Alternatively, the ADC may be administered to the subject by any preferred route of administration that is effective in vivo (e.g., intravenously, subcutaneously, or in direct contact with tumor tissue). This technique may be used for antibodies targeting other cell surface antigens (e.g., B7-H3 (CD276)).

[0411] The in vivo efficacy of the disclosed ADC therapeutic compositions can be evaluated in suitable animal models. For example, xenocarcinoma models may be used, in which cancer grafts or passaged xenograft tissues are introduced into immunocompromised animals such as nude mice or SCID mice (Klein et al. (1997) Nature Med. 3:402-8). Efficacy can be predicted using assays that measure inhibition of tumorigenesis, tumor regression, or metastasis.

[0412] In vivo assays can also be used to evaluate the promotion of tumor death through mechanisms such as apoptosis. In some embodiments, xenografts derived from tumor-bearing mice treated with the therapeutic composition may be tested for the presence of apoptotic lesions and compared to untreated control xenograft-bearing mice. The extent to which apoptotic lesions are found in the tumors of treated mice provides an indicator of the therapeutic efficacy of the composition.

[0413] Furthermore, methods for treating disorders, such as cancer, are provided herein. Compositions described herein, such as ADCs disclosed herein, may be administered to non-human mammals or human subjects for therapeutic purposes. The therapeutic method comprises administering to a subject having or suspected of having cancer a therapeutically effective amount of a composition comprising a panRAS inhibitor, such as an ADC, wherein the inhibitor is ligated to a targeted antibody that (1) is expressed in cancer cells, (2) is available for binding, and / or (3) binds to an antigen that is localized or primarily expressed on the surface of cancer cells compared to non-cancer cells.

[0414] An exemplary embodiment is a method for treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein, e.g., an ADC, a composition, or a pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytic myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

[0415] Another exemplary embodiment is a method for delivering a panRAS inhibitor to cells expressing EphA2, comprising conjugating the panRAS inhibitor to an antibody or antigen-binding fragment that immunospecifically binds to the EphA2 epitope and exposing the cells to the ADC. Exemplary cancer cells expressing EphA2 to which the ADC of this disclosure is applied include breast cancer, non-small cell lung cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric or stomach cancer, bladder cancer, and colorectal cancer cells.

[0416] Another exemplary embodiment is a method for delivering a panRAS inhibitor to cells expressing B7-H3(CD276), comprising conjugating the panRAS inhibitor to an antibody or antigen-binding fragment that immunospecifically binds to the B7-H3(CD276) epitope and exposing the cells to the ADC. Exemplary cancer cells expressing B7-H3(CD276) to which the ADC of this disclosure is applied include colorectal cancer, pancreatic cancer, lymphoma, and leukemia cells.

[0417] In certain embodiments, the disclosure further provides a method for reducing or inhibiting the growth of a tumor (e.g., an EphA2-expressing tumor, a B7-H3 (CD276)-expressing tumor), comprising administering a therapeutically effective amount of an ADC or a composition comprising an ADC. In some embodiments, the treatment is sufficient to reduce or inhibit the growth of the patient's tumor, reduce the number or size of metastatic lesions, reduce tumor volume, reduce primary tumor volume, reduce invasiveness, extend survival, and / or maintain or improve quality of life. In some embodiments, the tumor is resistant or refractory to treatment with an antibody or antigen-binding fragment of an ADC (e.g., an anti-EphA2 antibody or antigen-binding fragment, an anti-B7-H3 (CD276) antibody or antigen-binding fragment) when administered alone, and / or the tumor is resistant or refractory to treatment with a panRAS inhibitor drug portion when administered alone.

[0418] An exemplary embodiment is a method for reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the target antigens are BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2(NaPi2b), Nectin 4, TROP2, LIV1, CD46, MSLN, CD142(F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, C D25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimicking), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR) I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CD166 (ALCAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Epicialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human hepatocyte growth factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-related 2), Lewis Y antigen, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen (PSMA), PSCA (prostate stem cell antigen precursor), PRLR (prolactin receptor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, Prostate cancer-related gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, Tomoreglin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPThe target antigen is I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the tumor is breast cancer, including ER-positive breast cancer; multiple myeloma; plasmacytic myeloma; leukemia; lymphoma; sarcoma; gastric cancer or stomach cancer; acute myeloid leukemia; bladder cancer; brain tumor; bone marrow cancer; cervical cancer; chronic lymphocytic leukemia; colorectal cancer; pancreatic cancer; esophageal cancer; hepatocellular carcinoma; lymphoblastic leukemia, including acute lymphoblastic leukemia; follicular lymphoma; lymphoid tumor of T-cell or B-cell origin; metastatic castration-resistant prostate cancer; urothelial carcinoma of the bladder; melanoma; myeloid leukemia; myeloma; oral cancer; ovarian cancer; non-small cell lung cancer; prostate cancer; small cell lung cancer; splenic cancer; or head and neck cancer. In some embodiments, the tumor is gastric cancer. In some embodiments, administration of an ADC, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% compared to growth in the absence of treatment.

[0419] Another exemplary embodiment is a method for delaying or slowing tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the target antigen is EphA2 or B7-H3 (CD276). In some embodiments, the tumor is breast cancer, including ER-positive breast cancer; multiple myeloma; plasmacytic myeloma; leukemia; lymphoma; sarcoma; gastric cancer or stomach cancer; acute myeloid leukemia; bladder cancer; brain tumor; bone marrow cancer; cervical cancer; chronic lymphocytic leukemia; colorectal cancer; pancreatic cancer; esophageal cancer; hepatocellular carcinoma; lymphoblastic leukemia, including acute lymphoblastic leukemia; follicular lymphoma; lymphoid tumor of T-cell or B-cell origin; metastatic castration-resistant prostate cancer; urothelial carcinoma of the bladder; melanoma; myeloid leukemia; myeloma; oral cancer; ovarian cancer; non-small cell lung cancer; prostate cancer; small cell lung cancer; splenic cancer; or head and neck cancer. In ...

Claims

1. Antibody-drug conjugate of formula (1): A-(L-D) ｐ (1) (wherein Ab is an antibody or its antigen-binding fragment; L is a conjugate linker that covalently bonds Ab to D; p is an integer between 1 and 16; D is a panRAS inhibitor.

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

3. L, Binding group; At least one bridging spacer base; and At least one cleavable group, optionally, at least one cleavable group comprising a pyrophosphate group and / or a self-sacrificing group. The antibody-drug conjugate according to claim 1 or 2, comprising:

4. -(L-D) is given by equation (A): 【Chemistry 1】 (In the formula, R １ is a bonding group; L １ This is a cross-linking spacer base; E is a cleavable group. The antibody-drug conjugate according to claim 3.

