Antibody-drug conjugates of anti-neoplastic compounds and methods of use thereof

Abstract

Disclosed is an antibody-drug conjugate that binds to human oncology targets.The antibody-drug conjugate comprises an antibody or its antigen-binding fragment that is covalently linked to two anti-neoplastic drug payloads through a dual linker, where at least one of the anti-neoplastic drug payloads is a BH3 mimetic.The disclosure further relates to a method and composition for use in treating cancer by administering the antibody-drug conjugate provided herein.Also disclosed is a linker-drug conjugate that comprises at least one BH3 mimetic and a method for making it.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of the 35 U.S.C. §119(e) filing date of U.S. Provisional Application No. 63 / 344,510, filed May 20, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure relates to an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof covalently linked to two antineoplastic drug compounds through a dual linker, where at least one antineoplastic drug payload is a BH3 mimetic. The present disclosure further relates to methods and compositions useful for treating and / or diagnosing cancers that express target antigens and / or are suitable for treatment by modulating the expression and / or activity of Bcl-2 family proteins, and methods of making these compositions. Linker-drug conjugates comprising a dual linker and antineoplastic drug compounds (e.g., two BH3 mimetics or a BH3 mimetic moiety and an antineoplastic drug non-BH3 mimetic) and methods of making them are also disclosed. [Background technology]

[0003] 2. Background of the Invention Apoptosis (programmed cell death) is an evolutionarily conserved pathway essential for tissue homeostasis, development and elimination of damaged cells. Deregulation of apoptosis contributes to human diseases including malignant tumors, neurodegenerative disorders, immune system disorders and autoimmune diseases (Hanahan and Weinberg, Cell. 2011 Mar 4;144(5):646-74;Marsden and Strasser, Annu Rev Immunol. 2003;21:71-105;Vaux and Flavell, Curr Opin Immunol. 2000 Dec;12(6):719-24). Evasion of apoptosis has been recognized as a hallmark of cancer, involved in the development and sustained tumor growth and resistance to anticancer treatment (Hanahan and Weinberg, Cell. 2000 Jan 7;100(1):57-70).

[0004] The Bcl-2 protein family contains important regulators of cell survival that can suppress (e.g., Bcl-2, Bcl-xL, Mcl-1) or promote (e.g., Bad, Bax) apoptosis (Gross et al., Genes Dev. 1999 Aug 1;13(15):1899-911; Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan;9(1):47-59).

[0005] In the face of stress stimuli, whether a cell survives or undergoes apoptosis depends on the degree of pairing between Bcl-2 family members that promote cell death and family members that promote cell survival. Generally, these interactions involve the docking of the Bcl-2 homology 3 (BH3) domain of the proapoptotic family member into a groove on the surface of the prosurvival member. The presence of a Bcl-2 homology (BH) domain defines the membership of the Bcl-2 family, which is divided into three main groups depending on the specific BH domain present in the protein. Prosurvival members such as Bcl-2, Bcl-xL, and Mcl-1 contain BH domains 1-4, while Bax and Bak, the proapoptotic effectors of mitochondrial outer membrane permeabilization during apoptosis, contain BH domains 1-3 (Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan;9(1):47-59).

[0006] Overexpression of pro-survival members of the Bcl-2 family is a hallmark of cancer, and these proteins have been shown to play important roles in tumor initiation, maintenance, and resistance to anticancer therapy (Czabotar et al., Nat. Rev. Mol. Cell Biol. 2014 Jan;15(1):49-63). Bcl-xL (also named BCL2L1, from BCL2-like 1) is frequently amplified in cancer (Beroukhim et al., Nature 2010 Feb 18;463(7283):899-905), and its expression has been shown to inversely correlate with sensitivity to over 120 anticancer therapeutic molecules in a panel of representative cancer cell lines (NCI-60) (Amundson et al., Cancer Res. 2000 Nov 1;60(21):6101-10).

[0007] In addition, several studies using transgenic knockout mouse models and transgenic overexpression of Bcl-2 family members have highlighted the importance of these proteins in diseases of the immune system and autoimmune diseases (for review, see Merino et al., Apoptosis 2009 Apr;14(4):570-83. doi: 10.1007 / s10495-008-0308-4. PMID: 19172396). Transgenic overexpression of Bcl-xL in the T cell compartment resulted in resistance to apoptosis induced by glucocorticoids, gamma irradiation and CD3 crosslinking, suggesting that transgenic Bcl-xL overexpression may reduce apoptosis in resting and activated T cells (Droin et al., Biochim Biophys Acta 2004 Mar 1;1644(2-3):179-88. doi: 10.1016 / j.bbamcr.2003.10.011.PMID: 14996502). Persistent or high expression of antiapoptotic Bcl-2 family proteins was observed in patient samples (Pope et al., Nat Rev Immunol. 2002 Jul;2(7):527-35. doi: 10.1038 / nri846.PMID: 12094227). Notably, T cells isolated from the joints of patients with rheumatoid arthritis showed increased Bcl-xL expression and were resistant to spontaneous apoptosis (Salmon et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178.PMID: 9022077).

[0008] The findings presented above motivated the discovery and development of a new class of drugs named BH3 mimetics. These molecules are able to disrupt the interaction between pro- and anti-apoptotic members of the Bcl-2 family, which are potent inducers of apoptosis. This new class of drugs includes inhibitors of Bcl-2, Bcl-xL, Bcl-w and Mcl-1. The first BH3 mimetics described were ABT-737 and ABT-263, which target Bcl-2, Bcl-xL and Bcl-w (Park et al., J. Med. Chem. 2008 Nov 13;51(21):6902-15;Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96). Subsequently, selective inhibitors of Bcl-2 (ABT-199 and S55746 - Souers et al., Nat Med. 2013 Feb;19(2):202-8; Casara et al., Oncotarget 2018 Apr 13;9(28):20075-20088), Bcl-xL (A-1155463 and A-1331852 - Tao et al., ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci Transl Med. 2015 Mar 18;7(279):279ra40) and Mcl-1 (A-1210477, S63845, S64315, AMG-176 and AZD-5991 - Leverson et al., Cell Death Dis. 2015 Jan 15;6:e1590.;Kotschy et al., Nature 2016, 538, 477-482;Maragno et al., AACR 2019, Poster #4482;Kotschy et al., WO 2015 / 097123;Caenepeel et al., Cancer Discov. 2018 Dec;8(12):1582-1597;Tron et al., Nat. Commun. 2018 Dec 17;9(1):5341) have also been found.ABT-199, a selective Bcl-2 inhibitor, is currently approved for the treatment of patients with CLL and AML in combination therapy, while other inhibitors remain in preclinical or clinical development. In preclinical models, ABT-263 has shown activity in several hematological malignancies and solid tumors (Shoemaker et al., Clin. Cancer Res. 2008 Jun 1;14(11):3268-77; Ackler et al., Cancer Chemother. Pharmacol. 2010 Oct;66(5):869-80; Chen et al., Mol. Cancer Ther. 2011 Dec;10(12):2340-9). In clinical studies, ABT-263 has demonstrated objective antitumor activity in lymphoid malignancies (Wilson et al., Lancet Oncol. 2010 Dec;11(12):1149-59; Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96), and its activity is under investigation in combination with several therapies in solid tumors. The selective Bcl-xL inhibitors A-1155463 or A-1331852 have shown in vivo activity in preclinical models of T-ALL (T-cell acute lymphoblastic leukemia) and different types of solid tumors (Tao et al., ACS Med. Chem. Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci. Transl. Med. 2015 Mar 18;7(279):279ra40). The use of BH3 mimetics has also shown benefit in preclinical models of diseases of the immune system and autoimmune diseases. Treatment with ABT-737 (a Bcl-2, Bcl-xL, and Bcl-w inhibitor) resulted in a strong inhibition of lymphocyte proliferation in vitro.Importantly, mice treated with ABT-737 in animal models of arthritis and lupus erythematosus showed a significant reduction in disease severity (Bardwell et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178.PMID: 9022077). In addition, it has been shown that ABT-737 prevented allogeneic T-cell activation, proliferation, and cytotoxicity in vitro and inhibited allogeneic T-cell and B-cell responses after skin grafting with high selectivity for lymphoid cells (Cippa et al., .Transpl Int. 2011 Jul;24(7):722-32. doi: 10.1111 / j.1432-2277.2011.01272.x. Epub 2011 May 25.PMID: 21615547).

[0009] Preclinical studies have shown that BH3 mimetics are strongly synergistic in combinations including Mcl1i+Bcl2i, Mcl1i+Bcl-xli, and Bcl-xli+Bcl-2i (WO 2018 / 015526; Moujalled et al., Leukemia. 2019 Apr;33(4):905-917; Moujalled et al., Blood Adv. 2020 Jun 23;4(12):2762-2767; Grundy et al., Oncotarget. 2018 Dec 28;9(102):37777-37789; Soderquist et al., Nat Commun. 2018 Aug 29;9(1):3513; Weeden et al., Oncogene. 2018 Aug;37(32):4475-4488;Sarah Kehr et al., Cancer Lett. 2020 Jul 10;482:19-32).Furthermore, Bcl-xl and Mcl1 inhibitors, when combined with taxanes (Leverson et al, Science Translation Medicine, 2015 March 18 ; Vol 7(279) 279ra40;Bah et al, Cell Death and Disease, 2014 5, e1291;Wong et al, Mol Cancer Ther., 2012 Apr; 11(4) 1026-1035;Bennett et al, Open Biol., 2016 6: 160134; Topham et al, Cancer Cell, 2015 28, 129-140;Nguyen et al, Clin Cancer Res, 2011 March 15, 17(6) 1394-1404;Merino et al, Science Translational Medicine, 2017 Aug 2;9(401):eaam7049) or when combined with topoisomerase 1 inhibitors (Scherr et al, Cell Death and Disease, 2020 11:875; Hayward et al, Clin Cancer Res 2003 Jul;9(7):2856-65; Lalazar et al, Cancer Discov. 2021 Oct;11(10):2544-2563; Tolcher et al, Cancer Chemotherapy and Pharmacology, 2015 76,1041-1049). Even though the activity of these combinations is very promising, evidence of the tolerability of administration of two unconjugated BH3 mimetics in combination or a combined BH3 mimetic and an antineoplastic non-BH3 mimetic is still lacking, especially for Mcl1i+Bclxli. Additionally, the clinical potential of unconjugated BH3 mimetic combinations remains to be demonstrated.Thus, there is a need in the fields of oncology and immune and autoimmune diseases to find disease-modifying agents that therapeutically target Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, Mcl-1) or proteins upstream and / or downstream of the apoptotic signaling pathway. Summary of the Invention

[0010] In a first embodiment, the present disclosure provides an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof covalently linked to two antineoplastic drug payloads through a dual linker, where at least one antineoplastic drug payload is a BH3 mimetic, and the dual linker has one attachment point connected to the antibody and two attachment points to the two antineoplastic drug payloads, where the two antineoplastic drug payloads can be the same or different. In some embodiments, one antineoplastic drug payload is a BH3 mimetic and the other antineoplastic drug payload is an antineoplastic drug non-BH3 mimetic. In some embodiments, the antineoplastic drug non-BH3 mimetic is a topoisomerase 1 inhibitor or an antimitotic drug. In some embodiments, the topoisomerase 1 inhibitor is selected from topotecan, exatecan, deruxtecan, and SN-38. In some embodiments, the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane. In some embodiments, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel. In some embodiments, the two antineoplastic drug payloads are two BH3 mimetics. In some embodiments, the BH3 mimetics are selected from Mcl-1 inhibitors, Bcl-2 inhibitors, and Bcl-xL inhibitors. In some embodiments, the BH3 mimetics of the two antineoplastic drug payloads are the same. In some embodiments, the BH3 mimetics of the two antineoplastic drug payloads are different. In some embodiments, the antineoplastic drug payloads in the antibody-drug conjugates of the disclosure are as defined below: (i) one antineoplastic drug payload is an Mcl-1 inhibitor and the other antineoplastic drug payload is a Bcl-2 inhibitor; (ii) one antineoplastic drug payload is an Mcl-1 inhibitor and the other antineoplastic drug payload is a Bcl-xL inhibitor; or (iii) one antineoplastic drug payload is a Bcl-2 inhibitor and the other antineoplastic drug payload is a Bcl-xL inhibitor.In some embodiments, one antineoplastic payload is an Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other antineoplastic payload is a topoisomerase 1 inhibitor or an antimitotic drug. In some embodiments, one antineoplastic payload is a Bcl-xL inhibitor and the other antineoplastic payload is a topoisomerase 1 inhibitor. In some embodiments, one antineoplastic payload is a Bcl-xL inhibitor and the other antineoplastic payload is an antimitotic drug. In some embodiments, one antineoplastic payload is an Mcl-1 inhibitor and the other antineoplastic payload is a topoisomerase 1 inhibitor. In some embodiments, one antineoplastic payload is an Mcl-1 inhibitor and the other antineoplastic payload is an antimitotic drug. In some embodiments, one antineoplastic payload is a Bcl-2 inhibitor and the other antineoplastic payload is a topoisomerase 1 inhibitor. In some embodiments, one antineoplastic drug payload is a Bcl-2 inhibitor and the other antineoplastic drug payload is an antimitotic drug.

[0011] In a second embodiment, the present disclosure provides an antibody-drug conjugate having the formula (A):

[0012] [ka] (In the formula, Ab is an antibody or antigen-binding fragment thereof; R 1 is the attachment group; L 1 is a bridging spacer; W is a branching moiety; L 2’ and L 3’ are each independently a linker; D 1 and D. 2 are each independently an anti-neoplastic compound, 1 and D. 2 at least one of which is a BH3 mimetic); a is an integer from 1 to 16. In some embodiments, the antibody-drug conjugate of the first embodiment is represented by D 1 and D. 2 are each independently BH3 mimetics.

[0013] In a third embodiment, the disclosure provides the antibody-drug conjugate of the second embodiment, where a is an integer from 1 to 8, 1 to 6, 1 to 4, or a is 1 or 2, optionally where a is determined by liquid chromatography-mass spectrometry (LC-MS). Definitions of the remaining variables are provided in the second embodiment or any embodiment described therein. In some embodiments, a is an integer from 1 to 6 or 1 to 4, or a is 1 or 2, or a is determined by liquid chromatography-mass spectrometry (LC-MS).

[0014] In a fourth embodiment, the present disclosure provides a method for producing a cellular membrane comprising: 2’ and L 3’ comprises a cleavable group, and optionally at least one cleavable group comprises a glucuronide group, a pyrophosphate group, a peptide group, and / or a self-immolative group. 2’ and L 3’ Each of comprises a cleavable group, and optionally at least one cleavable group comprises a pyrophosphate group, a peptide group and / or a self-immolative group. Definitions of the remaining variables are provided in the second or third embodiment or any embodiment described therein.

[0015] In a fifth embodiment, the present disclosure provides an antibody-drug conjugate having the formula (B):

[0016] [ka] (In the formula, Ab is an antibody or antigen-binding fragment thereof; R 1is the attachment group; L 1 is a bridging spacer; W is N or CR w (where R w is H or C 1~6 is alkyl); L 2 and L 3 are each independently a connecting spacer; E 1 and E 2 are each independently an enzymatic cleavage element or a hydrophilic moiety; V 1 and V 2 each independently comprises i) a self-immolative group, ii) an enzymatic cleavage element, or iii) a self-immolative group and an enzymatic cleavage element; D 1 and D. 2 are each independently an anti-neoplastic compound, 1 and D. 2 At least one of them is a BH3 mimetic. The antibody-drug conjugate of the second embodiment is represented by: The definitions of the remaining variables are provided in the second embodiment or any embodiment described therein. 1 and V 2 are each independently i) a self-immolative group or ii) an enzymatic cleavage element; 1 and D. 2 are each independently BH3 mimetics.

[0017] In a sixth embodiment, the present disclosure provides a method for producing a medicament for the preparation of a medicament for use in ... 1 and V 2 each independently contains a phosphate, pyrophosphate and / or self-immolative group; (ii) V 1 and V 2 each independently contains a self-immolative group; (iii) V 1 and V 2 are each independently -CH 2 -O-, -OC(=O)-, -NH-CH2 -, 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; iv) V 1 and V 2 each independently comprises a group that comprises para-aminobenzyl-phosphate or para-aminobenzyl-pyrophosphate. The definitions of the remaining variables are provided in the fifth embodiment or any embodiment described therein.

[0018] In some embodiments, for the antibody-drug conjugate of the fifth embodiment, V 1 and V 2 is as defined below: (i) V 1 and V 2 each independently contains a phosphate, pyrophosphate and / or self-immolative group; (ii) V 1 and V 2 each independently contains a self-immolative group; or (iii) V 1 and V 2 are each independently -CH 2 -O-, -OC(=O)-, -NH-CH 2 -, containing a self-immolative group including 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.

[0019] In a seventh embodiment, the present disclosure relates to an antibody-drug conjugate having formula (C):

[0020] [ka] or a pharma- ceutically acceptable salt thereof, Ab is an antibody or antigen-binding fragment thereof; R 1 is the attachment group; L 1 is a bridging spacer; W is N or CR w (where R w is H or C 1~6 is alkyl); L 2 and L 3 are each independently a connecting spacer; E 1 and E 2 are each independently a peptide group consisting of 1 to 6 amino acids, wherein the peptide group is optionally substituted by a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)- * , -OC(=O)NH- * ,

[0021] [ka] -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * and (Here, each R aare independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; A 1 Or A 2 of * D 1 Or D 2 indicates the point of attachment to); D 1 and D. 2 are each independently an anti-neoplastic compound, 1 and D. 2 at least one of which is a BH3 mimetic); L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzymatic cleavage element; m and n are each independently 0 or 1. The antibody-drug conjugate of the fifth embodiment is provided, represented by: The definitions for the remaining variables are provided in the fifth embodiment or any embodiment described therein. 1 and D. 2 are each independently BH3 mimetics.

[0022] In an eighth embodiment, the present disclosure provides an antibody-drug conjugate having formula (D1), (D2), or (D3):

[0023] [ka] or a pharma- ceutically acceptable salt thereof (wherein, for formula (D2), 1 and D. 2 are each independently an anti-neoplastic compound, 1 and D. 2 At least one of the is a BH3 mimetic);R 2 and R 3are each independently an enzyme cleavage element; for formula (D3), R 2 is a hydrophilic group, R 3 is an enzyme cleavage element) The seventh embodiment provides an antibody-drug conjugate represented by the formula: 1 and D. 2 are each independently BH3 mimetics.

[0024] In a ninth embodiment, the present disclosure provides for formula (D1), R 2 and R 3 is each independently a hydrophilic group. The definitions of the remaining variables are provided in the eighth embodiment or any embodiment described therein.

[0025] In a tenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to ninth embodiments, wherein the attachment group is formed by a reaction involving at least one reactive group. Definitions of the remaining variables are provided in any one of the second to ninth embodiments or any embodiment described therein.

[0026] In an eleventh embodiment, the present disclosure provides a method for the preparation of a compound comprising the steps of: a first reactive group attached to the linker, and A second reactive group that is attached to the antibody or is an amino acid residue of the antibody. and optionally, (i) at least one of the reactive groups is Thiol, Maleimide, Haloacetamides, Azide, Alkynes, Cyclooctene, Triarylphosphine oxanobornadiene, Cyclooctyne, Diaryltetrazines, Monoaryltetrazines, Norbornene, aldehyde, Hydroxylamine, Hydrazine, NH 2 -NH-C(=O)-, Ketones, vinyl sulfone, Aziridine, Amino acid residues,

[0027] [ka] , -ONH 2 , -NH 2 ,

[0028] [ka] , -N 3 ,

[0029] [ka] , -SH, -SR 11 , -SSR 12 , -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,

[0030] [ka] , -C(O)NHNH 2 ,

[0031] [ka] Includes (where: Each R 11 are independently H and C 1 ~C 6 alkyl; Each R 12 is 2-pyridyl or 4-pyridyl; Each R 13 are independently H, C 1 ~C 6 selected from alkyl, F, Cl, and -OH; Each R 14 are independently H, C 1 ~C 6 Alkyl, F, Cl, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and -OH; Each R 15 are independently H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 Alkoxy and -C(=O)OH substituted C 1~4 alkyl); and / or (ii) the first reactive group and the second reactive group are Thiols and maleimides, Thiols and haloacetamides, Thiols and vinyl sulfones, Thiols and aziridines, Azides and alkynes, Azide and cyclooctyne, Azide and cyclooctene, Azides and triarylphosphines Azides and oxanobornadienes, diaryltetrazines and cyclooctenes, Monoaryltetrazines and norbornenes, Aldehydes and hydroxylamines, Aldehydes and hydrazines, Aldehydes and NH 2 -NH-C(=O)-, Ketones and hydroxylamines, Ketones and hydrazines, Ketones and NH 2 -NH-C(=O)-, Hydroxylamine and

[0032] [ka] Amines and

[0033] [ka] or CoA or CoA analog and serine residue Including, The antibody-drug conjugate of any one of the second to tenth embodiments is provided. Definitions for the remaining variables are provided in the second through tenth embodiments or any embodiment described therein.

[0034] In a twelfth embodiment, the present disclosure provides a method for the preparation of a cycloalkyl aryl group comprising administering to a subject an aryl group having an aryl group a cycloalkyl aryl group,

[0035] [ka]

[0036] [ka]

[0037] [ka]

[0038] [ka]

[0039] [ka] is selected from R 16 , H, C 1~4 alkyl, phenyl, pyrimidine or pyridine; R 18 , H, C 1~6 C substituted with alkyl, phenyl or 1-3 -OH groups 1~4 is alkyl; Each R 15 are independently H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 Alkoxy and -C(=O)OH substituted C 1~4 alkyl; R 17 is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 19 is H or methyl; R 20 -H, -CH 3 or phenyl; The antibody-drug conjugate of any one of the second to eleventh embodiments is provided. Definitions for the remaining variables are provided in the second through eleventh embodiments or any embodiment described therein.

