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

Abstract

The present invention discloses antibody-drug conjugates that bind to human oncology targets. The antibody-drug conjugate comprises an antibody or antigen-binding fragment thereof covalently linked to an anti-tumor payload via a dual linker, wherein at least one anti-tumor payload is a BH3 mimetic. The disclosure further relates to methods and compositions for treating cancer by administering the antibody-drug conjugates provided herein. Also disclosed are linker-drug conjugates comprising at least one BH3 mimetic and methods of making the same.

Description

[0001] Related applications

[0002] This application claims the benefit of the filing date under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 344,510, filed May 20, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to antibody-drug conjugates (ADCs) comprising an antibody or antigen-binding fragment thereof covalently linked to two anti-tumor compounds via a dual linker, wherein at least one of the anti-tumor payloads is a BH3 mimetic. The present disclosure also relates to methods and compositions for treating and / or diagnosing cancers that express a target antigen and / or that can be treated by modulating the expression and / or activity of Bcl-2 family proteins, as well as methods for preparing these compositions. Also disclosed are linker-drug conjugates comprising a dual linker and an anti-tumor compound (e.g., two BH3 mimetics or a BH3 mimetic portion and an anti-tumor non-BH3 mimetic) and methods for preparing the same. Background Art

[0004] Apoptosis (programmed cell death) is an evolutionarily conserved pathway that is crucial for tissue homeostasis, development, and clearance of damaged cells. Dysregulation of apoptosis can lead to human diseases, including malignancies, neurodegenerative disorders, immune system diseases, 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). Apoptosis escape is considered a hallmark of cancer, contributing to tumor progression, continued proliferation, and resistance to anticancer therapy (Hanahan and Weinberg, Cell. 2000 Jan 7; 100(1): 57-70).

[0005] The Bcl-2 protein family includes key regulators of cell survival that can inhibit (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).

[0006] 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. In most cases, these interactions involve docking the Bcl-2 homology 3 (BH3) domain of the pro-apoptotic family member into a groove on the surface of the pro-survival member. The presence of Bcl-2 homology (BH) domains defines the Bcl-2 family members, and the Bcl-2 family is divided into three main groups based on the specific BH domains present in the protein. Pro-survival members such as Bcl-2, Bcl-xL and Mcl-1 contain BH domains 1-4, while Bax and Bak are pro-apoptotic effectors of mitochondrial outer membrane permeability during apoptosis, which contain BH domains 1-3 (Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan; 9 (1): 47-59).

[0007] Overexpression of pro-survival members of the Bcl-2 family is a hallmark of cancer, and these proteins have been shown to play an important role in tumor development, maintenance, and resistance to anticancer therapies (Czabotar et al., Nat. Rev. Mol. Cell Biol. 2014 Jan; 15(1): 49-63). Bcl-xL (also known as 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 be inversely correlated with sensitivity to over 120 anticancer therapeutic molecules in a representative panel of cancer cell lines (NCI-60) (Amundson et al., Cancer Res. 2000 Nov 1; 60(21): 6101-10).

[0008] 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 immune 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, g-irradiation, and CD3 cross-linking, suggesting that transgenic Bcl-xL overexpression can 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). In patient samples, persistent or high expression of anti-apoptotic Bcl-2 family proteins has been observed (Pope et al., Nat Rev Immunol. 2002 Jul; 2(7): 527-35. doi: 10.1038 / nri846. PMID: 12094227). In particular, T cells isolated from the joints of patients with rheumatoid arthritis showed increased expression of Bcl-xL 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).

[0009] These findings have driven the discovery and development of a new class of drugs called BH3 mimetics. These molecules are able to disrupt the interaction between pro-apoptotic and anti-apoptotic members of the Bcl-2 family and are potent inducers of apoptosis. This class of new drugs includes inhibitors of Bcl-2, Bcl-xL, Bcl-w, and Mcl-1. The first described BH3 mimetics 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). Since then, 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). The selective Bcl-2 inhibitor ABT-199 is now approved for the treatment of CLL and AML patients in combination therapy, while other inhibitors are still 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 shown promising 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 in combination with several therapies is being studied in solid tumors. Selective Bcl-xL inhibitors A-1155463 or A-1331852 showed 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 benefits in preclinical models of immune system diseases and autoimmune diseases. Treatment with ABT-737 (Bcl-2, Bcl-xL, and Bcl-w inhibitors) resulted in effective inhibition of lymphocyte proliferation in vitro. Importantly, mice treated with ABT-737 showed a significant reduction in disease severity in animal models of arthritis and lupus (Bardwell et al., J Clin Invest. 1997 Feb 1; 99(3): 439-46. doi: 10.1172 / JCI119178. PMID: 9022077). In addition, ABT-737 has been found to prevent allogeneic T cell activation, proliferation, and cytotoxicity in vitro and to suppress allogeneic T and B cell responses after skin transplantation, with high selectivity for lymphocytes (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).