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

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

7. (i) The binding group is formed from at least one reactive group selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group; optionally, a) The maleimide group has the following structure: 【Transformation 3】 Having; b) The azide group has the structure: -N=N ＋ = N － Having; c) The cyclooctin group has the following structure: 【Chemistry 4】 Having; Here, 【Transformation 5】 This is binding to the antibody or its antigen-binding fragment; or d) The cyclooctin group has the following structure: 【Transformation 6】 Having; and During the ceremony, 【Transformation 7】 This is binding to the antibody or its antigen-binding fragment; or (ii) The bonding group is 【Transformation 8】 It is expressed as an expression that includes, and During the ceremony, 【Chemistry 9】 The antibody-drug conjugate according to claim 6, wherein the conjugate is bound to the antibody or its antigen-binding fragment.

8. The antibody or its antigen-binding fragment is bound to the conjugate linker (L) by a binding group selected from the following: 【Chemistry 10】 During the ceremony, 【Chemistry 11】 This is binding to the antibody or its antigen-binding fragment, in which, 【Chemistry 12】 The antibody-drug conjugate according to claim 7, wherein the bond is to the crosslinking spacer group.

9. The crosslinking spacer group is -CH ２ CH ２ -O-CH ２ CH ２ -CO-, and the antibody-drug conjugate according to claim 8.

10. The crosslinking spacer group is bonded to a cleavable group; optionally, the cleavable group is -pyrophosphate-CH ２ -CH ２ -NH ２ - The antibody-drug conjugate according to claim 8 or 9.

11. The antibody-drug conjugate according to any one of claims 8 to 10, wherein the cleavable group is bound to the panRAS inhibitor (D).

12. The aforementioned conjugate linker bonding group, At least one bridging spacer base, peptide group, and at least one cleavable group An antibody-drug conjugate according to any one of claims 1 to 3, comprising:

13. -(L-D) is given by equation (B): 【Chemistry 13】 (In the formula, R １ is a bonding group; L １ It is a bridging spacer; Lp is a peptide group containing 1 to 6 amino acid residues, or Lp is a group 【Chemistry 14】 Including; E is a cleavable group, L ２ It is a bridging spacer; m is 0 or 1; and D is a panRAS inhibitor. The antibody-drug conjugate according to claim 12.

14. (i) The binding group is formed from at least one reactive group comprising a maleimide group, a thiol group, a cyclooctin group, and / or an azide group, optionally a) The maleimide group has the following structure: 【Chemistry 15】 Having; b) The azide group has the structure: -N=N ＋ = N － Having; c) The cyclooctin group has the following structure: 【Chemistry 16】 Having; During the ceremony, 【Chemistry 17】 This is binding to the antibody or its antigen-binding fragment; or (ii) The bonding group is [Chemistry 18] It is expressed as an expression that includes, and During the ceremony, 【Chemistry 19】 The antibody-drug conjugate according to claim 12 or 13, wherein the conjugate is the binding to the antibody or its antigen-binding fragment.

15. (i) at least one bridging spacer includes a PEG group, optionally selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15; or (ii) At least one bridging spacer is *-C(O)-CH ２ -CH ２ -PEG1-**, *-C(O)-CH ２ -PEG3-**, *-C(O)-CH ２ -CH ２ -PEG12**, *-NH-CH ２ -CH ２ -PEG1-**, polyhydroxyalkyl group, *-C(O)-N(CH ３ ) - CH ２ -CH ２ -N(CH ３ )-C(O)-**, and *-C(O)-CH ２ -CH ２ -PEG12-NH-C(O)CH ２ -CH ２ An antibody-drug conjugate according to any one of claims 12 to 14, wherein selected from **, where ** represents a direct or indirect binding site of the at least one crosslinking spacer to the binding group, and * represents a direct or indirect binding site of the at least one crosslinking spacer to the peptide group.

16. L １ However, *-C(O)-CH ２ -CH ２ -PEG1-**, *-C(O)-CH ２ -PEG3-**, *-C(O)-CH ２ -CH ２ -PEG12**, *-NH-CH ２ -CH ２ -PEG1-** and selected from polyhydroxyalkyl groups, where ** is R １ L １ This indicates the direct or indirect connection point of Lp, where * represents L relative to Lp. １ An antibody-drug conjugate according to any one of claims 12 to 15, which shows a direct or indirect binding site.

17. m is 1, L ２ However, -C(O)-N(CH ３ ) - CH ２ -CH ２ -N(CH ３ The antibody-drug conjugate according to any one of claims 12 to 16, wherein it is )-C(O)-.

18. (i) The peptide group comprises 1 to 6, 1 to 4, 1 to 3, or 1 to 2 amino acid residues, wherein the amino acid residues are optionally selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr); (ii) The peptide group comprises Val-Cit, Val-Ala, Val-Lys, and / or sulfo-Ala-Val-Ala; (iii) The peptide group is 【Chemistry 20】 An antibody-drug conjugate according to any one of claims 12 to 17, selected from the above.

19. (i) the cleavable group comprises a pyrophosphate group and / or a self-sacrificing group; (ii) the cleavable group comprises a self-sacrificing group; or (iii) the cleavable group comprises a self-sacrificing group comprising para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium, according to any one of claims 12 to 18.

20. m is 0 or 1, or m is 1 and the bridging spacer is 【Chemistry 21】 An antibody-drug conjugate according to any one of claims 13 to 19, comprising:

21. - (L-D) is, 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 An antibody-drug conjugate according to any one of claims 13 to 20, formed from a compound selected from.

22. - (L-D) is, 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 Includes an expression selected from, and During the ceremony, 【Chemistry 35】 The antibody-drug conjugate according to any one of claims 13 to 21, wherein the conjugate is bound to the antibody or its antigen-binding fragment.

23. -(L-D) is given by equation (C): 【Transformation 36】 (In the formula, R １ is a bonding group; L １ It is a bridging spacer; L ｐ This is a peptide group containing 1 to 6 amino acids; D is a panRAS inhibitor; G １ -L ２ - A is a self-sacrificing spacer; L ２ is a bond, methylene, neopentylene or C ２ ~C ３ It is alkenylene, A is a bond, -OC (=O)-*, 【Chemistry 37】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; L ３ This is the spacer part; R ２ (This is the hydrophilic part.) The antibody-drug conjugate according to claim 1 or 2.

24. -(L-D) is equation (D): 【Transformation 38】 (In the formula, R １ is a bonding group; L １ It is a bridging spacer; Lp is a peptide group containing 1 to 6 amino acids; A is a bond, -OC (=O)-*, 【Chemistry 39】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ is independently selected from H, C １ to C ６ alkyl, and C ３ to C ８ cycloalkyl, and * of A indicates the bonding point to D; L ３ This is the spacer part; R ２ (This is the hydrophilic part.) An antibody-drug conjugate according to claim 23, or a pharmaceutically acceptable salt thereof.