[0040] In a thirteenth embodiment, the present disclosure provides a method for the preparation of a cycloalkyl aryl group comprising administering to a subject an aryl group having an aryl group a substituted or unsubstituted aryl group,

[0041] [ka] The antibody-drug conjugate of any one of the second to twelfth embodiments is provided, wherein:

[0042] In a fourteenth embodiment, the present disclosure provides a method for producing a composition comprising: (1) L 1 but,

[0043] [ka] or * -CH(OH)CH(OH)CH(OH)CH(OH)CH(OH)- ** Includes (wherein each n is an integer from 1 to 12, and L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1 indicates a direct or indirect point of attachment to); (2)L 1 but,

[0044] [ka] where n is an integer from 1 to 12, or n is 1, or n is 12, where L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1 indicates a direct or indirect point of attachment to); (3) L 1 but,

[0045] [ka] and n is an integer from 1 to 12 (wherein L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1indicates a direct or indirect point of attachment to); (4) L 1 but,

[0046] [ka] (where L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1 indicates a direct or indirect point of attachment 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 L1 ) 2 (CH 2 ) m C(=O)NR L1 (CH 2 ) m NR L1 C(=O)(CH 2 ) m - ** ; * -C(=O)O(CH 2 )m C(=O)NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)- ** ; * -C(=O)(CH 2 ) m X 1 (CH 2 ) m - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n - ** ; * -C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n - ** ; * -C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n - ** ; *-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m C(R L1 ) 2 - ** or * -C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m - ** (wherein L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1 indicates a direct or indirect point of attachment to); X 1 but,

[0047] [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; Each R L1 but independently, H and C 1 ~C 6 selected from alkyl, The antibody-drug conjugate of any one of the second to thirteenth embodiments is provided. Definitions for the remaining variables are provided in the second through thirteenth embodiments or any embodiment described therein.

[0048] In a fifteenth embodiment, the present disclosure provides a method for producing a cellular membrane comprising: 1 but,

[0049] [ka] (wherein n is an integer from 1 to 12, and L 1 of * indicates a direct or indirect attachment point to W, and L 1 of ** is R 1 (indicating the direct or indirect point of attachment to The antibody-drug conjugate of any one of the second to fourteenth embodiments is provided, comprising a moiety represented by: The definitions of the remaining variables are provided in the second to fourteenth embodiments or any embodiment described therein.

[0050] In a sixteenth embodiment, the present disclosure provides a method for producing a cellular membrane comprising: 1 But, the formula

[0051] [ka] (In the formula, n is an integer from 1 to 12; x is an integer from 0 to 6; y is 0 or 1; z is an integer from 0 to 6; u is 0 or 1; L 1 of * indicates the direct attachment point to W, and L 1 of ** is R 1 (Indicates direct attachment point to The antibody-drug conjugate of a fifteenth embodiment is provided, wherein the antibody-drug conjugate is represented by: The definitions of the remaining variables are provided in the fifteenth embodiment or any embodiment described therein.

[0052] In a seventeenth embodiment, the present disclosure provides a method for producing a medicament comprising: 1 but,

[0053] [ka] The antibody-drug conjugate of any one of the second to sixteenth embodiments is provided, wherein the antibody-drug conjugate is selected from the group consisting of: Definitions for the remaining variables are provided in the second through sixteenth embodiments or any embodiment described therein.

[0054] In an eighteenth embodiment, the present disclosure provides a method for producing a cellular membrane comprising: 2 and L 3 However, each independently,

[0055] [ka] wherein: k is an integer from 0 to 6; r is 0 or 1; o is an integer from 0 to 12; p is an integer from 0 to 6; L 2 or L 3 # is E 1 or E 2 indicates the direct or indirect point of attachment to the L 2 or L 3 ## indicates direct or indirect attachment point to W), The antibody-drug conjugate of any one of the fifth to seventeenth embodiments is provided. Definitions for the remaining variables are provided in the second through seventeenth embodiments or any embodiment described therein.

[0056] In a nineteenth embodiment, the present disclosure provides a method for producing a medicament comprising the steps of: 2 and L 3 However, each independently,

[0057] [ka]

[0058] [ka] is a connecting spacer selected from the group consisting of: k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R L23 is hydrogen or C 1~6 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; L 2 or L 3 # is E 1 or E 2 indicates the direct attachment point to L 2 or L 3 ## indicates direct attachment point to W; However, if W is N, then L 2 and L 3 is not (L2c), (L2d), (L2f), or (L2k)), An antibody-drug conjugate of an eighteenth embodiment is provided. The definitions of the remaining variables are provided in the eighteenth embodiment or any embodiment described therein.

[0059] In a twentieth embodiment, the present disclosure provides a method for producing a medicament comprising the steps of: 2 and L 3 However, each independently,

[0060] [ka]

[0061] [ka]

[0062] [ka] is a connecting spacer selected from the group consisting of: k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1~3 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; L 2 or L 3 # is E 1 or E 2 indicates the direct attachment point to L 2 or L 3 ## indicates direct attachment point to W; However, if W is N, then L 2 and L 3is not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP)), An antibody-drug conjugate of a nineteenth embodiment is provided. The definitions of the remaining variables are provided in the nineteenth embodiment or any embodiment described therein.

[0063] In a twenty-first embodiment, the present disclosure provides a method for producing a composition comprising: L 2 and L 3 But independently,

[0064] [ka]

[0065] [ka] wherein L is a connecting spacer selected from the group consisting of 2 or L 3 # is E 1 or E 2 indicates the direct attachment point to L 2 or L 3 ## indicates direct attachment point to W; R L is hydrogen or -C(O)-R H and; R H teeth,

[0066] [ka] and d is an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); The antibody-drug conjugates of the fifth to twentieth embodiments are provided. Definitions for the remaining variables are provided in the fifth through twentieth embodiments or any embodiment described therein.

[0067] In a twenty-second embodiment, the present disclosure provides the antibody-drug conjugate of the twenty-first embodiment, wherein d is 25. The remaining variable definitions are provided in the twenty-first embodiment or any embodiment described therein.

[0068] In a twenty-third embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to twenty-second embodiments, wherein the peptide group comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues. Definitions of the remaining variables are provided in the seventh to twenty-second embodiments or any embodiment described therein.

[0069] In a twenty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of the twenty-third embodiment, wherein the amino acid residue is selected from 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), L-tyrosine (Tyr) and β-alanine (β-Ala). Definitions of the remaining variables are provided in the twenty-third embodiment or any embodiment described therein.

[0070] In a twenty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the first to twenty-third embodiments, wherein the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly, and / or Sulfo-Ala-Val-Ala. Definitions of the remaining variables are provided in the first to twenty-third embodiments or any embodiment described therein.

[0071] In a twenty-sixth embodiment, the present disclosure provides a method for the preparation of a medicament ... 1 or E 2is an enzymatic cleavage element. Definitions of the remaining variables are provided in the 23rd to 25th embodiments or any embodiment described therein.

[0072] In a twenty-seventh embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1 or E 2 or a pharma- ceutically acceptable salt thereof, is a hydrophilic moiety. Definitions of the remaining variables are provided in the 23rd to 25th embodiments or any embodiment described therein.

[0073] In a twenty-eighth embodiment, the present disclosure provides a method for the preparation of a medicament ... 1 or E 2 But independently,

[0074] [ka] wherein E is an enzyme cleavage element selected from the group consisting of 1 or E 2 The ^ in formula (B) is V 1 or V 2 or to the -NH- group in formulas (C) and (D); E 1 or E 2 The ^^ in the table are L 2 or L 3 (indicating the direct attachment point to the The antibody-drug conjugate of the twenty-sixth embodiment, or a pharma- ceutically acceptable salt thereof, is provided. The definitions of the remaining variables are as provided in the twenty-sixth embodiment or any embodiment described therein.

[0075] In a twenty-ninth embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of a cancer, comprising: 1 or E 2 But independently,

[0076] [ka] (wherein R E is a hydrophilic group R H ), The antibody-drug conjugate of the twenty-seventh embodiment, or a pharma- ceutically acceptable salt thereof, is provided. The remaining variable definitions are as provided in the twenty-seventh embodiment or any embodiment described therein.

[0077] In a thirtieth embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of cancer, comprising 1 or E 2 Each hydrophilic group R H But independently,

[0078] [ka] wherein e is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30), or a pharma- ceutically acceptable salt thereof. Definitions for the remaining variables are provided in the 29th embodiment or any embodiment described therein.

[0079] In a thirty-first embodiment, the disclosure provides the antibody-drug conjugate of the thirtieth embodiment, wherein e is 24. The remaining variable definitions are provided in the thirtieth embodiment or any embodiment described therein.

[0080] In a thirty-second embodiment, the present disclosure provides a method for producing a medicament for the treatment of a cancer, comprising: 1 and A 2 are independently a bond, -OC(=O)- * ,or

[0081] [ka] (where: * D 1 Or D 2(showing the point of attachment to A), the antibody-drug conjugate of any one of the seventh to thirty-first embodiments, or a pharma- ceutically acceptable salt thereof, is provided. The definitions of the remaining variables are provided in the seventh to thirty-first embodiments or any embodiment described therein. In some embodiments, A 1 and A 2 is independently a bond or

[0082] [ka] (where: * D 1 Or D 2 In some embodiments, A 1 and A 2 are independently a bond or -OC(=O)- * (where: * D 1 Or D 2 In some embodiments, A 1 and A 2 is as defined below: (i) A 1 and A 2 is -OC(=O)- * (ii) A 1 and A 2 teeth,

[0083] [ka] (iii) A 1 is -OC(=O)- * And A 2 is a bond; (iv) A 1 is -OC(=O)- * And A 2 teeth,

[0084] [ka] (v) A 1 is a bond, and A 2 teeth,

[0085] [ka] or (vi) A 1 is a bond, and A 2 is -OC(=O)- * (where: * D 1 Or D 2 (Indicates the point of attachment to the

[0086] In a thirty-third embodiment, the present disclosure provides a method for producing a cellular membrane comprising: 1 and A 2 is a bond. Definitions of the remaining variables are provided in embodiments 7 to 32 or any embodiment described therein.

[0087] In a thirty-fourth embodiment, the present disclosure provides a method for producing a composition comprising the steps of: i)L 4 and L 5 However, each independently has the structure

[0088] [ka] or a spacer moiety having the formula: Z is -O-, -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR L45 -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NRL45 C(=O)NR L45 -, -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 L45 are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl); X is a bond, triazolyl, or -CH 2 -triazolyl-, X is R 2 or R 3 connected to); or (ii) L 4 and L 5 But independently, the structure

[0089] [ka] is a spacer moiety having the formula: Z is -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)-, -C(=O)O-, or -NH-, where each R L45 are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl); X is -CH 2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4~6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -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 where n is independently 1, 2, or 3; X is R 2 or R 3 connected to The antibody-drug conjugate of any one of the seventh to thirty-third embodiments is provided. Definitions for the remaining variables are provided in the seventh through thirty-third embodiments or any embodiment described therein.

[0090] In a thirty-fifth embodiment, the present disclosure provides a compound wherein Z is -O-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH- or -CH 2 and X is a bond, triazolyl, or -CH 2 -triazolyl-; R in each occurrence L45 are independently H or C 1~3 The antibody-drug conjugate of the thirty-fourth embodiment, or a pharma- ceutically acceptable salt thereof, is provided wherein R is alkyl. The definitions for the remaining variables are as provided in the thirty-fourth embodiment or any embodiment described therein.

[0091] In a thirty-sixth embodiment, the present disclosure provides a method for producing a medicament comprising the steps of: 4 and L 5 However, each independently,

[0092] [ka] where L is a spacer moiety selected from the group consisting of 4 or L 5 The @ in indicates the direct attachment point to the phenyl group, and L 4 or L 5 @@ is R 2 or R 3 (indicating the direct attachment point to the Provided is the antibody-drug conjugate of any one of the seventh to thirty-fifth embodiments, or a pharma- ceutically acceptable salt thereof. The definitions of the remaining variables are provided in the seventh to thirty-fifth embodiments or any embodiment described therein.

[0093] In a thirty-seventh embodiment, the present disclosure provides a method for the preparation of a compound comprising: 2 and R 3 Each of the hydrophilic groups represented by the formula (I) is independently selected from polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, and 1 to 3

[0094] [ka] C replaced with 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 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 The antibody-drug conjugate of any one of the seventh to thirty-sixth embodiments is provided, which comprises an alkyl. The definitions of the remaining variables are provided in the seventh to thirty-sixth embodiments or any embodiment described therein.

[0095] In a thirty-eighth embodiment, the present disclosure provides a method for the preparation of a compound comprising the steps of: 2 or R 3 But independently,

[0096] [ka] (wherein n is an integer from 1 to 6);

[0097] [ka] The antibody-drug conjugate of any one of the seventh to thirty-seventh embodiments is provided, wherein Definitions for the remaining variables are provided in embodiments 7 through 37 or any embodiment described therein.

[0098] In a thirty-ninth embodiment, the present disclosure provides a method for the preparation of a compound comprising the steps of: 2 or R 3 each independently represents a hydrophilic group represented by (i) the following part:

[0099] [ka] (where: f is an integer from 3 to 25; R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) or polysarcosine having (ii) Formula:

[0100] [ka] (In the formula, g and h are independently an integer of 2 to 30.) The antibody-drug conjugate of any one of the seventh to thirty-eighth embodiments is provided, comprising polyethylene glycol. In some embodiments, R 2 or R 3 Each hydrophilic group represented by the formula: The following part:

[0101] [ka] (where: f is an integer from 3 to 25; R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) The polysarcosine includes polysarcosine having the formula: Definitions for the remaining variables are provided in embodiments 7 through 38 or any embodiment described therein.

[0102] In a fortieth embodiment, the present disclosure provides a method for the preparation of a compound comprising: 2 or R 3 each independently represents an enzyme cleavage element represented by

[0103] [ka] The antibody-drug conjugate of any one of the seventh to thirty-sixth embodiments is provided, comprising: Definitions for the remaining variables are provided in embodiments 7 through 36 or any embodiment described therein.

[0104] In a forty-first embodiment, the present disclosure provides a compound comprising R 2 or R 3 But independently,

[0105] [ka] and g and h are independently an integer between 20 and 30. Definitions for the remaining variables are provided in embodiments 7 through 36 or any embodiment described therein.

[0106] In a forty-second embodiment, the present disclosure provides a method for producing a composition comprising: g is 23, 24, or 25; h is 23, 24, or 25; The antibody-drug conjugates of the thirty-ninth to forty-first embodiments are provided. Definitions for the remaining variables are provided in the thirty-ninth through forty-first embodiments or any embodiment described therein.

[0107] In a forty-third embodiment, the present disclosure relates to a dual linker having the following formula:

[0108] [ka]

[0109] [ka]

[0110] [ka] (In the formula, A 1 and A 2 are each independently a bond, -OC(=O)- * ,or

[0111] [ka] (where A 1 and A 2 In * D 1 Or D 2 indicates the point of attachment to); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 2 to 5); n is an integer from 1 to 12 (e.g., 2 to 5);

[0112] [ka] indicates the attachment point to Ab;

[0113] [ka] D 1 Or D 2 (Indicates direct attachment point to The antibody-drug conjugate of the seventh embodiment is provided, represented by: The definitions for the remaining variables are provided in the seventh embodiment or any embodiment described therein. 1 and A 2 each independently represents a bond or -OC(=O)- * (where A 1 and A 2 In * D 1 Or D 2 In some embodiments, A1 and A 2 In some embodiments, A 1 and A 2 are both -OC(=O)- * In some embodiments, A 1 and A 2 One of them is a bond and the other is OC(=O)- * It is.

[0114] In a forty-fourth embodiment, the present disclosure provides a dual linker having the formula (D5):

[0115] [ka] (In the formula, A 1 and A 2 are each independently a bond, -OC(=O)- * or

[0116] [ka] (where A 1 and A 2 In * D 1 Or D 2 indicates the point of attachment to); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); n is an integer from 1 to 12 (e.g., 5 to 10);

[0117] [ka] indicates the attachment point to Ab;

[0118] [ka] D 1 Or D 2 (Indicates direct attachment point to The seventh embodiment provides an antibody-drug conjugate represented by the formula: 1 and A 2 each independently represents a bond or -OC(=O)- * (where A 1 and A 2 In * D 1 Or D 2 (Indicates the point of attachment to the

[0119] In a forty-fifth embodiment, the present disclosure relates to a dual linker having the following formula:

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka] (Wherein, each A 1 Or A 2 are independently a bond, -OC(=O)- * or

[0131] [ka] (where: * D 1 Or D 2 indicates the point of attachment to);

[0132] [ka] indicates the attachment point to Ab;

[0133] [ka] D 1 Or D 2 (Indicates the direct attachment point to or a pharma- ceutically acceptable salt thereof. The definitions of the remaining variables are provided in the first embodiment. 1 Or A 2 are independently a bond or -OC(=O)- * In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 are both -OC(=O)- * In some embodiments, A 1 and A 2 One of them is a bond and the other is OC(=O)- * It is.

[0134] In a forty-sixth embodiment, the present disclosure provides a method for producing a medicament for the treatment of a cancer, comprising: 1 and D. 2 and D1 and D2 are each independently a BH3 mimetic. Alternatively, one of D1 and D2 is a BH3 mimetic selected from an Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other is an anti-neoplastic non-BH3 mimetic selected from a topoisomerase 1 inhibitor or an anti-mitotic agent. The remaining variable definitions are provided in the second to forty-fifth embodiments or any embodiment described therein. In some embodiments, D1 and D2 are each independently a BH3 mimetic. 1 is a BH3 mimetic and D 2 is an anti-neoplastic non-BH3 mimetic; the definitions of the remaining variables are provided in the second through forty-fifth embodiments or any embodiment described therein. In some embodiments, D 1 is selected from an Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor; 2 is a topoisomerase 1 inhibitor or an antimitotic drug. 1 is a Bcl-xL inhibitor and D 2 is a topoisomerase 1 inhibitor. In some embodiments, D 1 is a Bcl-xL inhibitor and D 2 is an antimitotic drug.

[0135] In some embodiments, D 1 and / or D. 2 are each independently selected from an Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor.

[0136] In a forty-seventh embodiment, the present disclosure provides a method for producing a medicament for the treatment of a cancer, comprising 1 and D. 2 but both are (i) an Mcl-1 inhibitor; (ii) a Bcl-2 inhibitor; or (iii) a Bcl-xL inhibitor. Definitions of the remaining variables are provided in embodiments 2 to 46 or any embodiment described therein.

[0137] In a forty-eighth embodiment, the present disclosure provides a method for producing a medicament comprising: 1 and D. 2 is the same. The definitions of the remaining variables are provided in embodiments 2 to 46 or any embodiment described therein.

[0138] In a forty-ninth embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of a cancer, 1 and D. 2 is different. The definitions of the remaining variables are provided in embodiments 2 to 47 or any embodiment described therein.

[0139] In a 50th embodiment, the present disclosure provides a method for producing a medicament comprising: (i) a method for producing a 1 and D. 2 one of which is an Mcl-1 inhibitor and the other is a Bcl-2 inhibitor; (ii) D 1 and D. 2 one of which is an Mcl-1 inhibitor and the other is a Bcl-xL inhibitor; or (iii) D 1 and D. 2and the other is a Bcl-xL inhibitor. Definitions of the remaining variables are provided in embodiments 2-47 or any embodiment described therein. Alternatively, the disclosure provides an antibody-drug conjugate of any one of embodiments 2-47, or a pharma- ceutically acceptable salt thereof, comprising: (i) D 1 is an Mcl-1 inhibitor, and D 2 (ii) is an Mcl-1 inhibitor; 1 is an Mcl-1 inhibitor, and D 2 is a Bcl-2 inhibitor; (iii) D 1 is a Bcl-xL inhibitor, and D 2 is a Bcl-xL inhibitor: (iv) D 1 is a Bcl-xL inhibitor, and D 2 is a Bcl-2 inhibitor; (v) D 1 is a Bcl-2 inhibitor, and D 2 is an Mcl-1 inhibitor; or (vi) D 1 is an Mcl-1 inhibitor, and D 2 is a Bcl-xL inhibitor, or a pharma- ceutically acceptable salt thereof. The definitions of the remaining variables are provided in embodiments 2 to 47 or any embodiment described therein.