25. (1) L １ but, 【Chemistry 40】 or *-CH(OH)CH(OH)CH(OH)CH(OH)-**, (where each n is an integer from 1 to 12, and L １ the * of indicates a direct or indirect bonding point to Lp, and L １ the ** of indicates a direct or indirect bonding point to R １ ).) (2) L １ but, 【Chemistry 41】 And n is an integer from 1 to 12, or n is 1, or n is 12, L １ The asterisk (*) indicates a direct or indirect connection point to Lp, and L １ ** is R １ This indicates direct or indirect connection points to; (3) L １ but, 【Chemistry 42】 And n is an integer from 1 to 12, L １ The asterisk (*) indicates a direct or indirect connection point to Lp, and L １ ** is R １ This indicates direct or indirect connection points to; (4) L １ but, 【Chemistry 43】 Includes, In the ceremony, L １ The asterisk (*) indicates a direct or indirect connection point to Lp, and L １ ** is R １ This indicates direct or indirect connection points to; (5) L １ but, *-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**; *-C(=O)NH((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ -**; *-C(=O)O(CH ２ ) ｍ SSC(R ３ ) ２ (CH ２ ) ｍ C(=O)NR ３ (CH ２ ) ｍ NR ３ C(=O)(CH ２ ) ｍ -**; *-C(=O)O(CH ２ ) ｍ C(=0)NH(CH ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ NH(CH) ２ ) ｍ -**; *-C(=O)(CH ２ ) ｍ NH(CH) ２ ) ｎ C(=O)-**;*-C(=O)(CH ２ ) ｍ X １ (CH) ２ ) ｍ -**; *-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ X １ (CH) ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC(=0)(CH ２ ) ｎ -**; *-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ -**; *-C(=O)(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 (CH) ２ ) ｎ -**; *-C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ C(=O)NH(CH ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ C(R ３ ) ２ -** or *-C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - A crosslinking spacer containing **, where L １ The asterisk (*) indicates a direct or indirect connection point to Lp, and L １ ** is R １ This indicates direct or indirect connection points to; X １ but, 【Chemistry 44】 And; and Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30; Each R ３ H and C are independent of each other. １ ~C ６ An antibody-drug conjugate according to claim 23 or 24, selected from alkyl groups.

26. R ２ However, polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 【Chemistry 45】 C replaced by ２ ~C ６ Alkyl, or -OC(=O)NHS(O) ２ NHCH ２ CH ２ OCH ３ , -NHC(=O)C １～４ Alkylene-P(O)(OCH) ２ CH ３ ) ２ and C substituted with one or two substituents independently selected from the -COOH group ２ ~C ６ The antibody-drug conjugate according to any one of claims 23 to 25, wherein the hydrophilic portion contains an alkyl group.

27. R ２ but, 【Chemistry 46】 (In the formula, n is an integer between 1 and 6.) 【Chemistry 47】 The antibody-drug conjugate according to any one of claims 23 to 26.

28. The hydrophilic portion is (i) Polysarcosine having the following portion: 【Chemistry 48】 (In the formula, n is an integer between 3 and 25, and R is H, -CH) ３ or -CH ２ CH ２ (It is C(=O)OH) or (ii) Polyethylene glycol of the following formula: 【Chemistry 49】 (In the formula, R is H, -CH) ３ ,CH ２ CH ２ NHC(=O)OR ａ ien-CH ２ CH ２ NHC(=O)R ａ or -CH ２ CH ２ C (=O) OR ａ And R' is OH, -OCH ３ ien-CH ２ CH ２ NHC(=O)OR ａ ien-CH ２ CH ２ NHC(=O)R ａ or -OCH ２ CH ２ C (=O) OR ａ And here, R ａ H, or optionally OH or C １～４ C substituted with any of the alkoxyls １～４ (It is an alkyl group, and m and n are independently integers between 2 and 25.) The antibody-drug conjugate according to claim 23 or 24, comprising:

29. The hydrophilic portion is [Transformation 50] An antibody-drug conjugate according to any one of claims 23 to 27, comprising:

30. i) L ３ However, structure 【Chemistry 51】 (In the formula, W is -CH ２ -ien-CH ２ O-, -CH ２ N(R) ｂ )C(=O)O-, -NHC(=O)C(R ｂ ) ２ NHC(=O)O-, -NHC(=O)C(R ｂ ) ２ NH-, -NHC(=O)C(R ｂ ) ２ NHC(=O)-,-CH ２ N (X-R ２ )C(=O)O-, -C(=O)N(X-R ２ ) -, -CH ２ N (X-R ２ )C(=O)-, -C(=O)NR ｂ -, -C(=O)NH-, -CH ２ NR ｂ C(=O)-, -CH ２ NR ｂ C(=O)NH-, -CH ２ NR ｂ C(=O)NR ｂ -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl; X is a bond, triazolyl, or -CH ２ -Triazolyl-, X is R ２ (It is connected to) A spacer portion having; or (ii) L ３ However, structure 【Chemistry 52】 (In the formula, W is -CH ２ -ien-CH ２ O-, -CH ２ N(R) ｂ )C(=O)O-, -NHC(=O)C(R ｂ ) ２ NHC(=O)O-, -NHC(=O)C(R ｂ ) ２ NH-, -NHC(=O)C(R ｂ ) ２ NHC(=O)-,-CH ２ N (X-R ２ )C(=O)O-, -C(=O)N(X-R ２ ) -, -CH ２ N (X-R ２ )C(=O)-, -C(=O)NR ｂ -, -C(=O)NH-, -CH ２ NR ｂ C(=O)-, -CH ２ NR ｂ C(=O)NH-, -CH ２ NR ｂ C(=O)NR ｂ -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl; X is -CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-, -C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-,-(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-,-(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -ien-CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -, -C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ - and each n is independently 1, 2, or 3, and X is R ２ (It is connected to) The antibody-drug conjugate according to any one of claims 23 to 29, wherein the spacer portion has a spacer portion.

31. The antibody-drug conjugate according to any one of claims 3 to 30, wherein the binding group is formed by a reaction involving at least one reactive group.

32. The aforementioned bonding group, A first reactive group bonded to the conjugate linker, and The antibody or its antigen-binding fragment is bound to it, or a second reactive group which is an amino acid residue of the antibody or its antigen-binding fragment is formed by reacting with it, optionally, (i) At least one of the reactive groups is Thiol, Maleimide, Haloacetamide, Azid, Alkin, Cyclocotene, Triarylphosphine, Oxanorbornadiene, Cyclooctin, diaryltetrazine, Monoaryltetrazine, Norbornen, aldehyde, Hydroxylamine, Hydrazine, NH ２ -NHH-C(=O)-、 Ketones, Vinyl sulfone, Aziridine, amino acid residues, 【Chemistry 53】 !-ONH ２ 、-NH ２ 、 【Chemistry 54】 、-N ３ 、 【Transformation 55】 、-SH、-SR ３ 、-SSR ４ 、-S(=O) ２ (CH=CH ２ )、-(CH ２ ) ２ S(=O) ２ (CH=CH ２ )、-NHS(=O) ２ (CH=CH ２ )、-NHC(=O)CH ２ Br、-NHC(=O)CH ２ I、 【Transformation 56】 、-C(O)NHNH ２ 、 【Chemistry 57】 【Transformation 58】 (In the formula, Each R ３ H and C １ ~C ６ Selected independently of alkyl; Each R ４ It is 2-pyridyl or 4-pyridyl; Each R ５ H and C are independent of each other. １ ~C ６ Selected from alkyl, F, Cl, and -OH, Each R ６ H and C are independent of each other. １ ~C ６ Alkyl, F, Cl, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -N(CH ３ ) ２ -CN, -NO ２ Selected from and -OH, Each R ７ H and C are independent of each other. １～６ Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH １～４ C substituted with alkoxy and -C(=O)OH １～４ Includes (selected from alkyl); and / or (ii) The first reactive group and the second reactive group Thiols and maleimides, Thiols and haloacetamides, Thiols and vinyl sulfones, Thiols and aziridines, Azid and Alkyne, Azide and cyclooctin, Azide and cyclooctene, Azide and triarylphosphine, Azide and oxanorbornadiene, diaryltetradine and cyclooctene, Monoaryltetrazine and norbornene, 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 59】 amines and 【Transformation 60】 or An antibody-drug conjugate according to any one of claims 3 to 31, comprising CoA or a CoA analog and a serine residue.