[0140] In a fifty-first embodiment, the present disclosure provides a compound according to the present invention, wherein the Mcl-1 inhibitor is of formula (I):

[0141] [ka] (In the formula, Ring D 0 is a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, Ring E 0 is a furyl, thienyl or pyrrolyl ring; X 01 , X 03 , X 04 and X 05are, independently of each other, a carbon atom or a nitrogen atom, X 02 CR 026 group or a nitrogen atom,

[0142] [ka] means that the ring is aromatic, Y 0 is a nitrogen atom or CR 03 It is based on Z 0 is a nitrogen atom or CR 04 It is based on R 01 is a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 )Haloalkyl group, hydroxy group, hydroxy(C 1 ~C 6 ) alkyl group, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) Alkyl group, cyano group, nitro group, -Cy 08 , -(C 0 ~C 6 )Alkyl-NR 011 R 011 ', -O-(C 1 ~C 6 )Alkyl-NR 011 R 011 ', -O-(C 1 ~C 6 ) Alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R011 ', -NR 011 -C(O)-OR 011 ', -(C 1 ~C 6 )Alkyl-NR 011 -C(O)-R 011 ',-SO 2 -NR 011 R 011 ', or -SO 2 -(C 1 ~C 6 ) alkyl, R 02 , R 03 , R 04 and R 05 are each independently a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 )Haloalkyl, hydroxyl, hydroxy(C 1 ~C 6 ) alkyl group, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) alkyl group, cyano group, nitro group, -(C 0 ~C 6 )Alkyl-NR 011 R 011 ',-O-Cy 01 , -(C 0 ~C 6 )Alkyl-Cy 01 , -(C 2 ~C 6 )Alkenyl-Cy 01 , -(C 2 ~C 6 )Alkynyl-Cy 01 , -O-(C 1 ~C 6 )Alkyl-NR 011 R 011 ', -O-(C1 ~C 6 ) Alkyl-R 031 ,-O-(C 1 ~C 6 ) Alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C 1 ~C 6 )Alkyl-NR 011 -C(O)-R 011 ',-SO 2 -NR 011 R 011 ', or -SO 2 -(C 1 ~C 6 ) alkyl or Or (R 01 , R 02 ), (R 02 , R 03 ), (R 03 , R 04 ), or (R 04 , R 05 ) together with the carbon atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing 1 to 3 heteroatoms selected from O, S and N, where the resulting ring is optionally substituted with halogen, linear or branched (C 1 ~C 6 ) alkyl, (C 0 ~C 6 )Alkyl-NR 011 R 011 ', -NR 013 R 013 ', -(C 0 ~C 6 )Alkyl-Cy 01 or oxo), R 06 and R 07are each independently a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 ) haloalkyl, hydroxyl, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) alkyl group, cyano group, nitro group, -(C 0 ~C 6 )Alkyl-NR 011 R 011 ', -O-(C 1 ~C 6 )Alkyl-NR 011 R 011 ',-O-Cy 01 , -(C 0 ~C 6 )Alkyl-Cy 01 , -(C 2 ~C 6 )Alkenyl-Cy 01 , -(C 2 ~C 6 )Alkynyl-Cy 01 , -O-(C 1 ~C 6 ) Alkyl-R 012 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C 1 ~C 6 )Alkyl-NR 011 -C(O)-R 011 ',-SO 2 -NR 011 R 011 ', or -SO 2 -(C1 ~C 6 ) alkyl, Or (R 06 , R 07 A pair of (C), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, forms an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing 1 to 3 heteroatoms selected from O, S and N, where the resulting ring is optionally linear or branched (C 1 ~C 6 ) alkyl group, -NR 013 R 013 ', -(C 0 ~C 6 )Alkyl-Cy 01 or oxo), W 0 -CH 2 - group, -NH- group or an oxygen atom, R 08 is a hydrogen atom, a straight-chain or branched (C 1 ~C 8 ) alkyl group, -CHR 0a R 0b Group, aryl group, heteroaryl group, aryl (C 1 ~C 6 ) alkyl group, or heteroaryl (C 1 ~C 6 ) alkyl group, R 09 is a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl group, -Cy 02 , -(C 1 ~C 6 )Alkyl-Cy 02 , -(C 2 ~C 6 )Alkenyl-Cy 02 , -(C 2 ~C 6 )Alkynyl-Cy 02, -Cy 02 -Cy 03 , -(C 2 ~C 6 )Alkynyl-O-Cy 02 , -Cy 02 -(C 0 ~C 6 )Alkyl-O-(C 0 ~C 6 )Alkyl-Cy 03 , halogen atom, cyano group, -C(O)-R 014 or -C(O)-NR 014 R 014 ' and R 010 is a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) Alkynyl group, aryl (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) cycloalkylalkyl groups, linear or branched (C 1 ~C 6 ) haloalkyl, or -(C 1 ~C 6 )Alkyl-O-Cy 04 or Or (R 09 , R 010 ), when fused with two adjacent carbon atoms, form together with the carbon atoms to which they are attached an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing 1 to 3 heteroatoms selected from O, S and N; R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C 1 ~C 6 ) alkyl group, or -(C 0 ~C 6 )Alkyl-Cy 01 or Or (R011 , R 011 The pair of ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, where the N atom is a straight or branched (C 1 ~C 6 ) alkyl groups, which may be substituted by one or two groups selected from linear or branched (C 1 ~C 6 ) one or more of the carbon atoms of the alkyl group are optionally deuterated; R 012 -Cy 05 , -Cy 05 -(C 0 ~C 6 )Alkyl-O-(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -(C 0 ~C 6 )Alkyl-NR 011 -(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C 0 ~C 6 )Alkyl-Cy 07 , -Cy 05 -(C 0 ~C 6 )Alkyl-O-(C 0 ~C 6 )Alkyl-Cy 09 , -Cy 05 -(C 0 ~C 6 )Alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -Cy 05 -(C 0 ~C 6 )Alkyl-NR 011 -(C0 ~C 6 )Alkyl-Cy 09 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ',-OR 011 , -NR 011 -C(O)-R 011 ', -O-(C 1 ~C 6 )Alkyl-OR 011 , -SO 2 -R 011 , -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C 1 ~C 6 ) alkyl group, R 0a is a hydrogen atom or a straight-chain or branched (C 1 ~C 6 ) alkyl group, R 0b is -OC(O)-OR 0c group, -OC(O)-NR 0c R 0c ' group, or -OP(O)(OR 0c ) 2 It is based on R 0c and R 0c ' are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 8 ) alkyl group, cycloalkyl group, (C 1 ~C 6 )Alkoxy(C 1 ~C 6 ) alkyl group, or (C 1 ~C 6 )Alkoxycarbonyl (C 1 ~C 6 ) an alkyl group, Or (R 0c , R 0cThe pair of ') together with the nitrogen atom to which they are attached form a non-aromatic ring consisting of 5 to 7 ring members, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from oxygen and nitrogen, where the nitrogen is optionally linear or branched (C 1 ~C 6 ) substituted by an alkyl group; Cy 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth,

[0143] [ka] or Cy 09 -OP(O)(OR 020 ) 2 ;-OP(O)(O - M + ) 2 ;-(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C 1 ~C 6 ) alkyl; -(CH 2 ) r0 -U 0 -(CH 2 ) s0 -heterocycloalkyl and -U 0 -(CH 2 ) q0 -NR 021 R 021 ', R015 is a hydrogen atom; -(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; linear or branched (C 1 ~C 6 )Alkoxy(C 1 ~C 6 ) alkyl group; -U 0 -(CH 2 ) q0 -NR 021 R 021 ' group; or -(CH 2 ) r0 -U 0 -(CH 2 ) s0 -heterocycloalkyl group, R 016 is a hydrogen atom; a hydroxyl group; a hydroxyl (C 1 ~C 6 ) alkyl group; -(CH 2 ) r0 -U 0 -(CH 2 ) s0 -heterocycloalkyl group; (CH 2 ) r0 -U 0 -V 0 -OP(O)(OR 020 ) 2 Group; -OP(O)(O - M + ) 2 Group; -OS(O) 2 OR 020 Base;-S(O) 2 OR 020 Group;-(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group;-(CH 2 ) p0 -OC(O)-NR 022 R 023 group; or -U 0 -(CH 2 ) q0 -NR021 R 021 ' is a base, R 017 is a hydrogen atom; -(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group;-CH 2 -P(O)(OR 020 ) 2 Group, -OP(O)(OR 020 ) 2 Group; -OP(O)(O - M + ) 2 Hydroxy group; Hydroxy (C 1 ~C 6 ) alkyl group; -(CH 2 ) r0 -U 0 -(CH 2 ) s0 -heterocycloalkyl group; -U 0 -(CH 2 ) q0 -NR 021 R 021 or an aldonic acid; M + is a pharma- ceutically acceptable monovalent cation; U 0 is a bond or an oxygen atom, V 0 is -(CH 2 ) s0 - or -C(O)-; R 018 is a hydrogen atom or (C 1 ~C 6 )Alkoxy(C 1 ~C 6 ) alkyl group, R 019 is a hydrogen atom or a hydroxyl (C 1 ~C 6 ) alkyl group, R 020 is a hydrogen atom or a straight-chain or branched (C 1 ~C 6 ) alkyl group, R021 and R 021 ' are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, or hydroxy (C 1 ~C 6 ) an alkyl group, Or (R 021 , R 021 The pair of ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, where the resulting ring optionally contains hydrogen atoms or linear or branched (C 1 ~C 6 ) substituted by an alkyl group; R 022 is (C 1 ~C 6 )Alkoxy(C 1 ~C 6 ) alkyl group, -(CH 2 ) p0 -NR 024 R 024 ' group, or -(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 20 It is based on R 023 is a hydrogen atom or (C 1 ~C 6 )Alkoxy(C 1 ~C 6 ) an alkyl group, Or (R 022 , R 023 ) together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 18 ring members and optionally containing, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, where the resulting ring optionally contains hydrogen atoms, linear or branched (C 1 ~C 6 ) substituted by an alkyl or heterocycloalkyl group; R 024 and R 024 ' are each independently a hydrogen atom or a linear or branched (C 1 ~C 6 ) an alkyl group, Or (R 024 , R 024 The pair of aryl groups, together with the nitrogen atom to which they are attached, form an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, where the resulting ring may optionally contain hydrogen atoms or linear or branched (C 1 ~C 6 ) substituted by an alkyl group; R 025 is a hydrogen atom, a hydroxyl group, or a hydroxyl (C 1 ~C 6 ) alkyl group, R 026 is a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) an alkyl group or a cyano group; R 027 is a hydrogen atom or a straight-chain or branched (C 1 ~C 6 ) alkyl group, R 028 -OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 030 ) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH 2 ) p0 -O-SO 2 -O- group, -(CH 2 ) p0 -SO 2 -O- group, -(CH 2 ) p0 -O-SO 2 -OR 030 Group, -Cy 010 , -(CH 2 ) p0 -SO2 -OR 030 Group, -OC(O)-R 029 The group -OC(O)-OR 029 Group or -OC(O)-NR 029 R 029 'The basis; R 029 and R 029 ' are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group or linear or branched amino (C 1 ~C 6 ) alkyl group, R 030 and R 030 ' are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group or aryl (C 1 ~C 6 ) alkyl group, R 031 teeth, teeth,

[0144] [ka] where ammonium is optionally present in zwitterionic form or has a monovalent anionic counterion; n 0 is an integer equal to 0 or 1 p 0 is an integer equal to 0, 1, 2, or 3, q 0 is an integer equal to 1, 2, 3, or 4, r 0 and s 0 are, independently, integers equal to 0 or 1; If present, the R 03 , R 09 , or R 012 at most one of the groups is covalently attached to the linker; The valency of an atom is not exceeded by one or more substituents attached to it. or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharma- ceutically acceptable salt thereof of any of the foregoing. Definitions for the remaining variables are provided in the forty-sixth through fiftieth embodiments or any embodiment described therein.

[0145] In a fifty-second embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of cancer, comprising 01 , Cy 02 , Cy 03 , Cy 04 , Cy 05 , Cy 06 , Cy 07 , Cy 08 and Cy 010 are each independently a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally selected from the group consisting of halo; -(C 1 ~C 6 )alkoxy;-(C 1 ~C 6 ) haloalkyl;-(C 1 ~C 6 ) haloalkoxy;-(CH 2 ) p0 -O-SO 2 -OR 030 ;-(CH 2 ) p0 -SO 2 -OR 030 ;-OP(O)(OR 020 ) 2 ;-OP(O)(O - M + ) 2 ;-CH 2 -P(O)(OR 020 ) 2 ;-(CH 2 ) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ;Hydroxy;Hydroxy(C 1 ~C 6 ) alkyl; -(CH2 ) r0 -U 0 -(CH 2 ) s0 -heterocycloalkyl or -U 0 -(CH 2 ) q0 -NR 021 R 021 ', wherein the antibody-drug conjugate is substituted with one or more groups selected from: The definitions for the remaining variables are provided in the fifty-first embodiment or any embodiment described therein.

[0146] In a fifty-third embodiment, the present disclosure relates to a compound having the formula (IA):

[0147] [ka] (In the formula, Z 0 is a nitrogen atom or CR 04 It is based on R 01 is a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 ) haloalkyl group, hydroxy group, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) Alkyl group, cyano group, -Cy 08 , -NR 011 R 011 ' and R 02 , R 03 and R 04 are each independently a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 ) haloalkyl, hydroxyl, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) alkyl group, cyano group, nitro group, -(C 0 ~C 6 )Alkyl-NR 011 R 011 ',-O-Cy 01 , -(C 0 ~C 6 )Alkyl-Cy 01 , -(C 2 ~C 6 )Alkenyl-Cy 01 , -(C 2 ~C 6 )Alkynyl-Cy 01 , -O-(C 1 ~C 6 )Alkyl-NR 011 R 011 ', -O-(C 1 ~C 6 ) Alkyl-R 031 , -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C 1 ~C 6 )Alkyl-NR 011 -C(O)-R 011 ',-SO 2 -NR 011 R 011 ', or -SO 2 -(C 1 ~C 6 ) alkyl, Or (R 02 , R 03 ) or (R 03 , R 04 A pair of (C ) together with the carbon atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing 1 to 3 heteroatoms selected from O, S and N, wherein the ring is optionally linear or branched (C 1 ~C 6 ) alkyl, -NR 013 R 013 ', -(C 0 ~C 6 )Alkyl-Cy 01 and oxo), R 06 and R 07 are each independently a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C 2 ~C 6 ) alkynyl radicals, linear or branched (C 1 ~C 6 ) haloalkyl, hydroxyl, linear or branched (C 1 ~C 6 ) alkoxy group, -S-(C 1 ~C 6 ) alkyl group, cyano group, nitro group, -(C 0 ~C 6 )Alkyl-NR 011 R 011 ',-O-Cy 01 , -(C 0 ~C 6 )Alkyl-Cy 01 , -(C 2 ~C 6 )Alkenyl-Cy 01 , -(C 2 ~C 6 )Alkynyl-Cy 01 , -O-(C 1 ~C 6 ) Alkyl-R 012, -C(O)-OR 011 , -OC(O)-R 011 , -C(O)-NR 011 R 011 ', -NR 011 -C(O)-R 011 ', -NR 011 -C(O)-OR 011 ', -(C 1 ~C 6 )Alkyl-NR 011 -C(O)-R 011 ',-SO 2 -NR 011 R 011 ', or -SO 2 -(C 1 ~C 6 ) alkyl, Or (R 06 , R 07 A pair of (C), when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, forms an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing 1 to 3 heteroatoms selected from O, S and N, where the resulting ring is optionally linear or branched (C 1 ~C 6 ) alkyl group, -NR 013 R 013 ', -(C 0 ~C 6 )Alkyl-Cy 01 and oxo), R 08 is a hydrogen atom, a straight-chain or branched (C 1 ~C 8 ) alkyl group, aryl group, heteroaryl group, aryl-(C 1 ~C 6 ) alkyl group, or heteroaryl (C 1 ~C 6 ) alkyl group, R 09 is a linear or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 2 ~C 6 ) alkenyl groups, linear or branched (C2 ~C 6 ) alkynyl group, -Cy 02 , -(C 1 ~C 6 )Alkyl-Cy 02 , -(C 2 ~C 6 )Alkenyl-Cy 02 , -(C 2 ~C 6 )Alkynyl-Cy 02 , -Cy 02 -Cy 03 , -(C 2 ~C 6 )Alkynyl-O-Cy 02 , -Cy 02 -(C 0 ~C 6 )Alkyl-O-(C 0 ~C 6 )Alkyl-Cy 03 , halogen atom, cyano group, -C(O)-R 014 , -C(O)-NR 014 R 014 ' and R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C 1 ~C 6 ) alkyl group, or -(C 0 ~C 6 )Alkyl-Cy 01 or Or (R 011 , R 011 The pair of aryl groups, together with the nitrogen atom to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, where the N atom is optionally a linear or branched (C 1 ~C 6 ) alkyl groups, linear or branched (C 1 ~C 6 ) one or more of the carbon atoms of the alkyl group are optionally deuterated; R 012 -Cy 05 , -Cy05 -(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -(C 0 ~C 6 )Alkyl-O-(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -(C 0 ~C 6 )Alkyl-NR 011 -(C 0 ~C 6 )Alkyl-Cy 06 , -Cy 05 -Cy 06 -O-(C 0 ~C 6 )Alkyl-Cy 07 , -Cy 05 -(C 0 ~C 6 )Alkyl-Cy 09 , -NH-C(O)-NH-R 011 , -C(O)-NR 011 R 011 ', -NR 011 R 011 ',-OR 011 , -NR 011 -C(O)-R 011 ', -O-(C 1 ~C 6 )Alkyl-OR 011 , -SO 2 -R 011 , or -C(O)-OR 011 and R 013 , R 013 ', R 014 and R 014 ' are each independently a hydrogen atom or an optionally substituted linear or branched (C 1 ~C 6 ) alkyl group, Cy 01 , Cy 02 , Cy 03 , Cy 05 , Cy 06 , Cy 07 and Cy 08are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth,

[0148] [ka] (where R 015 , R 016 , and R 017 is as defined for formula (I), R 031 teeth,

[0149] [ka] (where R 027 and R 028 is as defined for formula (I), If present, the R 03 , R 09 , or R 012 At most one of the groups is covalently attached to the linker. or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharma- ceutically acceptable salt of any of the foregoing. The definitions for the remaining variables are provided in the fifty-first embodiment or any embodiment described therein.

[0150] In a fifty-fourth embodiment, the present disclosure provides a compound according to the present invention, wherein the Mcl-1 inhibitor has the formula (IB):

[0151] [ka] (In the formula, R 01 is a linear or branched (C 1 ~C 6 ) alkyl group, R 03is -O-(C 1 ~C 6 )Alkyl-NR 011 R 011 ',or

[0152] [ka] Is it (where R 011 and R 011 ' are each independently a hydrogen atom, an optionally substituted linear or branched (C 1 ~C 6 ) alkyl group, or -(C 0 ~C 6 )Alkyl-Cy 01 ), Or (R 011 , R 011 The pair of ') together with the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members and optionally containing, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, where the N atom is a hydrogen atom or a linear or branched (C 1 ~C 6 ) alkyl groups, R 027 is a hydrogen atom, and R 028 is -(CH 2 ) p0 -O-SO 2 -O- group or -(CH 2 ) p0 -SO 2 -OR 030 (which is the base), R 09 is a linear or branched (C 2 ~C 6 ) an alkynyl group or -Cy 02 and R 012 -Cy 05 , -Cy 05 -(C 0 ~C 6 )Alkyl-Cy 06 , or -Cy05 -(C 0 ~C 6 )Alkyl-Cy 09 and Cy 01 , Cy 02 , Cy 05 and Cy 06 are, independently of each other, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, each of which is optionally substituted; Cy 09 teeth,

[0153] [ka] (R 015 , R 016 , and R 017 is as defined for formula (I), If present, the R 03 , R 09 , or R 012 At most one of the groups is covalently attached to the linker. or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharma- ceutically acceptable salt of any of the foregoing. Definitions of the remaining variables are provided in the fifty-first embodiment.

[0154] In a fifty-fifth embodiment, the present disclosure provides a method for the preparation of a compound comprising: 01 is methyl or ethyl. The definitions of the remaining variables are provided in the 54th embodiment or any embodiment described therein.

[0155] In a fifty-sixth embodiment, the present disclosure provides a method for the preparation of a compound comprising: 03 But -O-CH 2 -CH 2 -NR 011 R 011 ' (where R 011 and R 011' together with the nitrogen atom bearing them form a piperazinyl group, which is a hydrogen atom or a straight-chain or branched (C 1 ~C 6 ) optionally substituted by a group that is an alkyl group), the antibody-drug conjugate of the 54th embodiment is provided. The definitions of the remaining variables are provided in the 54th embodiment or any embodiment described therein.

[0156] In a fifty-seventh embodiment, the present disclosure relates to a method for producing 03 But the formula:

[0157] [ka] (In the formula, R 027 is a hydrogen atom, and R 028 is -(CH 2 ) p0 -SO 2 -OR 030 The antibody-drug conjugate of the 54th embodiment is provided, comprising:

[0158] In a fifty-eighth embodiment, the present disclosure provides a method for the preparation of a compound comprising: 03 But the formula:

[0159] [ka] (In the formula,

[0160] [ka] is the bond to the linker) The antibody-drug conjugate of the 54th embodiment is provided, comprising: The remaining variable definitions are provided in the 54th embodiment or any embodiment described therein.

[0161] In a fifty-ninth embodiment, the present disclosure provides a method for the preparation of a compound comprising the steps of: 09 But, Cy 02The antibody-drug conjugate of the 54th embodiment is provided, wherein: The remaining variable definitions are as provided in the 54th embodiment or any embodiment described therein.

[0162] In a sixtieth embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of Cy 02 is an optionally substituted aryl group. The definitions of the remaining variables are provided in the 59th embodiment or any embodiment described therein.

[0163] In a sixty-first embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of Cy 05 comprises a heteroaryl group selected from a pyrazolyl group and a pyrimidinyl group. The remaining variable definitions are as provided in the 54th embodiment or any embodiment described therein.

[0164] In a sixty-second embodiment, the present disclosure provides a method for the preparation of a medicament for the treatment of cancer, comprising administering to a patient a therapeutically effective amount of Cy 05 is a pyrimidinyl group. The remaining variable definitions are provided as in the 54th embodiment or any embodiment described therein.

[0165] In a sixty-third embodiment, the present disclosure relates to a Mcl-1 inhibitor comprising R of formula (I), (IA), or (IB): 03 or R of formula (I), (IA), or (IB) 09 The antibody-drug conjugate of any one of the 54 to 62 embodiments is provided, wherein N is covalently attached to N. Definitions of the remaining variables are provided in the 54 to 62 embodiments or any embodiment described therein.

[0166] In a sixty-fourth embodiment, the present disclosure relates to a compound having the formula:

[0167] [Table 1-1]

[0168] [Table 1-2]

[0169] [Table 1-3] or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharma-ceutically acceptable salt of any of the foregoing. Definitions of the remaining variables are provided as in embodiments 54 to 63 or any embodiment described therein.