33. The aforementioned bonding group, 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 Amido; 【Transformation 65】 ; and disulfide (In the formula, R ３２ H, C １～４ Alkyl, phenyl, pyrimidine, or pyridine; R ３５ H, C １～６ C substituted with alkyl, phenyl, or 1 to 3 -OH groups １～４ It is alkyl; Each R ７ H and C are independent of each other. １～６ Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH １～４ C substituted with alkoxy and -C(=O)OH １～４ Selected from alkyl groups; R ３７ These are independently selected from H, phenyl, and pyridine; q is 0, 1, 2, or 3; R ８ is H or methyl; and R ９ H, -CH ３ (or phenyl) An antibody-drug conjugate according to any one of claims 3 to 32, comprising a group selected from.

34. The antibody-drug conjugate according to any one of claims 23 to 33, wherein the peptide group comprises 1 to 4, 1 to 3, or 1 or 2 amino acid residues, wherein the amino acid residues are optionally selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr).

35. The antibody-drug conjugate according to any one of claims 23 to 33, wherein the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, sulfo-Ala-Val, and / or sulfo-Ala-Val-Ala.

36. LP, 【Chemical Formula 66】 An antibody-drug conjugate according to any one of claims 23 to 35, selected from the above.

37. -(L-D) is the compound shown in the following equation: 【Transformation 67】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Transformation 68】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Transformation 69】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Transformation 70】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 71】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Chemistry 72】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Transformation 73】 (In the formula, Each R is independently H, -CH ３ and -CH ２ CH ２ Selected from C(=O)OH; A is a bond, -OC (=O)-*, 【Chemistry 74】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 75】 (In the formula, Each R is independently H, -CH ３ and -CH ２ CH ２ Selected from C(=O)OH; A is a bond, -OC (=O)-*, 【Transformation 76】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemical 77】 (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 It is C(=O)OH; A is a bond, -OC (=O)-*, 【Transformation 78】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Transformation 79】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Chemistry 80】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 81】 (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 It is C(=O)OH; A is a bond, -OC (=O)-*, 【Chemistry 82】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 83】 (In the formula, A is a bond, -OC (=O)-*, 【Chemical 84】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemical 85】 (In the formula, A is a bond, -OC (=O)-*, 【Chemical 86】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Transformation 87】 (In the formula, A is a bond, -OC (=O)-*, 【Chemical 88】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemical 89】 (In the formula, A is a bond, -OC (=O)-*, 【Chemistry 90】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 91】 (In the formula, A is a bond, -OC (=O)-*, 【Chemistry 92】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemistry 93】 (In the formula, A is a bond, -OC (=O)-*, 【Chemical 94】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor; 【Chemical 95】 (In the formula, A is a bond, -OC (=O)-*, 【Chemistry 96】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor); or 【Chemistry 97】 (In the formula, Each R is independently H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Chem.98】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor), or 【Chem.99】 (In the formula, Each R is independently H, -CH ３ or -CH ２ CH ２ It is C(=O)OH; A is a bond, -OC (=O)-*, 【Chemistry 100】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; n is an integer between 2 and 24; and D is a panRAS inhibitor), or 【Chemistry 101】 (In the formula, A is a bond, -OC (=O)-*, 【Chemical Engineering 102】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)-* or -OC(=O)N(CH ３ ) C (R ａ ) ２ C(R ａ ) ２ N(CH ３ )C (=O) - *, Each R ａ H and C are independent of each other. １ ~C ６ Alkyl and C ３ ~C ８ Selected from cycloalkyl groups, the asterisk (*) in A indicates the bond site to D; D is a panRAS inhibitor. An antibody-drug conjugate according to any one of claims 23 to 36, comprising or formed therefrom.

38. A is a bond, and / or R is -CH ３ or -CH ２ CH ２ The antibody-drug conjugate according to any one of claims 23 to 37, wherein it is a COOH.

39. A is -OC (=O)-* and / or R is -CH ３ or -CH ２ CH ２ The antibody-drug conjugate according to any one of claims 23 to 37, wherein it is a COOH.

40. - (L-D) is, 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 【Chemical 115】 【Chemistry 116】 An antibody-drug conjugate according to any one of claims 23 to 39, formed from a compound selected from.