[0170] In a sixty-fifth embodiment, the present disclosure provides a compound according to the present invention, wherein the Bcl-xL inhibitor is represented by formula (II) or formula (III):

[0171] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, R 1 and R 2 are, independently of each other, hydrogen; hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl; trifluoromethyl; and linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl, where the heterocycloalkyl group is optionally a linear or branched C 1 ~C 6 substituted by an alkyl group; Or R 1 and R 2 are the carbon atoms that have them and C3 ~C 6 Forming a cycloalkylene group, R 3 is hydrogen; C 3 ~C 6 Cycloalkyl; straight or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and:

[0172] [ka] represents a group selected from the group consisting of R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N + R d R e R f ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 substituted by an alkoxy group); and the group:

[0173] [ka] or represents a group selected from the group consisting of Or R a and R b The nitrogen atom and ring B 1 Form or; Or, R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e , R f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0174] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0175] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 RG2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , -C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0176] [ka] R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl; R G5 is C optionally substituted with hydrogen or 1 to 3 halogen atoms 1 ~C 6 represents an alkyl group, R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, R 6 teeth, hydrogen; Linear or branched ~C 1 ~C 6 Alkylene-R 8 base; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0177] [ka] -X 2 -NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from the group consisting of R 7 is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0178] [ka] Cy represents a group selected from the group consisting of C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R'b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0179] [ka] represents a group selected from the group consisting of R 9 is a linear or branched C 1 ~C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 represents a group selected from the group consisting of alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C3 ~C 8 Cycloalkylene -CH 2 -R 8 , and C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 and X 2 are each independently selected from trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 substituted by an alkoxy group); and the group:

[0180] [ka] or represents a group selected from the group consisting of or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' fare each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8D forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2; B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1~C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; If present, R 3 and R 8 one of the groups is covalently attached to the linker, and the valency of the atom is not exceeded by one or more of the substituents attached to it; or

[0181] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, n=0, 1 or 2; ------ represents a single or double bond, A 4 and A 5 represent, independently of one another, a carbon or nitrogen atom, Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, R 1 is hydrogen; hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl; trifluoromethyl; and linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl, where the heterocycloalkyl group is optionally a linear or branched C 1 ~C 6 substituted by an alkyl group; R 2 represents hydrogen or methyl; R 3is hydrogen; linear or branched C 1 ~C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and:

[0182] [ka] represents a group selected from the group consisting of R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N+ R d R e R f ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 substituted by an alkoxy group); and the group:

[0183] [ka] or represents a group selected from the group consisting of Or R a and R b The nitrogen atom and ring B 1 Form or; Or R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e , R f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0184] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0185] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2, -C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0186] [ka] RG4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl; R G5 is C optionally substituted with hydrogen or 1 to 3 halogen atoms 1 ~C 6 represents an alkyl group, R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, R 6 teeth, hydrogen; Linear or branched ~C 1 ~C 6 Alkylene-R 8 base; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0187] [ka] -X 2-NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from the group consisting of R 7 is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0188] [ka] represents a group selected from the group consisting of (Here, Cy is C 3 ~C 8 represents cycloalkyl), R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R'c ;-N + R' a R' b R' c ;-O-R'c;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0189] [ka] represents a group selected from the group consisting of R 9 is a linear or branched C 1 ~C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 represents a group selected from the group consisting of alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, halogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , and C 3 ~C8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 6 represents alkylene, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl, wherein the phenyl is hydroxyl or C 1 ~C 6 substituted by an alkoxy group) and the group:

[0190] [ka] or represents a group selected from the group consisting of or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R'd , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2; B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; If present, R 3 , R 8 and one of the G groups is covalently attached to the linker, The valency of an atom is not exceeded by one or more substituents attached to it. The antibody-drug conjugate of any one of the 46th to 50th embodiments is represented by: The remaining variable definitions are provided in the 46th to 50th embodiments or any embodiment described therein.

[0191] In a sixty-sixth embodiment, the present disclosure relates to a Bcl-xL inhibitor having formula (IIA) or (IIIA):

[0192] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, Z 1 represents a bond or -O-; R 3 is hydrogen; C 3 ~C 6 Cycloalkyl; straight or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -ORc ;-X 1 -N 3 and

[0193] [ka] represents a group selected from the group consisting of R a and R b are each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; 1 ~C 6 Alkyl; and C 1 ~C 6 Alkylene-SO 2 O - represents a group selected from the group consisting of R c is hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Het 2 teeth,

[0194] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OH, -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , -C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, -C(O)NR G5 S(O) 2 R G4 , halogen, -NO 2 -CN; - R in each occurrence G1 , R G2 , R G4 and R G5 each independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 selected from the group consisting of alkyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 is alkyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C8 forming a heterocycloalkyl, R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 represents a group selected from the group consisting of alkyl; halogen and -CN; R 6 teeth, Linear or branched ~C 1 ~C 6 Alkylene-R 8 base; -X 2 -OR 7 ; and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from the group consisting of R 7 is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0195] [ka] Cy represents a group selected from the group consisting of C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R'b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0196] [ka] represents a group selected from the group consisting of R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i , -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , and C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 and X 2 are each independently selected from trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR'd R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 substituted by an alkoxy group); and the group:

[0197] [ka] or represents a group selected from the group consisting of or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, m=0, 1 or 2; p=1, 2, 3 or 4; B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl). The antibody-drug conjugate of a 65th embodiment is provided, wherein the antibody-drug conjugate is represented by: The definitions for the remaining variables are provided in the 65th embodiment or any embodiment described therein.

[0198] In a sixty-seventh embodiment, the present disclosure provides a method for the preparation of a cycloalkyl group comprising administering to a patient .... G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NRG1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 The antibody-drug conjugate of the 66th embodiment is provided, wherein -C is selected from the group consisting of -C, -D, -E, -F, -G, -H, -I ...

[0199] In a sixty-eighth embodiment, the present disclosure provides a method for the preparation of a compound comprising: 7 However, linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0200] [ka] Cy represents a group selected from the group consisting of C 3 ~C 8 represents cycloalkyl, providing the antibody-drug conjugate of any one of embodiments 65 to 67. The definitions of the remaining variables are provided in embodiments 65 to 67 or any embodiment described therein.

[0201] In a sixty-ninth embodiment, the present disclosure provides a method for the preparation of a compound comprising the steps of: 7 but,

[0202] [ka] The antibody-drug conjugate of any one of the sixty-fifth to sixty-seventh embodiments is provided, wherein the antibody-drug conjugate represents a group selected from the group consisting of: Definitions for the remaining variables are provided in embodiments 65-67 or any embodiment described therein.

[0203] In a seventieth embodiment, the present disclosure relates to a Bcl-xL inhibitor having formula (IIB), (IIC), (IIIB) or (IIIC):

[0204] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, For formula (IIB) or (IIC), R 3 is hydrogen; linear or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ; and -X 1 -OR c represents a group selected from: For formula (IIIB) or (IIIC), Z 1 represents a bond, R 3 represents hydrogen; or Z 1 represents -O-, R 3 -X 1 -NR a R b represents R a and R b are each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; 1 ~C 6 Alkyl; and C 1 ~C 6 Alkylene-SO 2 O - represents a group selected from R c is hydrogen or a linear or branched C 1 ~C6 represents an alkyl group, R 6 -X 2 -OR 7 or linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 represents a group, R 7 teeth,

[0205] [ka] represents a group selected from R 8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from R 10 represents fluorine, R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen or a methyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from alkoxy 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are, independently of each other, hydrogen; one or two hydroxyl or C1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-NR' d R' e represents a group selected from; or R' a and R' b The nitrogen atom and ring B 3 Forming R' d , R' e are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, B 3 is C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein the bicyclic group includes fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, linear or branched C 1 ~C 6 may be substituted with one or two groups selected from alkyl, hydroxyl, and oxo. The antibody-drug conjugate of a 65th embodiment is provided, wherein the antibody-drug conjugate is represented by: The definitions for the remaining variables are provided in the 65th embodiment or any embodiment described therein.

[0206] In a seventy-first embodiment, the present disclosure provides a method for the preparation of a compound comprising: 7 However, the following groups:

[0207] [ka] The antibody-drug conjugate of any one of the sixty-fifth to seventieth embodiments is provided, Definitions for the remaining variables are provided in embodiments 65-70 or any embodiment described therein.

[0208] In a 72nd embodiment, the present disclosure provides a method for the preparation of a compound comprising: 7 but,

[0209] [ka] The antibody-drug conjugate of any one of the sixty-fifth to seventieth embodiments is provided, wherein Definitions for the remaining variables are provided in embodiments 65-70 or any embodiment described therein.

[0210] In a 73rd embodiment, the present disclosure provides a method for the preparation of a compound comprising: 8 but,

[0211] [ka] represents a group selected from

[0212] [ka] represents attachment to the linker. Definitions for the remaining variables are provided in embodiments 65-72 or any embodiment described therein.

[0213] In a 74th embodiment, the present disclosure provides a method for producing a medicament for the treatment of cancer, comprising: 3 is selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group; 3 ~C 8 The antibody-drug conjugate of any one of embodiments 65 to 73 is provided wherein R represents a heterocycloalkyl group. The definitions of the remaining variables are as provided in embodiments 65 to 73 or any embodiment described therein.

[0214] In a seventy-fifth embodiment, the present disclosure provides a Bcl-xL inhibitor comprising:

[0215] [Table 2-1]

[0216] [Table 2-2]

[0217] [Table 2-3]

[0218] [Table 2-4]

[0219] [Table 2-5]

[0220] [Table 2-6]

[0221] [Table 2-7]

[0222] [Table 2-8]

[0223] [Table 2-9]

[0224] [Table 2-10]

[0225] [Table 2-11]

[0226] [Table 2-12] or an enantiomer, diastereoisomer, and / or pharma-ceutically acceptable salt of any one of the foregoing. Definitions of the remaining variables are provided in the 65th embodiment or any embodiment described therein.

[0227] In a seventy-sixth embodiment, the present disclosure relates to a Bcl-2 inhibitor having formula (IV) or formula (V):

[0228] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, A 1 is a hydrogen or halogen atom, a straight-chain or branched (C 1 ~C 6 ) polyhaloalkyl groups, linear or branched (C 1 ~C 6 ) an alkyl group or a cycloalkyl group; A 2 is a halogen, hydroxy, linear or branched (C 1 ~C 6 ) linear or branched, optionally substituted with a group selected from alkoxy, NR′R″ and morpholine; 1 ~C 6 ) an alkyl group or A 2 is a linear or branched (C 1 ~C 6 ) a polyhaloalkyl group or a cyclopropyl group; R' and R'' are each independently a hydrogen atom or a linear or branched (C 1 ~C 6 ) alkyl group, T is a hydrogen atom, a linear or branched (C 1 ~C 6 ) alkyl group, (C 1 ~C 4 )Alkyl-NR 1 R 2 Group, or (C 1 ~C 4 )Alkyl-OR 6 represents a group, R 1 and R 2 each independently represents a hydrogen atom or a linear or branched (C 1 ~C 6 ) an alkyl group, Or R 1 and R 2 form a heterocycloalkyl with the nitrogen atom carrying them, R 3 represents an aryl or heteroaryl group, it being understood that one or more carbon atoms of the preceding group or possible substituents thereof may be deuterated; R 4 represents a phenyl group, a 4-hydroxyphenyl group, a 3-fluoro-4-hydroxyphenyl group, a 2-hydroxypyrimidine group or a 3-hydroxypyridine group, it being understood that one or more carbon atoms of the preceding groups or possible substituents thereof may be deuterated; R 5 is a hydrogen or halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, or a linear or branched (C 1 ~C 6 ) an alkoxy group; R 6 is a hydrogen atom or a straight-chain or branched (C 1 ~C 6 ) an alkyl group; R a and R d each represents a hydrogen atom, (R b ,R c ) together with the carbon atom bearing them form a 1,3-dioxolane group or a 1,4-dioxane group, or R a , R c and R d each represents a hydrogen atom, and R b represents a hydrogen or halogen atom or a methoxy group; Or R a and R d each represents a hydrogen atom, and R b represents a hydrogen or halogen atom, R c represents a hydroxy or methoxy group, or R a and R d each represents a hydrogen atom, and R b represents a hydroxy or methoxy group, R c represents a halogen atom), or

[0229] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, Z 1 and Z 2 either represent a methyl group or they together with the atom carrying them form a fused piperidine group, T is a hydrogen atom, a linear or branched (C 1 ~C 6 ) alkyl group, (C 1 ~C 4 ) Alkylene-NR 1 R 2 group, (C 1 ~C 4 ) Alkylene-OR i represents a group, R 1 and R 2are each independently a hydrogen atom or a linear or branched (C 1 ~C 6 ) an alkyl group, Or R 1 and R 2 form a heterocycloalkyl group together with the nitrogen atom bearing them, the heterocycloalkyl optionally being 1 ~C 6 ) is substituted with 1 to 3 groups selected from an alkyl group and a halogen atom; R 3 teeth,

[0230] [ka] represents a group selected from R 4 teeth,

[0231] [ka] represents a group selected from R 5 represents a hydrogen atom, a halogen atom or a hydroxy group, R 6 is hydrogen, linear or branched (C 1 ~C 6 ) an alkyl group or a halogen atom; Alk is a linear or branched (C 1 ~C 6 ) an alkyl group; A 1 CY 4 or a nitrogen atom, A 2 represents CH or a nitrogen atom, Cy 1 represents a phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group, where the phenyl, heteroaryl, cyclo and heterocycloalkyl groups are optionally linear or branched (C 1 ~C 6) is substituted with 1 to 3 groups selected from an alkyl group, a hydroxy group, a cycloalkyl group, and a halogen atom, and the heterocycloalkyl group is optionally further substituted with an oxo group; Cy 2 represents a phenyl or heteroaryl group, the phenyl and heteroaryl groups being optionally linear or branched (C 1 ~C 6 ) substituted with 1 to 3 substituents selected from an alkyl group, a hydroxyl group, and a halogen atom; X is a bond, -O-, -S- or NR k represents Y 1 and Y 5 are each independently a hydrogen atom, a halogen atom, a cyano, a linear or branched (C 1 ~C 6 ) alkyl groups, and linear or branched (C 1 ~C 6 ) an alkoxy group; Y 2 and Y 4 are each independently a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, linear or branched (C 1 ~C 6 ) alkoxy groups, and linear or branched (C 1 ~C 6 ) a heterocycloalkyl group optionally substituted by an alkyl group, Y 3 is a hydrogen atom, a halogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl, linear or branched (C 1 ~C 6 ) alkynyl, -(C 1 ~C 4 ) Alkylene-OR l , linear or branched (C 1 ~C 6) alkoxy group, -O-phenyl, -S-phenyl, -O-(C 1 ~C 4 ) Alkylene-Cy 3 , -O-(C 1 ~C 4 ) Alkylene-Cy 4 , -O-Cy 3 , -O-(C 1 ~C 4 ) Alkylene-NR g R h , -(C 1 ~C 4 ) Alkylene-Cy 3 , -(C 1 ~C 4 ) Alkylene-Cy 4 , Cy 3 , Cy 4 and

[0232] [ka] wherein said alkylene moiety in the preceding group may be linear or branched; Cy 3 is a linear or branched (C 1 ~C 6 ) a heterocycloalkyl optionally substituted with 1 to 3 groups selected from an alkyl group, a hydroxy group, a cycloalkyl group, a heterocycloalkyl group, and a halogen atom; Cy 4 is a linear or branched (C 1 ~C 6 ) a cycloalkyl optionally substituted with 1 to 3 groups selected from an alkyl group, a hydroxy group, a cycloalkyl group, a heterocycloalkyl group, and a halogen atom; R a and R b represent, independently of one another, a hydrogen atom or a halogen atom, R cis a straight or branched (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) Alkylene-NR d R e , (C 1 ~C 6 ) Alkylene-OR j , cycloalkyl, heterocycloalkyl, and (C 1 ~C 6 ) alkylene-heterocycloalkyl groups, R' C and R'' c are each independently a hydrogen atom or a linear or branched (C 1 ~C 6 ) alkyl (preferably methyl); R d and R e are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) an alkyl group, a cycloalkyl group, or a heterocycloalkyl group; R f represents a hydrogen atom, a halogen atom or a cyano group, R' f represents a hydrogen atom or a halogen atom, R g and R h are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, cycloalkyl group, heterocycloalkyl group, or -(C 1 ~C 6 ) alkylene-heterocycloalkyl; R i , R j , and R k are each independently a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group, or -(C 1 ~C 6) an alkylene-cycloalkyl group; R l is a hydrogen atom, a straight-chain or branched (C 1 ~C 6 ) alkyl group or a linear or branched (C 1 ~C 6 ) an alkylene-heterocycloalkyl group, R m is hydrogen or a straight or branched (C 1 ~C 6 ) represents an alkyl group or a pharma- ceutically acceptable salt thereof. Definitions for the remaining variables are provided in the forty-sixth through fiftieth embodiments or any embodiment described therein. In some embodiments, it is understood that: "Aryl" means a phenyl, naphthyl, biphenyl, or indenyl group. "Heteroaryl" means any monocyclic or bicyclic group consisting of five to ten ring members, having at least one aromatic moiety and containing from one to four heteroatoms selected from oxygen, sulfur, and nitrogen (including quaternary nitrogen). "Cycloalkyl" means any mono- or bicyclic non-aromatic carbocyclic group containing three to ten ring members. "Heterocycloalkyl" refers to a group consisting of 3 to 10 ring members, including oxygen, sulfur, SO, SO 2 and nitrogen, It is possible that for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined, the alkyl, alkenyl, alkynyl and alkoxy groups are substituted by 1 to 3 groups selected from linear or branched (C1-C6)alkyl, (C3-C6)spiro, linear or branched (C1-C6)alkoxy, (C1-C6)alkyl-S-, hydroxy, oxo (or N-oxide, where appropriate), nitro, cyano, -COOR', -OCOR', NR'R'', linear or branched (C1-C6)polyhaloalkyl, trifluoromethoxy, (C1C6)alkylsulfonyl, halogen, aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups.

[0233] In a seventy-seventh embodiment, the disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, wherein the Bcl-2 inhibitor is represented by formula (IV), or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, or a pharma- ceutically acceptable salt thereof. Definitions of the remaining variables are provided in the seventy-sixth embodiment or any embodiment described therein.

[0234] In a 78th embodiment, the present disclosure provides a compound represented by the formula (IV), 1 represents a hydrogen atom or a methyl group; or (ii) A 1 and A 2 represent a methyl group. The definitions of the remaining variables are provided in the 76th or 77th embodiment or any embodiment described therein.

[0235] In a seventy-ninth embodiment, the disclosure provides the antibody-drug conjugate of the seventy-sixth to seventy-eighth embodiments, wherein in formula (IV), T represents methyl, aminomethyl, (morpholin-4-yl)methyl, (4-methylpiperazin-1-yl)methyl, 2-(morpholin-4-yl)ethyl, [2-(morpholin-4-yl)ethoxy]methyl, hydroxymethyl, [2-(dimethylamino)ethoxy]methyl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-ylmethyl, 1-oxa-6-azaspiro[3.3]hept-6-ylmethyl, 3-(morpholin-4-yl)propyl, or a trifluoromethyl group. Definitions of the remaining variables are provided as in the seventy-sixth to seventy-eighth embodiments or any embodiment described therein.

[0236] In an 80th embodiment, the present disclosure provides a compound represented by the formula (IV), 3 represents a group selected from phenyl, 1H-pyrazole, 1H-indole, 1H-indazole, pyridine, pyrimidine, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 1H-benzimidazole, 1H-pyrrole, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-b]pyridine, 5H-pyrrolo[3,2-d]pyrimidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole, and pyrazolo[1,5-a]pyrimidine, which groups may optionally be halogen, linear or branched (C 1 ~C 6 ) alkyl, linear or branched (C 1 C 6 )Alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, -CO-O-CH 3 , trideuteriomethyl, 2-(morpholin-4-yl)ethyl and 2-(morpholin-4-yl)ethoxy. Definitions for the remaining variables are provided in embodiments 76-79 or any embodiment described therein.

[0237] In an eighty-first embodiment, the disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, wherein the Bcl-2 inhibitor is represented by formula (V), or an enantiomer, diastereoisomer, and / or pharma-ceutically acceptable salt of any one of the foregoing. Definitions of the remaining variables are provided in the seventy-sixth embodiment or any embodiment described therein.

[0238] In an eighty-second embodiment, the present disclosure provides a compound according to the present invention, wherein the Bcl-2 inhibitor is represented by formula (Va):

[0239] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing. Definitions of the remaining variables are provided in the 76th embodiment or any embodiment described therein.

[0240] In an 83rd embodiment, the present disclosure provides R 3 However, the following groups:

[0241] [ka] R c is a straight-chain or branched (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) Alkylene-NR d R e , (C 1 ~C 6 ) Alkylene-OR j , cycloalkyl, heterocycloalkyl, and (C 1 ~C 6) alkylene-heterocycloalkyl group. The definitions for the remaining variables are provided in the 81 or 82 embodiment or any embodiment described therein.

[0242] In an 84th embodiment, the present disclosure provides the antibody-drug conjugate of the 83rd embodiment, wherein Rc represents a methyl group. The definitions of the remaining variables are provided in the 83rd embodiment or any embodiment described therein.

[0243] In an 85th embodiment, the present disclosure provides R 4 However, the following groups:

[0244] [ka] The antibody-drug conjugate of any one of the 81st to 83rd embodiments is provided, Definitions for the remaining variables are provided in embodiments 81-83 or any embodiment described therein.

[0245] In an eighty-sixth embodiment, the present disclosure provides a compound according to the present invention, wherein the Bcl-2 inhibitor is represented by formula (Vb):

[0246] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing. Definitions of the remaining variables are provided in the 81st embodiment or any embodiment described therein.

[0247] In an 87th embodiment, the present disclosure provides R c represents a methyl group. The definitions of the remaining variables are provided in the 86th embodiment or any embodiment described therein.

[0248] In an eighty-eighth embodiment, the present disclosure relates to a compound having the formula (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj):

[0249] [ka]

[0250] [ka]

[0251] [ka]

[0252] [ka]

[0253] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing. Definitions of the remaining variables are provided in the 81st embodiment or any embodiment described therein.