41. D is the compound of formula (Ia): 【Chemistry 117】 or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A Ｄ is -N(H or CH ３ )C(O)-(CH ２ )-(Here, amino nitrogen is -C(R Ｄ１０ａ ) (Caution Ｄ１０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; Y Ｘ teeth, 【Chemistry 118】 And, During the ceremony, 【Chemical 119】 is, X Ｄ３ Show the point of connection; 【Chemical 120】 is, W Ｘ It indicates the point of connection to; or Y Ｘ is -N(R Ｄ１１ )-CO-B Ｄ -L Ｄ - and; B Ｄ is -CH(R Ｄ９ ) - or > C = CR Ｄ９ R Ｄ９’ (Here, carbon is -N(R) Ｄ１１ ) bonded to the carbonyl carbon of C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L Ｄ It either does not exist or is a linker; G Ｄ is an arbitrarily substituted C １ ~C ４ Alkylene, optionally substituted C １ ~C ４ Alkenylene, optionally substituted C １ ~C ４ Heteroalkylene, -C(O)O-CH(R Ｄ６ ) - (Here, -CH(R Ｄ６ )- is -C(R Ｄ７ R Ｄ８ )--bonded),-C(O)NH-CH(R Ｄ６ ) - (Here, -CH(R Ｄ６ )- is -C(R Ｄ７ R Ｄ８ ) - which is joined to, optionally replaced C １ ~C ４ They are heteroalkylenes or 3- to 8-membered heteroarylenes; W Ｘ C is a hydrogen atom, a cyanonucleotide, or an optionally substituted carbon atom. １ ~C ３ Heteroalkyl, optionally substituted amino, optionally substituted C １ ~C ４ alkoxy, optionally substituted C １ ~C ４ Hydroxyalkyl, optionally substituted C １ ~C ４ aminoalkyl, optionally substituted C １ ~C ４ Haloalkyl, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ４ Guanidinoalkyl, C ０ ~C ４ Alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 3-8 member heteroaryl; X Ｄ１ is an arbitrarily substituted C １ ~C ２ Alkylene, NR Ｄ , O, or S(O) ｎＤ And; X Ｄ２ is O or NH; X Ｄ３ is N or CH; nd is 0, 1, or 2; R Ｄ C is a hydrogen atom, a cyanonucleotide, or an optionally substituted carbon atom. １ ~C ４ Alkyl, optionally substituted C ２ ~C ４ Alkenyl, optionally substituted C ２ ~C ４ Alkinyl, C(O)R Ｄ’ , C(O)OR Ｄ’ , C(O)N(R Ｄ’ ) ２ S(O)R Ｄ’ , S(O) ２ R Ｄ’ , or S(O) ２ N(R) Ｄ’ ) ２ and; each R Ｄ’ This is independently H or optionally substituted C. １ ~C ４ It is alkyl; Y Ｄ１ is C, CH, or N; Y Ｄ２ , Y Ｄ３ , Y Ｄ４ , and Y Ｄ７ It is independently C or N; Y Ｄ５ CH, CH ２ or N; Y Ｄ６ C(O), CH, CH ２ or N; R Ｄ１ C is a cyano, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R Ｄ１ and R Ｄ２ These combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ２ is either absent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ The elements are alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R Ｄ３ It does not exist, or R Ｄ２ and R Ｄ３ These combine with the atoms to which they are bonded to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ４ is either absent, or methyl optionally substituted with hydrogen, halogen, cyano, or one to three halogens; R Ｄ５ C is optionally substituted with hydrogen and halogen. １ ~C ４ Alkyl, cyano, hydroxy, or C １ ~C ４ It is an alkoxy, cyclopropyl, or cyclobutyl; R Ｄ６ is hydrogen or methyl; R Ｄ７ C is hydrogen, halogen, or optionally substituted C １ ~C ３ Alkyl, or R Ｄ６ and R Ｄ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ alkoxy, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７ and R Ｄ８ These combine with the carbon atoms to which they are bonded, resulting in C=CR Ｄ７’ R Ｄ８’ ;C=N(OH), C=N(OC １ ~C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ７ａ and R Ｄ８ａ These are, independently, hydrogen, halo, and optionally substituted C. １ ~C ３ They are alkyl, or combined with the carbon atom to which they are bonded, to form a carbonyl group; R Ｄ７’ C is hydrogen, halogen, or optionally substituted C １ ~C ３ It is alkyl; R Ｄ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ Alkoxyl, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７’ and R Ｄ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ９ is hydrogen, F, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group; R Ｄ９ and L Ｄ These combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ９’ C is hydrogen or optionally substituted C １ ~C ６ It is alkyl; R Ｄ１０ is hydrogen, halo, hydroxyl, C １ ~C ３ Alkoxyl, or C １ ~C ３ It is alkyl; R Ｄ１０ａ is hydrogen or halogen; R Ｄ１１ is hydrogen or C １ ~C ３ It is alkyl; R Ｄ１６ is hydrogen or C １ ~C ３ An antibody-drug conjugate according to any one of claims 1 to 40, wherein the conjugate is alkyl.

42. D is the compound of formula (I): 【Chemistry 121】 or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A Ｄ is -N(H or CH ３ )C(O)-(CH ２ )-(Here, amino nitrogen is -C(R Ｄ１０ａ ) (Caution Ｄ１０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B Ｄ is -CH(R Ｄ９ ) - or > C = CR Ｄ９ R Ｄ９’ (Here, carbon is -N(R) Ｄ１１ ) bonded to the carbonyl carbon of C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G Ｄ is optionally substituted C １ to C ４ alkylene, optionally substituted C １ to C ４ alkenylene, optionally substituted C １ to C ４ heteroalkylene, -C(O)O-CH(R Ｄ６ )(where -CH(R Ｄ６ )- is bonded to -C(R Ｄ７ R Ｄ８ )-), -C(O)NH-CH(R Ｄ６ )(where -CH(R Ｄ６ )- is bonded to -C(R Ｄ７ R Ｄ８ )-), optionally substituted C １ to C ４ heteroalkylene, or 3- to 8-membered heteroarylene; L Ｄ It either does not exist or is a drug linker; W Ｄ is hydrogen, cyano, optionally substituted amino, optionally substituted C １ ~C ４ alkoxy, optionally substituted C １ ~C ４ Hydroxyalkyl, optionally substituted C １ ~C ４ aminoalkyl, optionally substituted C １ ~C ４ Haloalkyl, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ４ Guanidinoalkyl, C ０ ~C ４ Alkyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 3-8 member heteroaryl, X Ｄ１ is an arbitrarily substituted C １ ~C ２ Alkylene, NR Ｄ , O, or S(O) ｎＤ And; X Ｄ２ is O or NH; X Ｄ３ is N or CH; nd is 0, 1, or 2; R Ｄ C is a hydrogen atom, a cyanonucleotide, or an optionally substituted carbon atom. １ ~C ４ Alkyl, optionally substituted C ２ ~C ４ Alkenyl, optionally substituted C ２ ~C ４ Alkinyl, C(O)R Ｄ’ , C(O)OR Ｄ’ , C(O)N(R Ｄ’ ) ２ S(O)R Ｄ’ , S(O) ２ R Ｄ’ , or S(O) ２ N(R) Ｄ’ ) ２ and; each R Ｄ’ This is independently H or optionally substituted C. １ ~C ４ It is alkyl; Y Ｄ１ is C, CH, or N; Y Ｄ２ , Y Ｄ３ , Y Ｄ４ , and Y Ｄ７ It is independently C or N; Y Ｄ５ CH, CH ２ or N; Y Ｄ６ C(O), CH, CH ２ or N; R Ｄ１ C is a cyano, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R Ｄ１ and R Ｄ２ are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R Ｄ２ is either absent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ The elements are alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R Ｄ３ It does not exist, or R Ｄ２ and R Ｄ３ These combine with the atoms to which they are bonded to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ４ is either absent, or methyl optionally substituted with hydrogen, halogen, cyano, or one to three halogens; R Ｄ５ C is optionally substituted with hydrogen and halogen. １ ~C ４ Alkyl, cyano, hydroxy, or C １ ~C ４ It is an alkoxy, cyclopropyl, or cyclobutyl; R Ｄ６ is hydrogen or methyl; R Ｄ７ C is hydrogen, halogen, or optionally substituted C １ ~C ３ Alkyl, or R Ｄ６ and R Ｄ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ alkoxy, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７ and R Ｄ８ These combine with the carbon atoms to which they are bonded, resulting in C=CR Ｄ７’ R Ｄ８’ ;C=N(OH), C=N(OC １ ~C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ７ａ and R Ｄ８ａ These are, independently, hydrogen, halo, and optionally substituted C. １ ~C ３ They are alkyl, or combined with the carbon atom to which they are bonded, to form a carbonyl group; R Ｄ７’ C is hydrogen, halogen, or optionally substituted C １ ~C ３ It is alkyl; R Ｄ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ Alkoxyl, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７’ and R Ｄ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ９ is hydrogen, F, and optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group; R Ｄ９ and L Ｄ These combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ９’ C is hydrogen or optionally substituted C １ ~C ６ It is alkyl; R Ｄ１０ is hydrogen, halo, hydroxyl, C １ ~C ３ Alkoxyl, or C １ ~C ３ It is alkyl; R Ｄ１０ａ is hydrogen or halogen; R Ｄ１１ is hydrogen or C １ ~C ３ It is alkyl; R Ｄ１６ is hydrogen or C １ ~C ３ The antibody-drug conjugate according to claim 41, wherein it is alkyl.