[0254] In an eighty-ninth embodiment, the present disclosure provides a compound according to the present invention, wherein in formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj): (i) X represents a bond; (ii)A 1 But, C.Y. 4 represents; (iii)R a and R b However, both represent hydrogen atoms; (iv) R 5represents a hydrogen atom, a hydroxy group or a fluorine atom, preferably a hydroxy group; (v)R 6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom; (vi) A 1 represents CH, and Y 2 represents a hydrogen atom; (vii) Y 1 and Y 5 However, either both represent hydrogen atoms or Y 1 and Y 5 represent a fluoro atom and a hydrogen atom, respectively; (viii) Y 3 But -O-(C 1 ~C 6 ) alkylene-heterocycloalkyl group or -O-(C 1 ~C 4 ) Alkylene-Cy 3 Represents the group; (ix) Y 3 However, 2-(morpholin-4-yl)ethoxy, 2-(oxan-4-yl)ethoxy, 2-(4-hydroxypiperidin-1-yl)ethoxy, 2-(4-cyclopropylpiperazin-1-yl)ethoxy, 2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethoxy, 2-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]ethoxy, 2-{2-[4-(2-{1,1-dioxo-1λ 6-thia-6-azaspiro[3.3]heptan-6-yl}ethoxy, 2-[2,6-dimethylmorpholin-4-yl]ethoxy, 2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy, 2-(3-fluoroazetidin-1-yl)ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-(thiomorpholin-4-yl)ethoxy, 2-(2-methylmorpholin-4-yl)ethoxy, 2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy, 2-{4 -oxa-7-azaspiro[2.5]octan-7-yl}ethoxy, 2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(2,2-dimethylmorpholin-4-yl)ethoxy, 2-(morpholin-4-yl)propoxy, [2-methyl-1-(morpholin-4-yl)propan-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy, 2-(3-methylmorpholin-4-yl)ethoxy, 2-(1,4-dioxan-2-yl)ethoxy; (x) group:

[0255] [ka] but,

[0256] [ka] represents; (xi) T is a linear or branched (C 1 ~C 6 ) alkyl group or (C 1 ~C 4 ) Alkylene-NR 1 R 2 and / or (xii) T is a methyl group, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, (piperidin-1-yl)ethyl, [(3R)-3-fluoropyrrolidin-1-yl]methyl, (4-fluoropiperidin-1-yl)methyl, [methyl(propan-2-yl)amino]methyl, (azepan-1-yl)methyl, (pyrrolidin-1-yl)methyl, [(3S)-3-methylpiperidin-1-yl]methyl, [(3R)-3-methylpiperidin-1-yl]methyl, [(1RS,5SR)-3-azabicyclo[3.1.0]hexan-3-yl]methyl, [(2S)-2-methylpiperidin-1-yl]methyl, {6-azaspiro[2.5]octan-6-yl}methyl, (4, represents a group selected from 4-difluoropiperidin-1-yl)methyl, (diethylamino)methyl, (4-methylpiperidin-1-yl)methyl, [ethyl(propan-2-yl)amino]methyl, {5-azaspiro[2.3]hexan-5-yl}methyl, (3,3-dimethylpyrrolidin-1-yl)methyl, (diisopropylamino)methyl, [ethyl(isopropyl)amino]methyl, [(3R)-3-methylpyrrolidin-1-yl]methyl, [(3S)-3-methylpyrrolidin-1-yl]methyl, [(2S)-2-methylpyrrolidin-1-yl]methyl, 5-azaspiro[2.4]heptan-5-ylmethyl, 2-azaspiro[3.3]heptan-2-ylmethyl, and aminomethyl, Provided is the antibody-drug conjugate of any one of embodiments 81 to 88. Definitions of the remaining variables are provided in embodiments 81 to 88 or any embodiment described therein.

[0257] In some embodiments, for the antibody-drug conjugate of the 88th embodiment, the Bcl-2 inhibitor is (i) X represents a bond; (ii)A 1 But, C.Y. 4 represents; (iii)R a and R b However, both represent hydrogen atoms; (iv) R 5represents a hydrogen atom, a hydroxy group or a fluorine atom, preferably a hydroxy group; (v)R 6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom; (vi) A 1 represents CH, and Y 2 represents a hydrogen atom; (vii) Y 1 and Y 5 However, either both represent hydrogen atoms or Y 1 and Y 5 represent a fluoro atom and a hydrogen atom, respectively; (viii) Y 3 But -O-(C 1 ~C 6 ) an alkylene-heterocycloalkyl group; (ix) Y 32-(morpholin-4-yl)ethoxy, 2-[4-(2,2-difluoroethyl)piperazin-1-yl]ethoxy, 2-(3-fluoroazetidin-1-yl)ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-(oxan-4-yl)ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-(thiomorpholin-4-yl)ethoxy 2-(2-methylmorpholin-4-yl)ethoxy, 2-{6-oxa-9-azaspiro[4.5]decan-9-yl}ethoxy, 2-(3,3-difluoropyrrolidin-1-yl)ethoxy, 2-{4-oxa-7-azaspiro[2.5]octan-7-yl}ethoxy, 2,6-dimethylmorpholin-4-yl]ethoxy, 2-[cyclopropyl(methyl)amino]ethoxy oxy, 2-{methyl[(oxetan-3-yl)methyl]amino}ethoxy, 2-[methyl(oxetan-3-yl)amino]ethoxy, 2-(4-fluoropiperidin-1-yl)ethoxy, 2-[(2-fluoroethyl)(methyl)amino]ethoxy, 2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(2,2-dimethylmorpholin-4-yl)ethoxy, 2-(morpholin-4-yl)propoxy, 2-(4,4-difluoropiperidin-1-yl)ethyl, [2-methyl-1-(morpholin-4-yl)propan-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy, and [(oxan-4-yl)methoxy]methyl; (x) group:

[0258] [ka] but,

[0259] [ka] represents; (xi) T is a linear or branched (C 1 ~C 6 ) alkyl group or (C 1 ~C 4) Alkylene-NR 1 R 2 and / or (xii) T is methyl, (piperidin-1-yl)methyl, (morpholin-4-yl)methyl, [(3R)-3-fluoropyrrolidin-1-yl]methyl, [methyl(propan-2-yl)amino]methyl, (azepan-1-yl)methyl, (pyrrolidin-1-yl)methyl, [(3S)-3-methylpiperidin-1-yl]methyl, [(3R)-3-methylpiperidin-1-yl]methyl, [(1RS,5SR)-3-azabicyclo[3.1.0]hexamethyl represents a group selected from among [(2S)-2-methylpiperidin-1-yl]methyl, {6-azaspiro[2.5]octan-6-yl}methyl, (4,4-difluoropiperidin-1-yl)methyl, (4-methylpiperidin-1-yl)methyl, [ethyl(propan-2-yl)amino]methyl, (3R)-3-methylpyrrolidin-1-yl]methyl, and (3S)-3-{[(3S)-3-methylpyrrolidin-1-yl]methyl, Represented by formula (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj). In some embodiments, in formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj), R 5 represents a hydroxy group, R 6 In some embodiments, in formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj), Y 3 is -O-(C 1 ~C 4 ) Alkylene-Cy 3 Represents a group.

[0260] In a ninetieth embodiment, the present disclosure relates to a Bcl-2 inhibitor, comprising any one of the following, or a pharma- ceutically acceptable salt thereof:

[0261] [Table 3-1]

[0262] [Table 3-2]

[0263] [Table 3-3] The antibody-drug conjugate of the 76th embodiment is provided, wherein the antibody-drug conjugate is represented by: Definitions for the remaining variables are provided in the 76th embodiment or any embodiment described therein.

[0264] In some embodiments, the disclosure provides that the topoisomerase 1 inhibitor is any one of the following, or a pharma- ceutically acceptable salt thereof:

[0265] [Table 4] The present invention provides an antibody-drug conjugate according to any one of the first to forty-sixth, forty-ninth, fifty-first to ninetyth embodiments, wherein the antibody-drug conjugate is represented by the formula: Definitions for the remaining variables are provided in any one of embodiments 1-46, 49, 51-90 or any embodiment described therein.

[0266] In some embodiments, the disclosure provides an antibody-drug conjugate as described in any one of the first to forty-sixth, forty-ninth, fifty-first to ninetyth embodiments, wherein the antimitotic agent is monomethyl auristatin E (MMAE) or a taxane. The remaining variable definitions are provided in any one of the first to forty-sixth, forty-ninth, fifty-first to ninetyth embodiments, or any embodiment described therein. In some embodiments, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

[0267] In a 91st embodiment, the present disclosure provides the antibody-drug conjugate of any one of the first to 90th embodiments, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell. Definitions of the remaining variables are provided in the first to 90th embodiments or any embodiment described therein.

[0268] In a 92nd embodiment, the present disclosure provides a method for producing a composition comprising: (i) the target antigen is selected from BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, SEZ6, DLL3, DLK1, B7-H3, EGFR, CD71, EphA2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; (ii) the target antigen is selected from EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; or (iii) the target antigen is MET, CD48, CD74, EphA2, PCAD, TROP2, B7-H3, or 5T4, or HER2; The antibody-drug conjugate of the 91st embodiment is provided. Definitions of the remaining variables are provided in the 91st embodiment.

[0269] In a 93rd embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment having CDR sequences is selected from those in Tables D3 and D8, or the antibody or antigen-binding fragment having variable regions is selected from those in Tables D2 and D8, or the antibody or antigen-binding fragment having full length is selected from those in Tables D4, D5, and D7. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0270] In a 94th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 268, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 172, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 269, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 172, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 263, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 6) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 7) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 267, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and 8) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174 The antibody-drug conjugate of the 91st embodiment is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0271] In a 95th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD74 antibody comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 262, or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 267. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0272] In a 96th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: (a) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence that is at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence that is at least 95% identical to SEQ ID NO: 237; (b) a heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence that is at least 95% identical to SEQ ID NO: 236, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence that is at least 95% identical to SEQ ID NO: 237; or (c) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence that is at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 239, or a sequence that is at least 95% identical to SEQ ID NO: 239. The antibody-drug conjugate of the 91st embodiment is an anti-CD74 antibody comprising: Definitions of the remaining variables are provided in the 91st embodiment.

[0273] In a 97th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof, 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 271, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 272, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 281, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 282, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 283; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 274, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 275, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 284, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 285, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 276, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 278; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 287, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 282, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 279, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 275, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 284, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 288, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; and 5) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 51, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 52, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 53; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 54, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 55, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 56 The antibody-drug conjugate of the 91st embodiment is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0274] In a 98th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD48 antibody comprising: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 270, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 280; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0275] In a 99th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD48 antibody comprising: (a) a heavy chain amino acid sequence of SEQ ID NO:240 or a sequence that is at least 95% identical to SEQ ID NO:240, and a light chain amino acid sequence of SEQ ID NO:243 or a sequence that is at least 95% identical to SEQ ID NO:243; or (b) a heavy chain amino acid sequence of SEQ ID NO:242 or a sequence that is at least 95% identical to SEQ ID NO:242, and a light chain amino acid sequence of SEQ ID NO:243 or a sequence that is at least 95% identical to SEQ ID NO:243; c) a heavy chain amino acid sequence of SEQ ID NO:240 or a sequence that is at least 95% identical to SEQ ID NO:240, and a light chain amino acid sequence of SEQ ID NO:69 or a sequence that is at least 95% identical to SEQ ID NO:70. Definitions of the remaining variables are provided in the 91st embodiment.

[0276] In a hundredth embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 291; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 297, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 298, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 299; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 292, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 291; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 300, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 301, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 293, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 294, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 295; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 302, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 298, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44; and 4) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 39, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 291; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 300, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 301, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44 The antibody-drug conjugate of the 91st embodiment is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0277] In a 101st embodiment, the present disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-Her2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 296. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0278] In a 102nd embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-Her2 antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 245, or a sequence that is at least 95% identical to SEQ ID NO: 245, and a light chain amino acid sequence of SEQ ID NO: 66, or a sequence that is at least 95% identical to SEQ ID NO: 66. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0279] In a 103rd embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 312, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 314; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 307, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 309, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 278; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 317, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316; and 4) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 310, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316 The antibody-drug conjugate of the 91st embodiment is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0280] In a 104th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-PCAD antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 303, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 311. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0281] In a 105th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-PCAD antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 248, or a sequence that is at least 95% identical to SEQ ID NO: 248, and a light chain amino acid sequence of SEQ ID NO: 250, or a sequence that is at least 95% identical to SEQ ID NO: 250. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0282] In a 106th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 319, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 320, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 330, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 331, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 332; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 322, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 324; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 325, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 326, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 327; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 336, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 331, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335; and 4) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335 The antibody-drug conjugate of a 91st embodiment is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0283] In a 107th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-EphA2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 318, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 329. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0284] In a 108th embodiment, the disclosure provides the antibody-drug conjugate of the 91st embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-EphA2 antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 252, or a sequence that is at least 95% identical to SEQ ID NO: 252, and a light chain amino acid sequence of SEQ ID NO: 254, or a sequence that is at least 95% identical to SEQ ID NO: 254. Definitions of the remaining variable regions are provided in the 91st embodiment.

[0285] In a 109th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 349, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 350, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 351; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 352, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 353, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 354; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 355, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 356, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 357; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 358, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 359, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 360; and 3) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 361, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 362, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 363; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 364, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 365, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 366 and wherein the antibody-drug conjugate is an anti-MET antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: AGA ...

[0286] In a 110th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 339, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 340; 2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 341, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 342; and 3) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 343, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; The antibody-drug conjugate of the 91st embodiment is an anti-MET antibody comprising a heavy chain variable region and a light chain variable region selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0287] In a 111th embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof comprising: 1) a heavy chain amino acid sequence of SEQ ID NO: 367, or a sequence that is at least 95% identical to SEQ ID NO: 367, and a light chain amino acid sequence of SEQ ID NO: 368, or a sequence that is at least 95% identical to SEQ ID NO: 368; 2) a heavy chain amino acid sequence of SEQ ID NO: 369, or a sequence that is at least 95% identical to SEQ ID NO: 369, and a light chain amino acid sequence of SEQ ID NO: 370, or a sequence that is at least 95% identical to SEQ ID NO: 370; 3) a heavy chain amino acid sequence of SEQ ID NO: 371, or a sequence that is at least 95% identical to SEQ ID NO: 371, and a light chain amino acid sequence of SEQ ID NO: 372, or a sequence that is at least 95% identical to SEQ ID NO: 372; 4) a heavy chain amino acid sequence of SEQ ID NO: 373, or a sequence that is at least 95% identical to SEQ ID NO: 373, and a light chain amino acid sequence of SEQ ID NO: 374, or a sequence that is at least 95% identical to SEQ ID NO: 374; 5) a heavy chain amino acid sequence of SEQ ID NO: 375 or a sequence that is at least 95% identical to SEQ ID NO: 375, and a light chain amino acid sequence of SEQ ID NO: 370 or a sequence that is at least 95% identical to SEQ ID NO: 370; and 6) a heavy chain amino acid sequence of SEQ ID NO: 376 or a sequence that is at least 95% identical to SEQ ID NO: 376, and a light chain amino acid sequence of SEQ ID NO: 372 or a sequence that is at least 95% identical to SEQ ID NO: 372 The antibody-drug conjugate of the 91st embodiment is an anti-MET antibody comprising a heavy chain variable region and a light chain variable region selected from the group consisting of: Definitions of the remaining variables are provided in the 91st embodiment.

[0288] In a 112th embodiment, the present disclosure provides the antibody-drug conjugate of any one of the 109th to 111th embodiments, wherein the two antineoplastic drug payloads are Bcl-xL inhibitors.

[0289] In a 113th embodiment, the present disclosure provides the antibody-drug conjugate of any one of the 94th to 112th embodiments, wherein the antibody or antigen-binding fragment thereof comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C in the heavy chain of the antibody or antigen-binding fragment thereof, and the positions are numbered according to the EU system. Definitions of the remaining variable regions are provided in the 94th to 112th embodiments.

[0290] In a 114th embodiment, the present disclosure provides the antibody-drug conjugate of any one of the 94th to 112th embodiments, wherein the antibody or antigen-binding fragment thereof comprises one or more Fc silencing mutations. Definitions of the remaining variable regions are provided in the 94th to 112th embodiments.

[0291] In some embodiments, the present disclosure provides, in part, novel antibody-drug conjugate (ADC) compounds that have biological activity against cancer cells. The compounds may slow, inhibit, and / or reverse tumor growth in mammals and / or may be useful for treating human cancer patients. The present disclosure more particularly relates to ADC compounds that, in some embodiments, can bind to and kill cancer cells. In some embodiments, the ADC compounds disclosed herein include a dual linker that attaches two BH3 mimetics to a full-length anti-Met antibody or antigen-binding fragment. In some embodiments, the ADC compounds can also be internalized into target cells after binding.

[0292] In some embodiments, the D in an ADC compound disclosed herein (e.g., an ADC of formula (A), (B), (C), (D1), (D2), or (D3) in this disclosure) 1 and / or D. 2 comprises a formula independently selected from any one of the formulas in Table A1a, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0293] [Table 5-1]

[0294] [Table 5-2]

[0295] [Table 5-3]

[0296] [Table 5-4] Where:

[0297] [ka] represents a bond to the linker.

[0298] In some embodiments, the D in an ADC compound disclosed herein (e.g., an ADC of formula (A), (B), (C), (D1), (D2), or (D3) in this disclosure) 1 and / or D. 2 comprises, independently, a formula selected from any one of the formulas in Table A2a, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0299] [Table 6-1]

[0300] [Table 6-2]

[0301] [Table 6-3]

[0302] [Table 6-4]

[0303] [Table 6-5]

[0304] [Table 6-6]

[0305] [Table 6-7]

[0306] [Table 6-8]

[0307] [Table 6-9]

[0308] [Table 6-10]

[0309] [Table 6-11]

[0310] [Table 6-12] Where:

[0311] [ka] represents a bond to the linker.

[0312] In some embodiments, the D in an ADC compound disclosed herein (e.g., an ADC of formula (A), (B), (C), (D1), (D2), or (D3) in this disclosure) 1 and / or D. 2 comprises, independently, a formula selected from any one of the formulas in Table A3a, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0313] [Table 7-1]

[0314] [Table 7-2]

[0315] [Table 7-3] Where:

[0316] [ka] represents a bond to the linker.

[0317] In some embodiments, the D in an ADC compound disclosed herein (e.g., an ADC of formula (A), (B), (C), (D1), (D2), or (D3) in this disclosure) 1 and / or D. 2 comprises, independently, a formula selected from any one of the formulas in Table A4a, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0318] [Table 8] Where:

[0319] [ka] represents a bond to the linker.

[0320] In some embodiments,

[0321] [ka] is formed from a compound selected from Table B, or an enantiomer, diastereoisomer, and / or a pharma- ceutically acceptable salt thereof. In some embodiments, the maleimide group in the compound of Table B

[0322] [ka] forms a covalent bond with an antibody or an antigen-binding fragment (Ab) to

[0323] [ka] Part (where * indicates the point of attachment to Ab. For the compounds in Tables A1, A2, A3, B, and C, depending on their electronic charge, these compounds may be provided with one pharma- ceutically acceptable monovalent anionic counterion, M 1 - In some embodiments, the monovalent anionic counterion M 1 - can be selected from bromine, chlorine, iodine, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, etc. In some embodiments, the monovalent anionic counterion M 1 - is a trifluoroacetate or formate.

[0324] [Table 9-1]

[0325] [Table 9-2]

[0326] [Table 9-3]

[0327]

Table 9-4

[0328]

Table 9-5

[0329]

Table 9-6

[0330]

Table 9-7

[0331]

Table 9-8

[0332]

Table 9-9

[0333]

Table 9-10

[0334]

Table 9-11

[0335]

Table 9-12

[0336]

Table 9-13

[0337]

Table 9-14

[0338]

Table 9-15

[0339]

Table 9-16

[0340]

Table 9-17

[0341]

Table 9-18

[0342]

Table 9-19

[0343]

Table 9-20

[0344]

Table 9-21

[0345]

Table 9-22

[0346]

Table 9-23

[0347]

Table 9-24

[0348] [Table 9-25] In some embodiments, the antibody-drug conjugate has a formula according to any one of the structures shown in Table C.

[0349] [Table 10-1]

[0350] [Table 10-2]

[0351] [Table 10-3]

[0352] [Table 10-4]

[0353] [Table 10-5]

[0354] [Table 10-6]

[0355] [Table 10-7]

[0356] [Table 10-8]

[0357]

Table 10-9

[0358]

Table 10-10

[0359]

Table 10-11

[0360]

Table 10-12

[0361]

Table 10-13

[0362]

Table 10-14

[0363]

Table 10-15

[0364]

Table 10-16

[0365]

Table 10-17

[0366]

Table 10-18

[0367] [Table 10-19]

[0368] [Table 10-20]

[0369] [Table 10-21]

[0370] [Table 10-22]

[0371] [Table 10-23]

[0372] [Table 10-24]

[0373] [Table 10-25]

[0374] The ADC represented above has the following formula:

[0375] [ka] (In the formula,

[0376] [ka] represents an antibody or antigen fragment thereof covalently linked to a linker-payload (L / P) as depicted above; a is an integer from 1 to 16. In some embodiments, a is an integer from 1 to 8. In some embodiments, a is an integer from 1 to 5. In some embodiments, a is an integer from 2 to 4. In some embodiments, a is 2. In some embodiments, a is 4. In some embodiments, a is determined by liquid chromatography-mass spectrometry (LC-MS).

[0377] In some embodiments, for the ADCs depicted in Table C, the antibody is an antibody or antigen fragment thereof described herein. In some embodiments, the antibody is an anti-HER2 antibody (e.g., trastuzumab, dicitamab, or Ab T). In some embodiments, the antibody is an anti-CD74 antibody (e.g., VHmil x VK1aNQ or milatuzumab). In some embodiments, the antibody is an anti-CD48 antibody (e.g., SGN-CD48A (MEM / MEM102) or NY920). In some embodiments, the antibody is an anti-PCAD antibody (e.g., CQY679). In some embodiments, the antibody is an anti-EphA2 antibody (e.g., 1C1). In some embodiments, the antibody is an anti-MET antibody (e.g., 9006, 9338, or 8902). In some embodiments, the antibody is an anti-TROP2 antibody (e.g., datopotamab). In some embodiments, the antibody is an anti-B7-H3 antibody (e.g., ABBV-155 or DS-5573a). In some embodiments, the antibody is an anti-5T4 antibody.

[0378] As used herein, "PLP" refers to a linker-payload, linker-drug, or linker-compound disclosed herein, and the term "P#-L#-P#" refers to a particular dual linker-drug disclosed herein, where each "P#" symbol refers to a particular antineoplastic drug compound (e.g., a BH3 mimetic) unless otherwise specified, and L# refers to a particular dual linker unless otherwise specified. The two "P#" symbols can be the same or different, i.e., refer to the same or different antineoplastic drug compounds (e.g., a BH3 mimetic). For example, "P1-L1-P1" refers to a linker-payload compound having a dual linker L1 attached to two P1 payloads, while "P1-L1-P2" refers to a linker-payload compound having a dual linker L1 attached to P1 and P2 payloads, including enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, for example, when the linker L1 is not symmetrical, the terms "P1-L1-P2" and "P2-L1-P1" refer to two different linker-drugs. In the present disclosure, "L#-P#" refers to a particular mono-linker-drug disclosed herein. For example, "L1-P1" refers to a linker-payload compound having a mono-linker L1 attached to one P1 payload.

[0379] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on a cancer cell. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is MET, CD74, CD48, HER2, TROP2, B7-H3, or 5T4.