43. D is the compound of formula (Ic): 【Chemistry 122】 or comprising a pharmaceutically acceptable salt thereof, in the formula, The dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A Ｄ is -N(H or CH ３ )C(O)-(CH ２ )-(Here, amino nitrogen is -CH(R Ｄ１０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B Ｄ is -CH(R Ｄ９ )-(Here, carbon is -N(R Ｄ１１ ) bonded to the carbonyl carbon of C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L Ｄ It either does not exist or is a drug linker; W Ｄ is hydrogen, optionally substituted amino acids, optionally substituted C １ ~C ４ alkoxy, optionally substituted C １ ~C ４ Hydroxyalkyl, optionally substituted C １ ~C ４ aminoalkyl, optionally substituted C １ ~C ４ Haloalkyl, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ４ Guanidinoalkyl, C ０ ~C ４ Alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X Ｄ２ is O or NH; X Ｄ３ is N or CH; R Ｄ C is a hydrogen atom, a cyanonucleotide, or an optionally substituted carbon atom. １ ~C ４ Alkyl, optionally substituted C ２ ~C ４ Alkenyl, optionally substituted C ２ ~C ４ Alkinyl, C(O)R Ｄ’ , C(O)OR Ｄ’ , C(O)N(R Ｄ’ ) ２ S(O)R Ｄ’ , S(O) ２ R Ｄ’ , or S(O) ２ N(R) Ｄ’ ) ２ And; Each R Ｄ’ This is independently H or optionally substituted C. １ ~C ４ It is alkyl; Y Ｄ１ is C, CH, or N; Y Ｄ２ , Y Ｄ３ , Y Ｄ４ , and Y Ｄ７ It is independently C or N; Y Ｄ５ and Y Ｄ６ These are independently CH or N; R Ｄ１ C is a cyano, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-6 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group; R Ｄ２ is hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ The alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R Ｄ３ It does not exist; or R Ｄ２ and R Ｄ３ These combine with the atoms to which they are bonded to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R Ｄ４ is either absent, or methyl optionally substituted with hydrogen, halogen, cyano, or one to three halogens; R Ｄ５ C is optionally substituted with hydrogen and halogen. １ ~C ４ Alkyl, cyano, hydroxy, or C １ ~C ４ It is an alkoxy, cyclopropyl, or cyclobutyl; R Ｄ６ is hydrogen or methyl; R Ｄ７ C is hydrogen, halogen, or optionally substituted C １ ~C ３ Alkyl, or R Ｄ６ and R Ｄ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ alkoxy, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７ and R Ｄ８ These combine with the carbon atoms to which they are bonded, resulting in C=CR ７’ R ８’ ;C=N(OH), C=N(OC １ ~C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ７’ C is hydrogen, halogen, or optionally substituted C １ ~C ３ It is alkyl; R Ｄ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ ~C ３ alkoxy, optionally substituted C １ ~C ３ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R Ｄ７’ and R Ｄ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R Ｄ９ is an arbitrarily substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group; R Ｄ１０ is hydrogen, hydroxyl, C １ ~C ３ Alkoxy, or C １ ~C ３ It is alkyl; R Ｄ１１ is hydrogen or C １ ~C ３ The antibody-drug conjugate according to claim 41 or 42, wherein it is alkyl.

44. D is the compound of formula (If): 【Chemical 123】 or comprising a pharmaceutically acceptable salt thereof, in the formula, A Ｄ is -N(H or CH ３ )C(O)-(CH ２ )-(Here, the amino nitrogen is -CH ２ - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B Ｄ is -CH(R Ｄ９ )-(where the carbon is bonded to the carbonyl carbon of -NHC(O)-), which are optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; L Ｄ It either does not exist or is a drug linker; W Ｄ is hydrogen, optionally substituted amino acids, optionally substituted C １ ~C ４ alkoxy, optionally substituted C １ ~C ４ Hydroxyalkyl, optionally substituted C １ ~C ４ aminoalkyl, optionally substituted C １ ~C ４ Haloalkyl, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ４ Guanidinoalkyl, C ０ ~C ４ Alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R Ｄ１ C is a cyano, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-6 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group; R Ｄ２ C １ ~C ６ They are alkyl or 3-6 membered cycloalkyl groups; R Ｄ７ C １ ~C ３ It is alkyl; R Ｄ８ C １ ~C ３ Alkyl; and R Ｄ９ is an arbitrarily substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The antibody-drug conjugate according to any one of claims 41 to 43, wherein the conjugate is a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, or an optionally substituted 3-7 membered heterocycloalkyl group.

45. R Ｄ１ The antibody-drug conjugate according to any one of claims 41 to 44, wherein the conjugate is a 5- to 10-membered heteroaryl.

46. R Ｄ１ The antibody-drug conjugate according to any one of claims 41 to 45, wherein the adjective is an optionally substituted six-membered aryl or an optionally substituted six-membered heteroaryl.

47. D is A Ｄ or R Ｄ１ The antibody-drug conjugate according to any one of claims 41 to 46, which is coupled to the conjugate linker represented by L at a given position.

48. D is the compound of formula (Ig): 【Chemistry 124】 or comprising a pharmaceutically acceptable salt thereof, in the formula, A Ｄ is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B Ｄ is -CH(R Ｄ９ )-(where the carbon is bonded to the carbonyl carbon of -NHC(O)-), which are optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes; L Ｄ It either does not exist or is a drug linker; W Ｄ is hydrogen, optionally substituted amino acids, optionally substituted C １ ~C ４ alkoxy, optionally substituted C １ ~C ４ Hydroxyalkyl, optionally substituted C １ ~C ４ aminoalkyl, optionally substituted C １ ~C ４ Haloalkyl, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ４ Guanidinoalkyl, C ０ ~C ４ Alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R Ｄ２ C １ ~C ６ They are alkyl or 3-6 membered cycloalkyl groups; R Ｄ７ C １ ~C ３ It is alkyl; R Ｄ８ C １ ~C ３ It is alkyl; R Ｄ９ is an arbitrarily substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group; X Ｄｅ is N, CH, or CR Ｄ１７ And; X Ｄｆ is N or CH; R Ｄ１２ is an arbitrarily substituted C １ ~C ６ Alkyl or optionally substituted C １ ~C ６ It is heteroalkyl; R Ｄ１７ is an arbitrarily substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ The antibody-drug conjugate according to any one of claims 41 to 47, wherein the conjugate is a heteroalkyl, an optionally substituted 3-6 member cycloalkyl, an optionally substituted 3-6 member cycloalkenyl, an optionally substituted 3-6 member heterocycloalkyl, an optionally substituted 6-10 member aryl, or an optionally substituted 5-10 member heteroaryl.