[0380] In some embodiments, the antibody or antigen-binding fragment is an antibody or antigen-binding fragment disclosed on the internet at go.drugbank.com / drugs / DB00002, in International Application Publication Nos. WO 2018 / 098306, WO 2016 / 179257, WO 2011 / 097627, WO 2017 / 214282, WO 2017 / 214301, WO 2017 / 214233, WO 2013 / 126810, WO 2008 / 056833, WO 2020 / 236817, WO 2017 / 214335, and WO 2012 / 147713, and in U.S. Pat. No. 6,870,034, which are incorporated by reference in their entireties.

[0381] In some embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-PCAD antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-CD48 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is an anti-CD74 antibody or antigen-binding fragment. In some embodiments, the present disclosure provides an antibody or antigen-binding fragment comprising one or more SEQ ID NOs listed in Tables D2-D5, D7 and D8 described herein.

[0382] Also provided herein, in some embodiments, are compositions comprising multiple copies of an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein). In some embodiments, the average p of the antibody-drug conjugates in the composition is about 2 to about 4.

[0383] Also provided herein, in some embodiments, is a pharmaceutical composition comprising an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein) or composition (e.g., any of the exemplary compositions described herein) and a pharma- ceutically acceptable carrier.

[0384] In some embodiments, therapeutic uses for the described ADC compounds and compositions, for example in the treatment of cancer, are further provided herein. In some embodiments, the present disclosure provides a method of treating cancer (e.g., a cancer expressing an antigen targeted by an antibody or antigen-binding fragment of an ADC, such as PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4). In some embodiments, the present disclosure provides a method of reducing a cancer cell population or slowing its expansion and growth in a subject. In some embodiments, the present disclosure provides a method of determining whether a subject having or suspected of having cancer will respond to treatment with an ADC compound or composition disclosed herein.

[0385] An exemplary embodiment is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer,In some embodiments, the cancer is lymphoma or a lymphoid cancer. In some embodiments, the cancer is lymphoma or a lymphoid cancer.

[0386] Another exemplary embodiment is a method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, pancreatic cancer, stomach cancer, or combination cancer.In some embodiments, the tumor is a gastric cancer. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0387] Another exemplary embodiment is a method of reducing or slowing the expansion and 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 antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer cell population is from a tumor or hematological cancer. In some embodiments, the cancer cell population is from breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer,In some embodiments, the cancer cell population is from lymphoma or gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer. In some embodiments, the cancer cell population is from lymphoma or gastric cancer. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition slows the expansion and 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%.

[0388] Another exemplary embodiment is an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject with cancer or a subject suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer,In some embodiments, the cancer is lymphoma or a lymphoid cancer. In some embodiments, the cancer is lymphoma or a lymphoid cancer.

[0389] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in the treatment of a subject having or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer,In some embodiments, the cancer is lymphoma or a lymphoid cancer. In some embodiments, the cancer is lymphoma or a lymphoid cancer.

[0390] 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 manufacturing a medicament for treating a subject with or suspected of having cancer. In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer,In some embodiments, the cancer is lymphoma or a lymphoid cancer. In some embodiments, the cancer is lymphoma or a lymphoid cancer.

[0391] Another exemplary embodiment is a method of determining whether a subject having or suspected of having cancer responds to treatment with an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample from a subject; contacting the sample with an antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample. In some embodiments, the cancer cells in the sample express the target antigen. In some embodiments, the cancer expresses the target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (mimetic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), episialin, ERBB3, ETBR (endothelin type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related gene I, TAG-72, TEMI, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPI (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, or EphA2. In some embodiments, the target antigen is CD74, CD48, HER2, TROP2, B7-H3, or 5T4. In some embodiments, the target antigen is MET. In some embodiments, the cancer is a tumor or a blood cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

[0392] Methods of producing the described ADC compounds and compositions are also disclosed. An exemplary embodiment is a method of producing an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a dual linker conjugated or covalently attached to two antineoplastic drug compounds, at least one of which is a BH3 mimetic (e.g., two BH3 mimetics or a BH3 mimetic and a non-BH3 mimetic (e.g., a topoisomerase I inhibitor)) under conditions that allow conjugation. [Brief description of the drawings]

[0393] [Figure 1] FIG. 1 shows tumor volume (mm3) in H929-implanted female SCID mice treated with IgG1-CysmAb Fcsilent_P1-L19-P2, anti-CD48 MEM_CysmAb Fcsilent, and anti-CD48 MEM_CysmAb Fcsilent_P1-L19-P2, administered once IV at 30 mg / kg (n=8). [Diagram 2] FIG. 2 shows % weight loss in H929 engrafted female SCID mice treated with 30 mg / kg IgG1-CysmAb Fcsilent_P1-L19-P2, anti-CD48 MEM_CysmAb Fcsilent, anti-CD48 MEM_CysmAb Fcsilent_P1-L19-P2 administered IV once (n=8). [Diagram 3] FIG. 3 shows tumor volume (mm3) in H929-implanted female SCID mice treated with IgG1-CysmAb Fc WT_P1-L19-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L19-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L29-P2, anti-CD48 MEM_CysmAb Fc WT_P2-L29-P1, anti-CD48 MEM_CysmAb Fc WT_P1-L31-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L32-P2 and anti-CD48 MEM_CysmAb Fc WT_P1-L30-P2 administered once IV at 30 mg / kg (n=6). [Figure 4] FIG. 4 shows the body weight of H929 engrafted female SCID mice treated with IgG1-CysmAb Fc WT_P1-L19-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L19-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L29-P2, anti-CD48 MEM_CysmAb Fc WT_P2-L29-P1, anti-CD48 MEM_CysmAb Fc WT_P1-L31-P2, anti-CD48 MEM_CysmAb Fc WT_P1-L32-P2 and anti-CD48 MEM_CysmAb Fc WT_P1-L30-P2 administered once IV at 30 mg / kg (n=6). [Diagram 5] FIG. 5 shows tumor volume (mm3) in KMS-21-BM engrafted female NSG mice treated with IgG1-CysmAb Fcsilent_P1-L29-P2, anti-CD48 MEM_CysmAb Fcsilent, and anti-CD48 MEM_CysmAb Fcsilent_P1-L29-P2 administered IV once (n=6). [Figure 6] FIG. 6 shows the body weight of KMS-21-BM engrafted female NSG mice treated with IgG1-CysmAb Fcsilent_P1-L29-P2, anti-CD48 MEM_CysmAb Fcsilent, and anti-CD48 MEM_CysmAb Fcsilent_P1-L29-P2 administered once IV (n=6). [Figure 7] FIG. 7 shows tumor volume (mm3) in KMS27-implanted female NSG mice treated with IgG1-CysmAb Fcsilent_P1-L19-P2, anti-CD48 MEM102_CysmAb Fcsilent and anti-CD48 MEM102_CysmAb Fcsilent_P1-L19-P2 once IV at 10 and / or 30 mg / kg (n=6). [Figure 8] FIG. 8 shows the body weight of KMS27-engrafted female NSG mice upon treatment with IgG1-CysmAb Fcsilent_P1-L19-P2, anti-CD48 MEM102_CysmAb Fcsilent and anti-CD48 MEM102_CysmAb Fcsilent_P1-L19-P2 once IV at 10 and / or 30 mg / kg (n=6). [Figure 9] FIG. 9 is a graph showing dose response curves for three ADCs datopotamab-P5-L12-P7, datopotamab-mono-L1-P5, and datopotamab-mono-L3-P8 in the NCI-H441 cell line. [Figure 10-1]FIG. 10A is a graph showing dose response curves of the five ADCs trastuzumab-mono-L3-P8, trastuzumab-mono-L3-P8, trastuzumab-mono-L1-P5, trastuzumab-mono-L1-P7, and trastuzumab-P5-L12-P7 in HCC1419 and ZR-75-30 cell lines. [Figure 10-2] FIG. 10B is a graph showing dose response curves of the four ADCs trastuzumab-mono-L3-P8, dicitamab-mono-L1-P5, dicitamab-mono-L3-P8, and dicitamab-P5-L12-P7 in the UACC-812 cell line. [Figure 11] FIG. 11 is a graph showing dose response curves for three ADCs, NY920-P5-L12-P4, NY920-mono-L1-P4, and NY920-mono-L2-P5, in the KMS-27 cell line. [Figure 12] FIG. 12 is a graph showing dose response curves for the three ADCs VHmil x VK1aNQ-P5-L12-P4, VHmil x VK1aNQ-mono-L1-P4, and VHmil x VK1aNQ-mono-L2-P5 in the EOL-1 cell line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0394] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The disclosed compositions and methods may be more readily understood by reference to the following detailed description considered in connection with the accompanying drawings, which form a part of this disclosure.

[0395] Throughout this text, the description refers to compositions and methods of using the compositions. When this disclosure describes or claims features or embodiments related to compositions, such features or embodiments are equally applicable to methods of using the compositions. Similarly, when this disclosure describes or claims features or embodiments related to methods of using the compositions, such features or embodiments are equally applicable to the compositions.

[0396] When a range of values ​​is expressed, this includes embodiments using any specific value within that range. Moreover, reference to values ​​stated in a range includes each and every value within that range. All ranges are inclusive of their endpoints and are combinable. When values ​​are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of "or" means "and / or," unless the specific context of its use dictates otherwise. All references cited herein are incorporated by reference for any purpose. In the event of a conflict between the reference and the specification, the specification will control.

[0397] Unless the context of the description dictates otherwise, e.g., where a structure or fragment of a structure is depicted in the absence of a symbol indicating a particular point of attachment, it may be used by itself or attached to other components of the ADC, and it may do so in any orientation, e.g., an antibody may be attached at any suitable point of attachment to a chemical moiety such as a linker-drug. However, where indicated, the components of the ADC are attached in the orientation shown in a given formula. For example, if formula (1) is

[0398] [ka] It is described as

[0399] [ka] but,

[0400] [ka] When written as: the detailed structure of formula (1) is:

[0401] [ka] This is because

[0402] [ka] but

[0403] [ka] But no.

[0404] It should be understood that certain features of the disclosed compositions and methods that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0405] As used throughout this application, antibody drug conjugates can be identified using a naming convention in the general format of "target antigen / antibody-payload-dual linker-payload". For example, simply if an antibody drug conjugate is referred to as "target X-P1-L1-P2", such a conjugate would include an antibody that binds to target X, a dual linker designated as L1, and two payloads designated as P1 and P2, respectively. Alternatively, if an antibody drug conjugate is referred to as "anti-target X-P1-L1-P2", such a conjugate would include an antibody that binds to target X, a dual linker designated as L1, and two payloads designated as P1 and P2, respectively. In another alternative, if an antibody drug conjugate is referred to as "AbX-P1-L1-P2", such a conjugate would include an antibody designated as AbX, a dual linker designated as L1, and two payloads designated as P1 and P2, respectively. A control antibody drug conjugate that includes a non-specific isotype control antibody may be referred to as "isotype control IgG1-P1-L1-P2" or "IgG1-P1-L1-P2."

[0406] Any formula given herein is also intended to represent unlabeled forms of the compound, as well as isotopically labeled forms of the compound.Isotopically labeled compounds have the structure represented by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, and 36 Thus, the present disclosure provides, for example, 3 H and 14 Compounds incorporating one or more of any of the preceding isotopes, including radioisotopes such as C; or 2 H and 13 It should be understood that this includes compounds in which non-radioactive isotopes such as C are present. Such isotope-labeled compounds may be used for metabolic studies ( 14 C), kinetic reaction studies (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0407] definition Various terms relating to the described embodiments are used throughout the specification and claims. Such terms should be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0408] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. The terms "being of," "including," and "containing," as in "comprising," "having," and "being of chemical formula," should be construed as open-ended terms (i.e., meaning "including but not limited to") unless otherwise stated. In addition, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment could be more narrowly claimed using the middle term "consisting essentially of" or the closed term "consisting of."

[0409] The terms "about" or "approximately," when used in the context of numerical values ​​and ranges, refer to a value or range that is close to or near the recited value or range, such that the implementation may be performed as intended, as would be apparent to one of ordinary skill in the art from the teachings contained herein. In some embodiments, about means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of the numerical amount. In one embodiment, the term "about" refers to a range of values ​​that is 10% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​that is 5% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​that is 1% greater or less than the stated value.

[0410] The terms "antibody-drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to one or more therapeutic compounds (e.g., an anti-neoplastic drug payload, e.g., a BH3 mimetic moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug) linked to one or more antibodies or antigen-binding fragments. In some embodiments, an ADC has the general formula:

[0411] [ka] where Ab=antibody or antigen-binding fragment, L=dual linker moiety, and D 1 and D. 2 = drug moiety (e.g., Mcl-1 inhibitor, Bcl-2 inhibitor, Bcl-xL inhibitor drug moiety), and a = attached D per antibody or antigen-binding fragment. 1 and D. 2 In ADCs that include an anti-neoplastic drug payload (e.g., a BH3 mimetic compound, a topoisomerase 1 inhibitor, or an anti-mitotic drug), "2a" refers to the number of an anti-neoplastic drug payloads (e.g., a BH3 mimetic compound, a topoisomerase 1 inhibitor, or an anti-mitotic drug) linked to the antibody or antigen-binding fragment.

[0412] The term "antibody" is used in the 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 of the above, by at least one antigen recognition site in the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural or recombinant sources. An "intact" antibody is typically a glycoprotein that includes at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interrupted by more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The antibody can be a monoclonal antibody, a human antibody, a humanized antibody, a camelized antibody, or a chimeric antibody. The antibody can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass. The antibody can be an intact antibody or an antigen-binding fragment thereof.

[0413] In some embodiments, the antibody or antibody fragment disclosed herein comprises modified or engineered amino acid residues, e.g., 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 present disclosure provides modified antibodies or antibody fragments comprising substitutions of one or more amino acids with cysteines at the positions described herein. The sites for cysteine ​​substitutions are in the constant region of the antibody or antibody fragment, and thus are applicable to a variety of antibodies or antibody fragments, and the sites are selected to provide stable, homogenous conjugates. The modified antibody or fragment can have one, two, or more cysteine ​​substitutions, and these substitutions can be used in combination with other modification and conjugation methods described herein. Methods for inserting cysteines at specific locations in an antibody are known in the art, see, e.g., Lyons et al., (1990) Protein Eng., 3:703-708, WO 2011 / 005481, WO 2014 / 124316, WO 2015 / 138615. In certain embodiments, the modified antibody comprises a substitution of one or more amino acids with cysteines 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 of the antibody heavy chain, where the positions are numbered according to the EU system.In some embodiments, the modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine ​​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, where the positions are 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 thereof comprises a combination of substitutions of two or more amino acids with cysteine ​​in its constant region, where the combination includes a substitution 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, where the positions are numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​in its constant region, the substitution being at position 375 of the antibody heavy chain, at position 152 of the antibody heavy chain, at position 360 of the antibody heavy chain, at position 107 of the antibody light chain, at position 165 of the antibody light chain, or at position 159 of the antibody light chain, where the positions are numbered according to the EU system, and the light chain is a kappa chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two amino acids with cysteine ​​in its constant region, the combination comprising substitutions at position 375 of the antibody heavy chain and at position 152 of the antibody heavy chain, where the positions are numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​at position 360 of the antibody heavy chain, where the positions are numbered according to the EU system. In other specific embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with a cysteine ​​at position 107 of the antibody light chain, where the positions are numbered according to the EU system, and where the light chain is a kappa chain.

[0414] The term "antibody fragment" or "antigen-binding fragment" or "functional antibody fragment", as used herein, refers to at least a portion of an antibody that retains the ability to specifically interact (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) with an epitope of an antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4). Antigen-binding fragments may also retain the ability to be internalized into antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, and the like are intended to encompass the use of antibody-derived binding domains in the context of larger macromolecules, such as ADCs. It has been shown that fragments of full-length antibodies can perform the antigen-binding function of the full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies, e.g., sdAb (either VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bis-scFvs (see, e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):1126-36). Antigen-binding fragments can also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see US Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies).The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment comprising a variable region of a light chain and at least one antigen-binding fragment comprising a variable region of a heavy chain, where the light and heavy chain variable regions are contiguously linked, for example, via a synthetic linker, e.g., a short flexible polypeptide linker, and expressed as a single-chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, the scFv may have, for example, the VL and VH variable regions in either order relative to the N-terminus and C-terminus of the polypeptide, and the svFv may comprise VL-linker-VH or VH-linker-VL. Antigen-binding fragments are obtained using conventional techniques known to those skilled in the art, and the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. For example, antigen-binding fragments may be prepared by cleavage of the intact protein, for example, by protease or chemical cleavage.

[0415] The term "complementarity determining region" or "CDR" as used herein refers to the sequence of amino acids in an antibody variable region that confers antigen specificity and binding affinity. For example, there are generally three CDRs (e.g., HCDR1, HCDR2, and HCDR3) in each heavy chain variable region, and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable region. The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991) "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (the "Kabat" numbering scheme); Al-Lazikani et al. (1997) J Mol Biol. 273(4):927-48 (the "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) (the "IMGT" numbering scheme), or a combination thereof. In the combined Kabat and Chothia numbering scheme for a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, the CDRs correspond to the amino acid residues defined as part of the Kabat CDRs together with the amino acid residues defined as part of the Chothia CDRs. As used herein, CDRs defined according to the "Chothia" numbering scheme may also be referred to as "hypervariable loops."

[0416] In some embodiments, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered under Kabat as follows: 31 to 35 (HCDR1) (e.g., an insertion after position 35), 50 to 65 (HCDR2), and 95 to 102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered as follows: 24 to 34 (LCDR1) (e.g., an insertion after position 27), 50 to 56 (LCDR2), and 89 to 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); 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 CDRs comprise or consist of, 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 regions of an antibody may be determined using the program IMGT / DomainGap Align.

[0417] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that make up the population are identical except for naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-8, and Marks et al. (1991) J Mol Biol. 222:581-97. The term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope.

[0418] The monoclonal antibodies described herein can be non-human, human, or humanized. This term specifically includes "chimeric" antibodies in which a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0419] The term "human antibody" as used herein refers to an antibody produced by a human or an antibody having an amino acid sequence of an antibody produced by a human. This term includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such a human sequence, e.g., a human germline sequence, or a mutated version of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik et al. ((2000) J Mol Biol. 296(1):57-86). The structure and location of immunoglobulin variable domains, e.g., CDRs, 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 the ImMunoGenTics (IMGT) numbering. The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, or by somatic mutation in vivo, or by conservative substitutions that promote stability or manufacturing). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been grafted onto human framework sequences.

[0420] The term "recombinant human antibody," as used herein, refers to a human antibody that has been prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes, or hybridomas prepared therefrom, antibodies isolated from host cells transformed to express human antibodies, e.g., from transfectomas, antibodies isolated from recombinant combinatorial human antibody libraries, and antibodies prepared, expressed, created, or isolated by any other means including splicing all or a portion of a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In some embodiments, however, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from, and related to, human germline VH and VL sequences, sequences that may not naturally exist within the human antibody germline repertoire in vivo.

[0421] The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some instances, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species with the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize the immune response in the latter species.

[0422] As used herein, the term "humanized antibody" refers to forms of antibodies that contain sequences derived from human antibodies as well as non-human (e.g., murine) antibodies. Such antibodies are a type of chimeric antibody that contains minimal sequence derived from non-human immunoglobulin. In general, a humanized antibody comprises substantially all of at least one, typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. A humanized antibody can be further modified by substitution of residues in the Fv framework regions and / or within the replaced non-human residues to refine and / or optimize the specificity, affinity, and / or activity of the antibody.

[0423] 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 an antibody. Optionally, the Fc region may comprise a CH4 domain present in some antibody classes. The Fc region may comprise the entire hinge region of the constant domain of an antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region and the CH1 region of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region CH3 region of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region, the CH1 region, and the kappa / lambda region from the constant domain of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises a constant region, e.g., a heavy chain constant region and / or a light chain constant region. In some embodiments, such constant regions are modified compared to the wild-type constant region. That is, the polypeptide may comprise changes or modifications to one or more of the three heavy chain constant domains (CH1, CH2, or CH3) and / or to the light chain constant region domain (CL). Examples of modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc.

[0424] "Internalizing" as used herein with respect to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that, upon binding to a cell, can be taken up (i.e., "internalized") through the lipid bilayer membrane of the cell into an internal compartment, preferably into a degradable compartment in the cell. For example, an internalizing anti-HER2 antibody is one that can be taken up into the cell after binding to HER2 on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) and is an internalizing antibody or internalizing antigen-binding fragment (i.e., the ADC translocates through the cell membrane after antigen binding). In some embodiments, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. An internalizing antibody or internalizing antigen-binding fragment that targets a receptor on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is taken up into a cell via receptor-mediated endocytosis.

[0425] "Non-internalizing" as used herein with respect to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that remains on the cell surface upon binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., the ADC remains on the cell surface and does not translocate through the cell membrane after antigen binding). In some embodiments, the non-internalizing antibody or antigen-binding fragment binds to a non-internalizing receptor or other cell surface antigen. Exemplary non-internalizing cell surface antigens include, but are not limited to, CA125 and CEA, and antibodies that bind to non-internalizing antigen targets are also known in the art (see, e.g., Bast et al. (1981) J Clin Invest. 68(5):1331-7; Scholler and Urban (2007) Biomark Med. 1(4):513-23; and Boudousq et al. (2013) PLoS One 8(7):e69613).

[0426] The term "EPH receptor A2" or "EphA2" as used herein refers to any native form of human EphA2 (also known as ephrin type A receptor 2). The term encompasses full-length human EphA2 (e.g., NCBI Reference Sequence: NP_004422.2; SEQ ID NO: 337) and any form of human EphA2 that may result from cellular processing. The term also encompasses functional variants or fragments of human EphA2, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human EphA2 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to wild-type protein). EphA2 can be isolated from humans or produced recombinantly or by synthetic methods.

[0427] The term "anti-EphA2 antibody" or "antibody that binds to EphA2" as used herein refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically binds, to EphA2. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, as long as they bind, e.g., specifically bind, to EphA2. WO 2007 / 030642 provides exemplary EphA2 binding sequences, including exemplary anti-EphA2 antibody sequences, and is hereby incorporated by reference. In some embodiments, the anti-EphA2 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. 1C1 (WO 2007 / 030642) is an exemplary anti-EphA2 antibody.

[0428] The term "P-cadherin" or "PCAD" as used herein refers to any native form of human PCAD (also known as cadherin 3, type 1 or CDH3). The term encompasses full-length human PCAD (e.g., UniProt Reference Sequence: P22223; SEQ ID NO: 74) and any form of human PCAD that may result from cellular processing. The term also encompasses functional variants or fragments of human PCAD, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human PCAD (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). PCAD can be isolated from humans or produced recombinantly or by synthetic methods.

[0429] The term "anti-PCAD antibody" or "antibody that binds to PCAD" as used herein refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to PCAD. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, so long as they bind, e.g., specifically bind, to PCAD. WO 2016 / 203432 provides exemplary PCAD binding sequences, including exemplary anti-PCAD antibody sequences, and is hereby incorporated by reference. In some embodiments, the anti-PCAD antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antigen-binding fragment. NOV169N31Q (WO 2016 / 203432) is an exemplary anti-PCAD antibody.

[0430] The term "human epidermal growth factor receptor 2", "HER2" or "HER2 / NEU" as used herein refers to any native form of human HER2. The term encompasses full-length human HER2 (e.g., UniProt Reference Sequence: P04626; SEQ ID NO: 75), and any form of human HER2 that may result from cellular processing. The term also encompasses functional variants or fragments of human HER2, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human HER2 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). HER2 can be isolated from humans or produced recombinantly or by synthetic methods.

[0431] The term "anti-HER2 antibody" or "antibody that binds to HER2" as used herein refers to any form of antibody or antigen-binding fragment that binds, e.g., specifically binds, to HER2. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, as long as they bind, e.g., specifically bind, to HER2. U.S. Patent Nos. 5,821,337 and 6,870,034 provide exemplary HER2 binding sequences, including exemplary anti-HER2 antibody sequences, and are incorporated herein by reference thereto. In some embodiments, the anti-HER2 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. Trastuzumab (see U.S. Pat. Nos. 5,821,337 and 6,870,034; also Molina et al. (2001) Cancer Res. 61(12):4744-9) is an exemplary anti-HER2 antibody.

[0432] The term "cluster of differentiation 48" or "CD48" as used herein refers to any native form of human CD48 (also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocyte activation molecule 2 (SLAMF2)). The term encompasses full-length human CD48 (e.g., UniProt Reference Sequence: P09326; SEQ ID NO: 77), and any form of human CD48 that may result from cellular processing. The term also encompasses functional variants or fragments of human CD48, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD48 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD48 can be isolated from humans or produced recombinantly or by synthetic methods.

[0433] The term "anti-CD48 antibody" or "antibody that binds to CD48" as used herein refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to CD48. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, so long as they bind, e.g., specifically bind, to CD48. International Patent Application Nos. PCT / IB2021 / 060871, PCT / US2021 / 060560, and PCT / US2021 / 060620 provide exemplary CD48 binding sequences, including exemplary anti-CD48 antibody sequences, and are incorporated herein by reference thereto. In some embodiments, the anti-CD48 antibodies used in the ADCs disclosed herein are internalizing antibodies or internalizing antigen-binding fragments. SGN-CD48A (MEM102) and NY920 are exemplary anti-CD48 antibodies.

[0434] The term "cluster of differentiation 74" or "CD74" as used herein refers to any native form of human CD74 (also known as HLA class II histocompatibility antigen gamma chain or HLA-DR antigen-associated invariant chain). The term encompasses full-length human CD74 (e.g., NCBI Reference Sequence: NP_001020330.1; SEQ ID NO: 140) and any form of human CD74 that may result from cellular processing. The term also encompasses functional variants or fragments of human CD74, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD74 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). CD74 can be isolated from humans or produced recombinantly or by synthetic methods.

[0435] The term "anti-CD74 antibody" or "antibody that binds to CD74" as used herein refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to CD74. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, so long as they bind, e.g., specifically bind, to CD74. WO 2020 / 236817 provides exemplary CD74 binding sequences, including exemplary anti-CD74 antibody sequences, and is hereby incorporated by reference in this regard. In some embodiments, the anti-CD74 antibodies used in the ADCs disclosed herein are internalizing antibodies or internalizing antigen-binding fragments. Milatuzumab (WO 2003 / 074567) and VHmil x VK1aNQ (WO 2020 / 236817) are exemplary anti-CD74 antibodies.

[0436] The term "binding specificity" as used herein refers to the ability of an individual antibody or antigen-binding fragment to preferentially react with one antigenic determinant over a different antigenic determinant. Specificity indicates the degree to which an antibody or fragment preferentially binds to one antigenic determinant over a different antigenic determinant. Also as used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an anti-HER2 antibody) and a target antigen (e.g., HER2) in a heterogeneous population of proteins and other biologics. An antibody can be tested for binding specificity by comparing binding to the appropriate antigen with binding to an unrelated antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to the appropriate antigen with at least 2, 5, 7, 10, or more times higher affinity than to an unrelated antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is one that binds only to a target antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) and does not bind (or shows minimal binding to) other antigens. In some embodiments, an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) is present at a concentration of 1×10 -6 Less than M, 1×10 -7 Less than M, 1×10 -8 Less than M, 1×10 -9 Less than M, 1×10 -10 Less than M, 1×10 -11 Less than M, 1×10 -12 Less than M or 1×10 -13 K less than M D In some embodiments, K D In some embodiments, K D is 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0437] The term "affinity" as used herein refers to the strength of interaction between an antibody and an antigen at a single antigenic site. Without being bound by theory, within each antigen-binding site, the variable region of an antibody "arm" interacts with the antigen at multiple sites through weak non-covalent forces, and the more interactions, the stronger the affinity typically is. The binding affinity of an antibody is the sum of the attractive and repulsive forces operating between an antigenic determinant and the binding site of the antibody.

[0438] "k on " or "k a The term "on-rate constant" refers to the on-rate constant for the association of an antibody to an antigen to form an antibody / antigen complex. The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0439] "k off " or "k d The term "off-rate constant" refers to the off-rate constant for dissociation of an antibody from the antibody / antigen complex. The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0440] "K D The term K" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. D is k a / k d The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0441] The term "epitope" refers to a portion of an antigen that can be recognized and specifically bound by an antibody (or antigen-binding fragment). Epitope determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. When the antigen is a polypeptide, epitopes can be formed from adjacent amino acids, or non-adjacent amino acids juxtaposed by tertiary folding of the polypeptide. Epitopes can be "linear" or "conformational". Conformational and linear epitopes are distinguished in that binding to the former is lost in the presence of denaturing solvents, but not to the latter. The epitope bound by an antibody (or antigen-binding fragment) may be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of antigen-antibody complexes, as well as monitoring the binding of the antibody to fragments or mutated variants of the antigen, or monitoring the solvent accessibility of different portions of the antibody and antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) BioDrugs 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev Proteomics 2:745-56).

[0442] Competitive binding and epitope binning can also be used to determine antibodies that share the same or overlapping epitopes. Competitive binding can be performed as described in "Antibodies, A Laboratory Manual," Cold Spring Harbor Laboratory, Harlow and Lane (1 st edition 1988, 2 ndCompetitive binding can be assessed using a cross-blocking assay, such as that described in the American Cancer Society (American Journal of Clinical Chemistry, 2014 edition). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein (e.g., a binding protein comprising a CDR and / or variable domain selected from those identified in Tables 3-5) to a target antigen, such as PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4, by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage therebetween) in a cross-blocking assay. In some embodiments, competitive binding may be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance where antibodies or binding proteins bind at nearby epitopes (see, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66)). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes. For example, binding proteins that compete for binding can be "binned" into a group of binding proteins with overlapping or nearby epitopes, while those that do not compete are placed into another group of binding proteins that do not have overlapping or nearby epitopes.

[0443] As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues. The term encompasses amino acid polymers that contain two or more amino acids joined together by peptide bonds, amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as naturally occurring and non-naturally occurring amino acid polymers. The term includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, and the like. The term also includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0444] A "recombinant" protein refers to a protein (eg, an antibody) made using recombinant techniques, e.g., by the expression of a recombinant nucleic acid.

[0445] An "isolated" protein refers to a protein that is not associated with at least some of the materials with which it is normally associated in its natural state. For example, a naturally occurring polynucleotide or polypeptide present in a living organism is not isolated, but the same polynucleotide or polypeptide separated from some or all of the coexisting materials in a living organism is isolated. This definition includes the production of antibodies in a wide variety of organisms and / or host cells known in the art.

[0446] "Isolated antibody" as used herein is an antibody that has been identified and separated from one or more (e.g., most) of the components (by weight) of its original environment, for example, from the components of the hybridoma cell culture or different cell culture used for its production. In some embodiments, separation is performed to sufficiently remove components that may otherwise interfere with 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 include, but are not limited to, protein A chromatography, anion exchange chromatography, cation exchange chromatography, virus retention filtration, and ultrafiltration.

[0447] As used herein, the term "variant" refers to a nucleic acid sequence or amino acid sequence that differs from a reference nucleic acid sequence or amino acid sequence, respectively, but retains one or more biological properties of the reference sequence. A variant may contain one or more amino acid substitutions, deletions, and / or insertions (or corresponding substitutions, deletions, and / or insertions of codons) relative to the reference sequence. The changes in the nucleic acid variant may not change the amino acid sequence of the peptide encoded by the reference nucleic acid sequence, or may result in amino acid substitutions, additions, deletions, fusions, and / or truncations. In some embodiments, the nucleic acid variants disclosed herein encode the same amino acid sequence as that encoded by the unmodified nucleic acid, or encode modified amino acid sequences that retain one or more functional properties of the unmodified amino acid sequence. The changes in the sequence of the peptide variant are typically limited or conservative, such that the sequences of the unmodified peptide and the variant are overall very similar and, in many regions, identical. In some embodiments, the peptide variants retain one or more functional properties of the unmodified peptide sequence. Variants and unmodified peptides may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination.

[0448] Nucleic acid or peptide variants can be naturally occurring variants or variants that are not known to occur naturally. Nucleic acid and peptide variants can be made by mutagenesis techniques, by direct synthesis, or by other techniques known in the art. Variants do not necessarily require physical manipulation of a reference sequence. As long as a sequence contains different nucleic acids or amino acids compared to a reference sequence, it is considered a "variant" regardless of how it is synthesized. In some embodiments, variants have high sequence identity (i.e., 60% or more nucleic acid or amino acid sequence identity) compared to a reference sequence. In some embodiments, peptide variants encompass polypeptides with amino acid substitutions, deletions, and / or insertions, e.g., variants that also retain one or more functions of the reference sequence, so long as the polypeptide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% amino acid sequence identity with a reference sequence, or with a corresponding segment (e.g., a functional fragment) of a reference sequence. In some embodiments, nucleic acid variants include polynucleotides having amino acid substitutions, deletions, and / or insertions, so long as the polynucleotide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% nucleic acid sequence identity with a reference sequence, or with a corresponding segment (e.g., a functional fragment) of a reference sequence.

[0449] The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. For nucleic acid sequences, conservatively modified variants refer to nucleic acids that code for identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids code for any given protein. For example, the codons GCA, GCC, GCG and GCU all code for the amino acid alanine. Thus, at any position where alanine is specified by a codon, the codon can be changed to any of the corresponding codons described without changing the encoded polypeptide. Such nucleic acid variations are "silent variations", which are one species of conservatively modified variations. Every nucleic acid sequence herein that codes for a polypeptide also describes every possible silent variation of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be modified to give a functionally identical molecule. Thus, each silent variation of a nucleic acid that codes for a polypeptide is implicit in each described sequence. For polypeptide sequences, conservatively modified variants include individual substitutions, deletions, or additions to the polypeptide sequence that result in the replacement of an amino acid with a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art.

[0450] The term "conservative sequence modification" as used herein refers to an amino acid modification that does not significantly affect or change the binding characteristics of, for example, an antibody or antigen-binding fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into an antibody or antigen-binding fragment by standard techniques known in the art, such as, for example, site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue that has a similar side chain. Families of amino acid residues that have similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, in some embodiments, one or more amino acid residues within an antibody can be replaced with other amino acid residues from the same side chain family, and the altered antibodies can be tested using the functional assays described herein.

[0451] The term "homologous" or "identity" as used herein refers to the subunit sequence identity between two polymer molecules, e.g., between two nucleic acid molecules, such as between two DNA molecules or between two RNA molecules, or between two polypeptide molecules. If a subunit position in both of the two molecules is occupied by the same monomeric subunit, e.g., if a position in each of the two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a linear function of the number of matching or homologous positions. For example, if half of the positions in the two sequences (e.g., 5 positions in a polymer 10 subunits in length) are matched or homologous, the two sequences are 50% homologous, and if 90% of the positions (e.g., 9 out of 10) are matched or homologous, the two sequences are 90% homologous.

[0452] The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where the amino acid sequence fragment in the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to the 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 are present in both sequences to obtain the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity. The output is the percent identity of the subject sequence to the query sequence. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Generally, amino acid identity or homology between the proteins disclosed herein and variants thereof, including variants of target antigens (such as PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) and variants of antibody variable domains (including individual variant CDRs), is at least 80% to the sequences represented herein, e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, nearly 100%, or 100% identity or homology.

[0453] The comparison of sequences and the determination of percent identity between two sequences can be accomplished using mathematical algorithms. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J Mol Biol. 48:444-53) algorithm implemented in the GAP program in the GCG software package, using either a Blossum62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna.CMP matrix, and a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. An exemplary set of parameters is the Blossum62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences may also be determined using the algorithm of Meyers and Miller ((1989) CABIOS 4:11-17) as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0454] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination of two or more thereof. The term "therapeutic agent" or "drug" refers to an agent that can modulate a biological process and / or has biological activity. The Bcl-xL inhibitors described herein and ADCs containing them are exemplary therapeutic agents.

[0455] The term "chemotherapeutic agent" or "anti-cancer agent" is used herein to refer to any agent that is effective in the treatment of cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Chemotherapeutic agents include antibodies, biomolecules, and small molecules, including the Bcl-xL inhibitors described herein and ADCs containing them. A chemotherapeutic agent may be a cytotoxic agent or a cytostatic agent. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or proliferation of cells. The term "cytotoxic agent" refers to a substance that primarily causes cell death by interfering with the expression activity and / or function of a cell.

[0456] The term "antineoplastic payload" or "antineoplastic compound" as used herein refers to one or more compounds that slow or inhibit the division of cancerous cells or kill cancerous cells. Non-limiting examples of antineoplastic payloads include BH3 mimetic compounds (e.g., MCl-1 inhibitors, Bcl-xL inhibitors, or Bcl-2 inhibitors), topoisomerase 1 inhibitors (e.g., topotecan, exatecan, deruxtecan, or SN-38), or antimitotic drugs (e.g., monomethyl auristatin E (MMAE) or taxanes). In one embodiment, the antineoplastic payload is a BH3 mimetic compound. In one embodiment, the antineoplastic payload is a topoisomerase 1 inhibitor. In one embodiment, the antineoplastic payload is an antimitotic drug.

[0457] The term "anti-neoplastic non-BH3 mimetic" as used herein refers to one or more compounds that are not BH3 mimetics and slow or inhibit the division of cancerous cells or kill cancerous cells. Non-limiting examples of anti-neoplastic non-BH3 mimetics include topoisomerase 1 inhibitors (e.g., topotecan, exatecan, deruxtecan or SN-38) or antimitotic drugs (e.g., monomethyl auristatin E (MMAE) or taxanes). In one embodiment, the anti-neoplastic non-BH3 mimetic is a topoisomerase 1 inhibitor. In one embodiment, the anti-neoplastic non-BH3 mimetic is an antimitotic drug.

[0458] The term "BH3 mimetics" as used herein refers to agents that can disrupt the interaction between pro- and anti-apoptotic members of the Bcl-2 family and are potent inducers of apoptosis. Exemplary BH3 mimetics include inhibitors of Bcl-2, Bcl-xL, Bcl-w and Mcl-1.

[0459] The term "myeloid cell leukemia 1" or "Mcl-1" as used herein refers to any native form of human Mcl-1, an anti-apoptotic member of the Bcl-2 protein family. The term encompasses full-length human Mcl-1 (e.g., UniProt Reference Sequence: Q07820; SEQ ID NO: 71), as well as any form of human Mcl-1 that may result from cellular processing. The term also encompasses functional variants or fragments of human Mcl-1, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Mcl-1 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). Mcl-1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0460] The terms "inhibit" or "inhibition" or "inhibiting" as used herein means reducing a measurable amount, biological activity or biological process, which may include, but does not require, complete prevention or inhibition. In some embodiments, "inhibition" means reducing the expression and / or activity of Bcl-xL and / or one or more upstream modulators or downstream targets thereof.

[0461] The term "Mcl-1 inhibitor" as used herein refers to an agent capable of reducing the expression and / or activity of Mcl-1 and / or one or more of its upstream modulators or downstream targets. Exemplary Mcl-1 modulators (including exemplary inhibitors of Mcl-1) are described in WO 2015 / 097123; WO 2016 / 207216; WO 2016 / 207217; WO 2016 / 207225; WO 2016 / 207226; WO 2017 / 125224; WO 2019 / 035899, WO 2019 / 035911, WO 2019 / 035914, WO 2019 / 035915, WO 2019 / 035916, WO 2019 / 035917, WO 2019 / 035918, WO 2019 / 035919 ... No. 9 / 035927, U.S. Patent Application Publication No. 2019 / 0055264, WO 2016 / 033486, WO 2017 / 147410, WO 2018 / 183418, and WO 2017 / 182625, each of which is incorporated by reference herein as an exemplary Mcl-1 modulator, including an exemplary Mcl-1 inhibitor, that may be included as a drug moiety in the disclosed ADCs. For example, an exemplary Mcl-1 inhibitor that may be included as a drug moiety in the disclosed ADCs has the formula:

[0462] [ka] (wherein each variable is as defined in WO 2019 / 035911; WO 2019 / 035899; WO 2019 / 035914; or WO 2019 / 035927). Specific examples include, for example:

[0463] [ka] Each compound as a drug payload can be conjugated to an antibody or linker via the nitrogen atom of the N-methyl in the piperazinyl functional group of the compound. As used herein, the terms "derivative" and "analog" when referring to Mcl-1 inhibitors and the like refer to any such compound that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound, but has an altered chemical or biological structure.

[0464] As used herein, "Mcl-1 inhibitor drug moiety," "Mcl-1 inhibitor," and the like, refer to an Mcl-1 inhibitor compound, or a component of an ADC or composition that provides a modified compound structure for attachment to an ADC that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, the Mcl-1 inhibitor drug moiety is a component (D) in an ADC of formula (A). 1 and / or D. 2 In some embodiments, the Mcl-1 inhibitor is of formula (I) as described herein.

[0465] [ka] In some embodiments, the Mcl-1 inhibitor is a compound described in any one of the fifty to sixty-third embodiments in the Summary section of this disclosure.

[0466] The term "B-cell lymphoma-extra-large" or "Bcl-xL" as used herein refers to any native form of human Bcl-xL, an anti-apoptotic member of the Bcl-2 protein family. The term encompasses full-length human Bcl-xL (e.g., UniProt Reference Sequence: Q07817-1; SEQ ID NO: 71), as well as any form of human Bcl-xL that may result from cellular processing. The term also encompasses functional variants or fragments of human Bcl-xL, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Bcl-xL (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to wild-type protein). Bcl-xL can be isolated from humans or produced recombinantly or by synthetic methods.

[0467] The term "Bcl-xL inhibitor," as used herein, refers to an agent capable of reducing the expression and / or activity of Bcl-xL and / or one or more of its upstream modulators or downstream targets. Exemplary Bcl-xL modulators (including exemplary inhibitors of Bcl-xL) are described in WO 2010 / 080503, WO 2010 / 080478, WO 2013 / 055897, WO 2013 / 055895, WO 2016 / 094509, WO 2016 / 094517, WO 2016 / 094505, WO 2021 / 018858, WO 2021 / 018857, Tao et al., ACS Medicinal Chemistry Letters (2014), 5(10), 1088-109, and Wang et al., ACS Medicinal Chemistry Letters (2020), 11(10), 1829-1836, each of which is incorporated by reference herein as exemplary Bcl-xL modulators, including exemplary Bcl-xL inhibitors that can be included as drug moieties in the disclosed ADCs.

[0468] As used herein, "Bcl-xL inhibitor drug moiety," "Bcl-xL inhibitor," and the like, refer to a Bcl-xL inhibitor compound, or a component of an ADC or composition that provides a modified compound structure for attachment to an ADC that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, a Bcl-xL inhibitor drug moiety is a component (D 1 and / or D. 2 In some embodiments, the Bcl-xL inhibitor is represented by formula (II) or formula (III) as described herein:

[0469] [ka] In some embodiments, the Bcl-xL inhibitor is a compound described in any one of embodiments 64 to 74 in the Summary section of this disclosure.

[0470] The term "B cell lymphoma 2" or "Bcl-2" as used herein refers to any native form of human Bcl-2, an anti-apoptotic member of the Bcl-2 protein family. The term encompasses full-length human Bcl-2 (e.g., UniProt Reference Sequence: P10415; SEQ ID NO:X) and any form of human Bcl-2 that may result from cellular processing. The term also encompasses functional variants or fragments of human Bcl-2, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Mcl-1 (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). Mcl-1 can be isolated from humans or produced recombinantly or by synthetic methods.

[0471] The term "Bcl-2 inhibitor," as used herein, refers to an agent capable of reducing the expression and / or activity of Bcl-2 and / or one or more upstream modulators or downstream targets thereof. Exemplary Bcl-2 modulators (including exemplary inhibitors of Bcl-2) are described in WO 2013 / 110890, WO 2015 / 011400, WO 2015 / 011399, WO 2015 / 011397, WO 2015 / 011396, WO 2015 / 011164, and WO 2019 / 081559, each of which is incorporated by reference herein as exemplary Bcl-2 modulators, including exemplary Bcl-2 inhibitors, that may be included as a drug moiety in the disclosed ADCs.