49. A Ｄ The antibody-drug conjugate according to any one of claims 41 to 48, wherein the six-membered arylene is optionally substituted.

50. A Ｄ The antibody-drug conjugate according to any one of claims 41 to 49, wherein the 5-6 member heteroarylene is optionally substituted.

51. B Ｄ However, -CHR Ｄ９ - The antibody-drug conjugate according to any one of claims 41 to 50.

52. R Ｄ９ However, C is arbitrarily substituted. １ ~C ６ The antibody-drug conjugate according to any one of claims 41 to 51, wherein it is an alkyl or optionally substituted 3- to 6-membered cycloalkyl.

53. The drug linker has the structure of formula II: A Ｄ１ -(B Ｄ１ ) ｆＤ -(C Ｄ１ ) ｇＤ -(B Ｄ２ ) ｈＤ -(D Ｄ１ )-(B Ｄ３ ) ｉＤ -(C Ｄ２ ) ｊＤ -(B Ｄ４ ) ｋＤ -A Ｄ２ Formula II And, During the ceremony, A Ｄ１ This is the bond between the drug linker and B; A Ｄ２ This is the bond between W and the drug linker; B Ｄ１ , B Ｄ２ , B Ｄ３ , and B Ｄ４ Each of these is an independently and arbitrarily substituted C １ ~C ２ Alkylene, optionally substituted C １ ~C ３ Heteroalkylenes, O, S, and NR ＤＮ Selected from; R ＤＮ is hydrogen, optionally substituted C １ ~C ４ Alkyl, optionally substituted C １ ~C ３ Cycloalkyl, optionally substituted C ２ ~C ４ Alkenyl, optionally substituted C ２ ~C ４ Alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C １ ~C ７ It is heteroalkyl; C Ｄ１ and C Ｄ２ Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; fD, gD, hD, iD, jD, and kD are each independently either 0 or 1; D Ｄ１ is an arbitrarily substituted C １ ~C １０ Alkylene, optionally substituted C ２ ~C １０ Alkenylene, optionally substituted C ２ ~C １０ Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C ２ ~C １０ Polyethylene glycolen, or optionally substituted C １ ~C １０ Heteroalkylene, or A Ｄ１ - (B Ｄ１ ) ｆＤ - (C Ｄ１ ) ｇＤ - (B Ｄ２ ) ｈＤ - to - (B Ｄ３ ) ｉＤ - (C Ｄ２ ) Ｄｊ - (B Ｄ４ ) Ｄｋ -A Ｄ２ An antibody-drug conjugate according to any one of claims 41 to 52, wherein the chemical bond is linked to the

54. The drug linker has the structure of formula IIa: 【Chemistry 125】 It has, During the ceremony, X Ｄａ It either does not exist or is N; R Ｄ１４ is either absent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ ~C ６ Alkyl or optionally substituted C １ ~C ３ It is a cycloalkyl; L Ｄ２ It does not exist, or -C(O)-, -SO ２ -, arbitrarily substituted C １ ~C ４ Alkylene or optionally substituted C １ ~C ４ It is a heteroalkylene, and here, X Ｄａ , R Ｄ１４ , or L Ｄ２ An antibody-drug conjugate according to any one of claims 41 to 53, wherein at least one of the following exists.

55. W Ｄ The antibody-drug conjugate according to any one of claims 41 to 54, wherein is hydrogen.

56. W Ｄ However, C ０ ~C ４ The antibody-drug conjugate according to any one of claims 41 to 54, wherein the conjugate is an alkyl or an optionally substituted 3 to 11-membered heterocycloalkyl.

57. D is A Ｄ or R Ｄ１７ An antibody-drug conjugate according to any one of claims 46 to 56, which is coupled to the conjugate linker represented by L at a given position.

58. D is the compound of formula (Ih): 【Chemistry 126】 or comprising a pharmaceutically acceptable salt thereof, in the formula, R Ｄ２ C １ ~C ３ It is alkyl; R Ｄ７ C １ ~C ３ It is alkyl; R Ｄ８ C １ ~C ３ It is alkyl; R Ｄ９ C １ ~C ６ It is alkyl; R Ｄ１４ is hydrogen or C １～ C ６ It is alkyl, R Ｄ１７ is an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl; W Ｄ The antibody-drug conjugate according to any one of claims 41 to 47, wherein is an optionally substituted 3 to 11-membered heterocycloalkyl group.

59. R Ｄ９ C １ ~C ３ It is alkyl; R Ｄ１４ C １ ~C ３ It is alkyl; R Ｄ１７ is an optionally substituted 3- to 6-membered heterocycloalkyl; W Ｄ The antibody-drug conjugate according to claim 58, wherein is an optionally substituted 5-6 member heterocycloalkyl.

60. D is 【Chemistry 127】 Compounds represented by The antibody-drug conjugate according to claim 58 or 59, comprising a pharmaceutically acceptable salt thereof.

61. D is the compound of formula (In): 【Chemistry 128】 The antibody-drug conjugate according to claim 41, comprising or a pharmaceutically acceptable salt thereof, wherein aD is 0 or 1.

62. D is the compound of formula (Ij): 【Chemistry 129】 The antibody-drug conjugate according to claim 41, comprising or a pharmaceutically acceptable salt thereof, wherein aD is 0 or 1.

63. D is the compound of formula (Ik): 【Chemistry 130】 The antibody-drug conjugate according to claim 41, comprising the pharmaceutically acceptable salt thereof, wherein aD is 0 or 1.

64. D is the compound of formula (Im): 【Chemistry 131】 The antibody-drug conjugate according to claim 41, comprising the pharmaceutically acceptable salt thereof, wherein aD is 0 or 1.

65. The antibody-drug conjugate according to any one of claims 1 to 40, wherein D comprises a group represented by a formula selected from Table A2.

66. The antibody-drug conjugate according to any one of claims 1 to 65, wherein the antibody or its antigen-binding fragment binds to a target antigen on cancer cells.

67. The antibody-drug conjugate according to claim 66, wherein the target antigen is EphA2 or B7-H3 (CD276).

68. The antibody-drug conjugate according to any one of claims 1 to 67, wherein the antibody or its antigen-binding fragment is an anti-EphA2 antibody or its antigen-binding fragment.

69. The anti-EphA2 antibody or its antigen-binding fragment, 1) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 17, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 18, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 26, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 28; 2) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 20, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 21, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 29, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 30, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31; 3) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 22, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 23, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 24; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 32, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31; and 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 25, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 21, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 29, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 30, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 31 The antibody-drug conjugate according to claim 68, comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of the following.

70. The anti-EphA2 antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 11 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

12. The antibody-drug conjugate according to claim 68 or 69, comprising:

71. The anti-EphA2 antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 3 and a light chain containing the amino acid sequence of SEQ ID NO: 5 An antibody-drug conjugate according to any one of claims 68 to 70, comprising:

72. The antibody-drug conjugate according to any one of claims 1 to 67, wherein the antibody or its antigen-binding fragment is an anti-B7-H3 (CD276) antibody or an antigen-binding fragment.