[0472] As used herein, "Bcl-2 inhibitor drug moiety," "Bcl-2 inhibitor," and the like, refer to a Bcl-2 inhibitor compound, or a component of an ADC or composition that provides a modified compound structure for attachment to an ADC that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, a Bcl-2 inhibitor drug moiety is a component (D) in an ADC of formula (A). 1 and / or D. 2 In some embodiments, the Bcl-2 inhibitor is represented by formula (IV) or formula (V) described herein:

[0473] [ka] In some embodiments, the Bcl-2 inhibitor is a compound described in any one of the 75th to 89th embodiments in the Summary section of this disclosure.

[0474] The term "topoisomerase 1 inhibitor," as used herein, refers to one or more compounds that interfere with the action of the topoisomerase 1 enzyme. In one embodiment, such agents include, but are not limited to, topotecan, exatecan, deruxtecan, or SN-38.

[0475] The term "antimitotic agent" as used herein refers to one or more compounds that target mitotic regulatory enzymes, such as microtubule regulatory enzymes, Polo-like kinase (PLK), kinesin-spindle protein (KSP), Aurora kinase, etc. In one embodiment, the antimitotic agent is monomethyl auristatin E (MMAE) or a taxane. In some embodiments, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

[0476] The term "cancer" as used herein refers to the presence of cells with characteristics characteristic of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological features. Often, cancer cells may be in the form of a tumor or mass, but such cells may exist alone in a subject or circulate in the bloodstream as independent cells, such as leukemia or lymphoma cells. The term "cancer" includes all types of cancer and cancer metastasis, including blood cancer, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Blood cancers may include B-cell malignancies, cancers of the blood (leukemia), cancers of plasma cells (myeloma, e.g., multiple myeloma), or cancers of the lymph nodes (lymphoma). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias may include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), and the like. The terms "acute lymphoblastic leukemia" and "acute lymphocytic leukemia" may be used interchangeably to describe ALL. Lymphomas may include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and the like. Other hematological cancers may include myelodysplastic syndromes (MDS). Solid tumors may include carcinomas, such as adenocarcinomas, such as breast cancer, pancreatic cancer, prostate cancer, colon or colorectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, and the like.In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0477] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, either benign or malignant, including precancerous lesions.In some embodiments, the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, pancreatic cancer, stomach cancer, colon cancer, head and neck cancer, or splenic cancer.In some embodiments, the tumor is gastric cancer.

[0478] The terms "tumor cell" and "cancer cell" may be used interchangeably herein and refer to an individual cell or the total population of cells derived from a tumor or cancer, including both non-tumorigenic cells and cancer stem cells. When referring only to cells that lack the ability to reproduce and differentiate, the terms "tumor cell" and "cancer cell" are modified by the term "non-tumorigenic" to distinguish the cells from cancer stem cells.

[0479] The terms "target negative", "target antigen negative", or "antigen negative" as used herein refer to the absence of target antigen expression by a cell or tissue. The terms "target positive", "target antigen positive", or "antigen positive" refer to the presence of target antigen expression. For example, a cell or cell line that does not express a target antigen may be described as target negative, while a cell or cell line that expresses a target antigen may be described as target positive.

[0480] 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, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[0481] The term "subject in need of treatment," as used herein, refers to a subject who would benefit biologically, medically, or in quality of life from treatment (e.g., treatment with any one or more of the exemplary ADC compounds described herein).

[0482] As used herein, the terms "treat," "treating," or "treatment" refer to any improvement in any outcome of a disease, disorder, or condition, e.g., extended survival, lower mortality, and / or reduced side effects, resulting from an alternative therapeutic modality. In some embodiments, treatment includes delaying or ameliorating the disease, disorder, or condition (i.e., delaying, halting, or reducing the onset of the disease, or at least one of its clinical symptoms). In some embodiments, treatment includes delaying, alleviating, or ameliorating at least one physical parameter of the disease, disorder, or condition, including those that may be unrecognizable by the patient. In some embodiments, treatment includes modulating the disease, disorder, or condition physically (e.g., stabilization of a recognizable symptom), physiologically (e.g., stabilization of a physical parameter), or both. In some embodiments, treatment includes administration of a described ADC compound or composition to a subject, e.g., a patient, to obtain the treatment benefits enumerated herein. Treatment may be to cure, heal, relieve, delay, prevent, alleviate, alter, correct, ameliorate, ameliorate, improve, or affect a disease, disorder, or condition (e.g., cancer), a symptom of a disease, disorder, or condition (e.g., cancer), or a predisposition to a disease, disorder, or condition (e.g., cancer). In some embodiments, in addition to treating a subject having a disease, disorder, or condition, the compositions disclosed herein may also be provided prophylactically to prevent or reduce the likelihood of the occurrence of the disease, disorder, or condition.

[0483] As used herein, the terms "prevent," "preventing," or "prevention" of a disease, disorder, or condition refers to prophylactic treatment of a disease, disorder, or condition, or delaying the onset or progression of a disease, disorder, or condition.

[0484] As used herein, a "pharmaceutical composition" refers to a composition, e.g., a preparation of an ADC compound or composition, in addition to at least one other (and optionally two or more other) components suitable for administration to a subject, e.g., a pharma- ceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical compositions provided herein are in a form that allows for administration and thereafter provides the intended biological activity of the active ingredient and / or achieves a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that are unacceptably toxic to the subject to whom the formulation will be administered.

[0485] As used herein, the terms "pharmaceutical acceptable carrier" and "physiologically acceptable carrier", which may be used interchangeably, refer to a carrier or diluent that does not cause significant irritation to a subject and does not neutralize the biological activity and properties of the administered ADC compound or composition, and / or any additional therapeutic agent in the composition. Pharmaceutically acceptable carriers may enhance or stabilize the composition, or can be used to facilitate the preparation of the composition. Pharmaceutically acceptable carriers may include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption retardants, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.Carrier may be selected to minimize adverse side effects in the subject and / or to minimize the degradation of the active ingredient.Adjuvants may also be included in any of these formulations.

[0486] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Formulations for parenteral administration can contain excipients such as, for example, sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalenes. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, including, for example, polysorbate 20.

[0487] The term " pharmaceutically acceptable salt " as used herein refers to salt that does not nullify the biological activity and properties of the compound 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) the acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and the 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) the salts formed with elemental anions, such as chlorine, bromine, and iodine. See, e.g., 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.

[0488] In some embodiments, depending on their electronic charge, the antibody-drug conjugates (ADCs), linkers, payloads, and linker-payloads described herein are coupled to a monovalent anionic counterion M 1 - Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharma- ceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M 1 - may be selected from bromine, chlorine, iodine, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, and the like. In some embodiments, the monovalent anionic counterion M 1 - is a trifluoroacetate or formate.

[0489] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound described herein, e.g., an ADC compound or composition described herein, that produces a desired therapeutic result (i.e., reduction or inhibition of enzyme or protein activity, relief of symptoms, alleviation of symptoms or conditions, delay of disease progression, reduction of tumor size, inhibition of tumor growth, prevention of metastasis). In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount induces or causes side effects, but only as tolerated by the treating clinician, given the patient's condition. In some embodiments, a therapeutically effective amount is effective in detectably killing, reducing, and / or inhibiting the growth or spread of cancer cells, the size or number of tumors, and / or other measures of the level, stage, progression, and / or severity of cancer. The term also applies to a dose that induces a specific response in a target cell, e.g., reduction, delay, or inhibition of cell growth. A therapeutically effective amount can be determined by initially administering a low dose and then gradually increasing the dose until the desired effect is achieved. The therapeutically effective amount may also vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be easily determined by those skilled in the art. The specific amount may vary depending, for example, on the specific pharmaceutical composition, the subject and its age, and existing health conditions or risk of health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered. In the case of cancer, a therapeutically effective amount of the ADC may reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0490] As used herein, the term "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a compound disclosed herein, e.g., an ADC compound or composition described herein, that is effective at dosages and for periods of time necessary to achieve the desired prophylactic result. Typically, a prophylactically effective amount is lower than a therapeutically effective amount, since a prophylactic dose is used in subjects at a pre- or early stage of disease. In some embodiments, a prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with cancer.

[0491] The term "p" or "drug loading" or "drug:antibody ratio" or "drug to antibody ratio" or "DAR" refers to the number of drug moieties per antibody or antigen-binding fragment, i.e., the drug loading, or the number of BH3 mimetic moieties per antibody or antigen-binding fragment (Ab) in an ADC of formula (1). In an ADC that includes an anti-neoplastic drug compound (e.g., a BH3 mimetic drug moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug), "p" refers to the number of an anti-neoplastic drug compounds (e.g., a BH3 mimetic drug moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug) linked to the antibody or antigen-binding fragment. In the present disclosure, a dual linker attaches two anti-neoplastic drug compounds (e.g., two BH3 mimetic drug moieties, or a BH3 mimetic and a non-BH3 mimetic (e.g., a topoisomerase 1 inhibitor or an antimitotic drug)) to an antibody or antigen-binding fragment, and thus, p is 2 when only the antibodies or antigen-binding fragments are linked with a dual linker having two anti-neoplastic drug compounds attached thereto (e.g., two BH3 mimetic drug moieties, or a BH3 mimetic and a non-BH3 mimetic (e.g., a topoisomerase 1 inhibitor or an antimitotic drug)). In compositions comprising multiple copies of an ADC of Formula (1), "average p" refers to the average number of antineoplastic drug compounds (e.g., two BH3 mimetic drug moieties, or a BH3 mimetic and a non-BH3 mimetic (e.g., a topoisomerase 1 inhibitor or an antimitotic drug)) per antibody or antigen-binding fragment, also referred to as the "average drug loading."

[0492] 1. Antibody-drug conjugates The antibody-drug conjugate (ADC) compounds of the present disclosure include those that have anti-cancer activity. In particular, the ADC compounds include an antibody or antigen-binding fragment conjugated (i.e., covalently attached by a dual linker) to two antineoplastic compounds, such as a BH3 mimetic drug moiety (e.g., an Mcl-1 inhibitor, a Bcl-2 inhibitor, or a Bcl-xL inhibitor, or a combination thereof), a topoisomerase 1 inhibitor (e.g., topotecan, exatecan, deruxtecan, or SN-38), or an antimitotic drug (e.g., monomethyl auristatin E (MMAE) or a taxane), where at least one antineoplastic compound is a BH3 mimetic drug moiety and the antineoplastic compound when not conjugated to an antibody or antigen-binding fragment has a cytotoxic or cytostatic effect. In some embodiments, the BH3 mimetic drug moiety when not conjugated to an antibody or antigen-binding fragment can reduce expression and / or activity of Bcl-2 family proteins (e.g., Mcl-1, Bcl-2 and / or Bcl-xL) and / or one or more upstream modulators or downstream targets thereof. Without being bound by theory, by targeting Bcl-2 family proteins (e.g., Mcl-1, Bcl-2 and / or Bcl-xL) expression and / or activity, in some embodiments, the ADCs disclosed herein may provide potent anti-cancer agents. Also, without being bound by theory, by conjugating an anti-neoplastic drug compound to an antibody that binds to an antigen associated with expression in tumor cells or cancer, the ADCs may provide improved activity, better cytotoxicity specificity, and / or reduced off-target killing compared to the antineoplastic drug compound when administered alone.

[0493] In some embodiments, the components of the ADC are thus selected so that: (i) in isolation, they retain one or more therapeutic properties exhibited by the antibody and the antineoplastic drug compound; (ii) they maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) they optimize drug loading and drug-to-antibody ratio; (iv) they enable delivery, e.g., intracellular delivery, of the antineoplastic drug compound via stable attachment to the antibody or antigen-binding fragment; (v) they maintain ADC stability as an intact conjugate until transport or delivery to the target site; (vi) they minimize aggregation of the ADC before or after administration; (vii) they enable the therapeutic effect, e.g., cytotoxic effect, of the antineoplastic drug compound after cleavage or other release mechanisms in the cellular environment; (viii) they exhibit in vivo anti-cancer treatment efficacy, equivalent to or superior to that of the antibody and the antineoplastic drug compound; (ix) they minimize off-target killing by the antineoplastic drug compound; and / or (x) they exhibit desirable pharmacokinetic and pharmacodynamic properties, formulatability, and toxicological / immunological profiles. Each of these properties may provide improved ADCs for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0494] The disclosed ADC compounds may selectively deliver an effective dose of a cytotoxic or cytostatic agent to cancer cells or tumor tissues. In some embodiments, the cytotoxic and / or cytostatic activity of the ADC depends on the target antigen expression in the cells. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells that express the target antigen while minimizing off-target killing. In some embodiments, the disclosed ADCs do not exhibit cytotoxic and / or cytostatic effects on cancer cells that do not express the target antigen.

[0495] Exemplary BCMA-expressing cancers include, but are not limited to, multiple myeloma (Cho et al. (2018) Front Immunol. 9:1821).

[0496] Exemplary CD33-expressing cancers include, but are not limited to, colorectal cancer, pancreatic cancer, lymphoma, and leukemia (e.g., acute myeloid leukemia) (Human Protein Atlas; Walter (2014) Expert Opin Ther Targets 18(7):715-8).

[0497] Exemplary PCAD-expressing cancers include, but are not limited to, breast cancer, gastric cancer, endometrial cancer, ovarian cancer, pancreatic cancer, bladder cancer, prostate cancer, and melanoma (Vieira and Paredes (2015) Mol Cancer 14:178).

[0498] Exemplary HER2-expressing cancers include, but are not limited to, breast cancer, gastric cancer, bladder cancer, urothelial cell carcinoma, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial carcinoma), salivary duct cancer, cervical cancer, endometrial cancer, and ovarian cancer (English et al. (2013) Mol Diagn Ther. 17:85-99).

[0499] In certain embodiments, two anti-neoplastic drug payloads, such as a BH3 mimetic, a topoisomerase 1 inhibitor, or an antimitotic drug (D 1 and D. 2Provided herein are ADC compounds comprising an antibody or antigen-binding fragment (Ab) covalently linked to a BH3 mimetic, where at least one antineoplastic payload is a BH3 mimetic, and the dual linker has one attachment point connecting to the antibody and two attachment points to the two antineoplastic payloads, e.g., the BH3 mimetics, where the two antineoplastic payloads, e.g., the BH3 mimetics, can be the same or different. In some embodiments, for the ADC compounds defined herein, the antibody or antigen-binding fragment (Ab) targets cancer cells. In some embodiments, the antibody or antigen-binding fragment can bind, e.g., with high specificity and high affinity, to a tumor-associated antigen (e.g., CD74, CD48, EphA2, PCAD, or HER2). In some embodiments, the antibody or antigen-binding fragment is internalized into the target cell upon binding, e.g., into a degradative compartment in the cell. In some embodiments, the ADC, upon binding to a target cell, is internalized and undergoes degradation, releasing the Bcl-xL inhibitor drug moiety and killing the cancer cell. The anti-neoplastic drug payload, e.g., a BH3 mimetic, a topoisomerase 1 inhibitor, or an antimitotic drug, may be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0500] An exemplary ADC has formula (1):

[0501] [ka] where Ab=antibody or antigen-binding fragment, L=dual linker moiety, and D 1 and D. 2 = antineoplastic drug payload, e.g., a BH3 mimetic, a topoisomerase 1 inhibitor, or an antimitotic drug (where D 1 and D. 2 at least one of which is a BH3 mimetic, and a = the number of attached anti-neoplastic drug payloads D per antibody or antigen-binding fragment. 1 Or D 2 (the number of has.

[0502] A.Antibodies An antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cell. In some embodiments, an antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. An antibody or antigen-binding fragment may have a dissociation constant (K ) of ≦1 mM, ≦100 nM or ≦10 nM, or any amount therebetween, as measured, for example, by BIAcore® analysis. D ) can bind to a target antigen. In some embodiments, K D In some embodiments, K D is between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[0503] In some embodiments, the antibody or antigen-binding fragment is a four-chain antibody (also called immunoglobulin or full-length or intact antibody), which comprises two heavy chains and two light chains.In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin.In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin, which retains the ability to bind to target cancer antigen and / or provide at least one function of an immunoglobulin.

[0504] In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody or an internalizing antigen-binding fragment thereof binds to a target cancer antigen expressed on the surface of a cell and, upon binding, enters the cell. In some embodiments, the Bcl-xL inhibitor drug moiety of the ADC is released from the antibody or antigen-binding fragment of the ADC after the ADC enters and resides in a cell expressing the target cancer antigen (i.e., after the ADC is internalized), e.g., by cleavage, by degradation of the antibody or antigen-binding fragment, or by any other suitable release mechanism.

[0505] In some embodiments, the antibody comprises a mutation that mediates reduced or absent antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, these mutations are known as Fc-silencing, Fc-silent, or Fc-silence mutations. In some embodiments, amino acid residues L234 and L235 of the IgG1 constant region are replaced with A234 and A235 (also known as "LALA"). In some embodiments, amino acid residue N297 of the IgG1 constant region is replaced with A297 (also known as "N297A"). In some embodiments, amino acid residues D265 and P329 of the IgG1 constant region are replaced with A265 and A329 (also known as "DAPA"). Other antibody Fc-silencing mutations may be used. In some embodiments, Fc-silencing mutations are used in combination with, for example, D265A, N297A, and P329A (also known as "DANAPA").

[0506] As shown herein, when modifications are made to antibodies, they are further designated with the modification.For example, if selected amino acids in the antibody are changed to cysteine ​​(for example, E152C, S375C according to EU numbering of antibody heavy chain to facilitate conjugation to linker-drug moiety), they are designated as "CysMab", or if the antibody is modified with Fc silencing mutations D265A, N297A and P329A of IgG1 constant region according to EU numbering, "DANAPA" is added to the name of the antibody, or if the antibody is modified with Fc silencing mutations D265A and P329A of IgG1 constant region according to EU numbering, "DAPA" is added to the name of the antibody.

[0507] The amino acid sequences of exemplary antibodies of the disclosure, along with exemplary antigen targets, are provided in Tables D1-D8.

[0508] [Table 11-1]

[0509] [Table 11-2]

[0510] [Table 12-1]

[0511] [Table 12-2]

[0512] [Table 12-3]

[0513] [Table 12-4]

[0514]

Table 12-5

[0515]

Table 13-1

[0516]

Table 13-2

[0517]

Table 14-1

[0518]

Table 14-2

[0519]

Table 14-3

[0520]

Table 14-4

[0521]

Table 14-5

[0522]

Table 15-1

[0523]

Table 15-2

[0524]

Table 15-3

[0525]

Table 15-4

[0526]

Table 15-5

[0527]

Table 15-6

[0528]

Table 15-7

[0529]

Table 15-8

[0530]

Table 15-9

[0531]

Table 15-10

[0532]

Table 15-11

[0533]

Table 16-1

[0534]

Table 16-2

[0535]

Table 16-3

[0536]

Table 16-4

[0537]

Table 16-5

[0538]

Table 16-6

[0539]

Table 16-7

[0540]

Table 16-8

[0541]

Table 16-9

[0542]

Table 16-10

[0543]

Table 16-11

[0544]

Table 16-12

[0545]

Table 17-1

[0546]

Table 17-2

[0547]

Table 17-3

[0548]

Table 17-4

[0549]

Table 17-5

[0550]

Table 17-6

[0551]

Table 17-7

[0552]

Table 17-8

[0553]

Table 17-9

[0554]

Table 17-10

[0555]

Table 17-11

[0556]

Table 17-12

[0557]

Table 17-13

[0558]

Table 17-14

[0559]

Table 17-15

[0560]

Table 18-1

[0561]

Table 18-2

[0562]

Table 18-3

[0563]

Table 18-4

[0564]

Table 18-5

[0565]

Table 18-6

[0566]

Table 18-7

[0567]

Table 18-8

[0568]

Table 18-9

[0569]

Table 18-10

[0570]

Table 18-11

[0571]

Table 18-12

[0572]

Table 18-13

[0573]

Table 18-14

[0574]

Table 18-15

[0575]

Table 19-1

[0576]

Table 19-2

[0577]

Table 19-3

[0578]

Table 19-4

[0579]

Table 19-5

[0580]

Table 19-6

[0581]

Table 19-7

[0582]

Table 19-8

[0583]

Table 19-9

[0584]

Table 19-10

[0585] 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 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 any set of heavy and light chain variable domains listed in the table above, or a set of six CDRs from any set of heavy and light chain variable domains listed in the table above. 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 from any set of heavy and light chain variable domains listed in the table above. -8 K less than M D In particular, the ADCs may comprise amino acid sequences that are conservatively modified and / or homologous to the sequences listed in the table above, so long as they retain the sequence described above (e.g., in the Table 1) and retain one or more functional properties of the ADCs disclosed herein (e.g., ability to be internalized, ability to bind to an antigen target, e.g., an antigen expressed on a tumor or other cancer cell, etc.).

[0586] In some embodiments, the antibodies or antigen-binding fragments of the ADCs disclosed herein further comprise human heavy and light chain constant domains or fragments thereof. For example, the antibodies or antigen-binding fragments of the described ADCs may comprise a human IgG heavy chain constant domain (e.g., IgG1) and a human kappa or lambda light chain constant domain. In some embodiments, the antibodies or antigen-binding fragments of the described ADCs comprise a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain with a human Ig kappa light chain constant domain.

[0587] In some embodiments, the target cancer antigen for the ADC is PCAD.

[0588] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 33, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 34, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 35; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 36, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 37, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 38.

[0589] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 312, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 314.

[0590] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 307, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316.

[0591] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 309, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 278; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 317, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316.

[0592] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 310, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316.

[0593] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO:7 and a light chain variable region amino acid sequence of SEQ ID NO:8, or a sequence that is at least 95% identical to a disclosed sequence. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8.

[0594] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 303 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 311. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 303 and a light chain variable region amino acid sequence of SEQ ID NO: 311, or a sequence that is at least 95% identical to a disclosed sequence. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 303, 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: 311.

[0595] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof is an internalizing antibody or an internalizing antigen-binding fragment. In some embodiments, the anti-PCAD antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises cysteine ​​residues (C) at amino acid positions corresponding to 152 and 375 in the wild-type (unmodified) IgG1 heavy chain constant domain numbered according to the EU numbering system.

[0596] In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO:63, or a sequence that is at least 95% identical to SEQ ID NO:63, and a light chain amino acid sequence of SEQ ID NO:64, or a sequence that is at least 95% identical to SEQ ID NO:64. In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO:63 and a light chain amino acid sequence of SEQ ID NO:64, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-PCAD antibody has a...

Claims

[Claim 1] The invention described in the specification.

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