73. The anti-B7-H3 (CD276) antibody is 1) Heavy chain CDR1 (HCDR1) consisting of sequence number 33, heavy chain CDR2 (HCDR2) consisting of sequence number 34, heavy chain CDR3 (HCDR3) consisting of sequence number 35; light chain CDR1 (LCDR1) consisting of sequence number 42, light chain CDR2 (LCDR2) consisting of sequence number 43, and light chain CDR3 (LCDR3) consisting of sequence number 44; 2) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 36, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 37, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 45, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 46, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47; 3) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 38, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 39, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 40; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 48, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47; 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 41, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 37, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 45, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 46, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 47 The antibody-drug conjugate according to claim 72, comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of the above.

74. The anti-B7-H3 (CD276) antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 13 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

14. The antibody-drug conjugate according to claim 72 or 73, comprising:

75. The anti-B7-H3 (CD276) antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 7 and a light chain containing the amino acid sequence of SEQ ID NO:

8. An antibody-drug conjugate according to any one of claims 72 to 74, comprising:

76. The anti-B7-H3 (CD276) antibody is 1) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 49, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 50, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 58, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 59, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 60; 2) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 52, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 53, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 61, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 62, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63; 3) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 54, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 55, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 56; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 58, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 59, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63; and 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 57, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 53, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 51; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 61, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 62, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 63 The antibody-drug conjugate according to claim 72, comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of the above.

77. The anti-B7-H3 (CD276) antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 15 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

16. The antibody-drug conjugate according to claim 72 or 76, comprising:

78. The anti-B7-H3 (CD276) antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10. An antibody-drug conjugate according to any one of claims 72, 76, or 77, comprising:

79. (a) The antibody or its antigen-binding fragment comprises an IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain, optionally the IgG1 heavy chain constant domain comprising cysteine ​​residues (C) at positions 152 and 375, the positions numbered according to the EU system; and / or (b) The antibody-drug conjugate according to any one of claims 1 to 78, wherein the antibody or antigen-binding fragment thereof comprises an Igκ light chain constant domain.

80. A composition comprising a plurality of copies of an antibody-drug conjugate according to any one of claims 1 to 79, wherein the average p of the antibody-drug conjugate in the composition is about 2 to about 16, for example, about 2 to about 8, for example, about 2 to about 4.

81. A pharmaceutical composition comprising an antibody-drug conjugate according to any one of claims 1 to 79 or the composition according to claim 80 and a pharmaceutically acceptable carrier.

82. A method for treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81.

83. The method according to claim 82, wherein the cancer expresses a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

84. The method according to claim 82 or 83, wherein the cancer is a tumor or hematological cancer, and optionally the cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytotic myeloma, leukemia, lymphoma, sarcoma, gastric cancer or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T cell or B cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

85. A method for reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81.

86. The method according to claim 85, wherein the tumor expresses a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

87. The method according to claim 85 or 86, wherein the tumor is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytotic myeloma, leukemia, lymphoma, sarcoma, gastric cancer or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T-cell or B-cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

88. A method for reducing or inhibiting hematological cancer in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81.

89. The method according to claim 88, wherein the hematological cancer expresses a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

90. The method according to claim 88 or 89, wherein the hematological cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin lymphoma, non-Hodgkin lymphoma, or myelogenesis imperfecta (MDS).

91. The method according to any one of claims 85 to 90, wherein administration of the antibody drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor or hematological cancer 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%.

92. A method for reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81.

93. The method according to claim 92, wherein the cancer cell population expresses a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

94. The method according to claim 92 or 93, wherein the cancer cell population originates from a tumor or hematological cancer, and optionally, the cancer cell population originates from breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytotic myeloma, leukemia, lymphoma, sarcoma, gastric cancer or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T cell or B cell origin, metastatic castration-resistant prostate cancer, bladder urothelial carcinoma, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

95. The method according to any one of claims 92 to 94, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

96. The method according to any one of claims 82 to 95, wherein the antibody-drug conjugate is administered as monotherapy.

97. The method according to any one of claims 82 to 95, wherein the antibody-drug conjugate is administered incidentally to another therapeutic agent or radiotherapy.

98. The method according to claim 97, wherein the antibody-drug conjugate is administered in an amount effective to sensitize the tumor cells to one or more additional therapeutic agents and / or radiotherapy.

99. The method according to any one of claims 82 to 95, further comprising administering at least one additional therapeutic agent to the subject requiring treatment.

100. A method for inhibiting panRAS activity in cells expressing panRAS, comprising contacting the cells with an antibody-drug conjugate according to any one of claims 1 to 79, which is capable of binding to the cells, under conditions that the antibody-drug conjugate binds to the cells.

101. A method for determining whether a subject having or suspected of having cancer will respond to treatment with an antibody-drug conjugate according to any one of claims 1 to 79, a composition according to claim 80, or a pharmaceutical composition according to claim 81, the method comprising: providing a biological sample derived from the subject; contacting the sample with the antibody-drug conjugate; and detecting the binding of the antibody-drug conjugate to cancer cells in the sample.

102. The method according to claim 101, wherein the cancer cells in the sample express a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

103. The method according to claim 101 or claim 102, wherein the cancer expresses a target antigen, and optionally the target antigen is EphA2 or B7-H3 (CD276).

104. The method according to any one of claims 101 to 103, wherein the cancer is a tumor or hematological cancer, and optionally the cancer is breast cancer including ER-positive breast cancer, multiple myeloma, plasmacytotic myeloma, leukemia, lymphoma, sarcoma, gastric cancer or stomach cancer, acute myeloid leukemia, bladder cancer, brain tumor, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid tumor of T cell or B cell origin, metastatic castration-resistant prostate cancer, urothelial carcinoma of the bladder, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, splenic cancer, or head and neck cancer.

105. The method according to any one of claims 101 to 104, wherein the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

106. The method according to any one of claims 83 to 105, wherein the target antigen is EphA2.

107. The method according to any one of claims 83 to 105, wherein the target antigen is B7-H3 (CD276).

108. A method for generating an antibody-drug conjugate according to any one of claims 1 to 80, comprising reacting an antibody or antigen-binding fragment with a cleavable linker conjugated to a panRAS inhibitor under conditions that enable conjugation.

109. The method according to claim 108, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody or antigen-binding fragment or a B7-H3 (CD276) antibody or antigen-binding fragment.

110. The method according to claim 109, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody or an antigen-binding fragment.

111. The method according to claim 109, wherein the antibody or antigen-binding fragment is a B7-H3 (CD276) antibody or antigen-binding fragment.

112. Use of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81 for the manufacture of a drug for treating a subject having or suspected of having cancer.

113. Use of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81 for the manufacture of a drug for reducing or inhibiting tumor growth in a target.

114. Use of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81 for the manufacture of a drug for reducing or inhibiting blood cancer in a subject.

115. Use of an antibody-drug conjugate according to any one of claims 1 to 79, the composition according to claim 80, or the pharmaceutical composition according to claim 81 for the manufacture of a drug for reducing or inhibiting the expansion of a cancer cell population in a target.

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