[0010] In preclinical studies, BH3 mimetics have been found to have strong synergistic effects when combined, including Mcl1i+Bcl2i, Mcl1i+Bcl-xli, and Bcl-xli+Bcl-2i (WO 2018015526A1; 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). In addition, it has been found that Bcl-xl inhibitors and Mcl1 inhibitors are effective when used in combination 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 April; 11(4)1026-1035; Bennett et al., Open Biol., 2016 6: 160-134; 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 ... Medicine, 2017Aug2;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 2003Jul;9(7):2856-65; Lalazar et al., Cancer Discov. 2021Oct;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, there is still a lack of evidence of tolerability for the combined administration of two unconjugated BH3 mimetics or the combined administration of a BH3 mimetic and an anti-tumor non-BH3 mimetic, particularly for Mcl1i + Bclxli. In addition, the clinical potential of unconjugated BH3 mimetic combinations remains to be demonstrated. Therefore, there is a need to find disease modifiers that therapeutically target Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, Mcl-1) or upstream and / or downstream proteins in the apoptosis signaling pathway in the fields of oncology, as well as immune and autoimmune diseases. Summary of the Invention

[0011] In a first embodiment, the present disclosure provides an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof covalently linked to two anti-tumor payloads via a dual linker, wherein at least one anti-tumor payload is a BH3 mimetic, and wherein the dual linker has one attachment point for connection to the antibody and two attachment points for connection to the two anti-tumor payloads, and wherein the two anti-tumor payloads can be the same or different. In some embodiments, one anti-tumor payload is a BH3 mimetic and the other anti-tumor payload is an anti-tumor non-BH3 mimetic. In some embodiments, the anti-tumor non-BH3 mimetic is a topoisomerase 1 inhibitor or an anti-mitotic drug. In some embodiments, the topoisomerase 1 inhibitor is selected from topotecan, exotecan, derunotecan, and SN-38. In some embodiments, the anti-mitotic 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 anti-tumor payloads are two BH3 mimetic. In some embodiments, the BH3 mimetic is selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor. In some embodiments, the BH3 mimetic of the two anti-tumor payloads is the same. In some embodiments, the BH3 mimetic of the two anti-tumor payloads is different. In some embodiments, the anti-tumor payload in the antibody-drug conjugate of the present disclosure is defined as: (i) one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a Bcl-2 inhibitor; (ii) one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a Bcl-xL inhibitor; or (iii) one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is a Bcl-xL inhibitor. In some embodiments, one anti-tumor payload is a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other anti-tumor payload is a topoisomerase 1 inhibitor or an anti-mitotic drug. In some embodiments, one anti-tumor payload is a Bcl-xL inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor. In some embodiments, one anti-tumor payload is a Bcl-xL inhibitor and the other anti-tumor payload is an anti-mitotic drug. In some embodiments, one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor. In some embodiments, one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is an anti-mitotic drug. In some embodiments, one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor.In some embodiments, one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is an anti-mitotic drug.

[0012] In a second embodiment, the present disclosure provides the antibody-drug conjugate of the first embodiment, wherein the antibody-drug conjugate is represented by formula (A):

[0013]

[0014] in:

[0015] Ab is an antibody or its antigen-binding fragment;

[0016] R 1 is an attachment group;

[0017] L 1 is a bridging spacer;

[0018] W is the branch part;

[0019] L 2’ and L 3’ Each independently is a joint;

[0020] D 1 and D 2 are each independently an antitumor compound, wherein D 1 and D 2 At least one of is a BH3 mimetic; and

[0021] a is an integer from 1 to 16. In some embodiments, D 1 and D 2 Each is independently a BH3 mimetic.

[0022] In a third embodiment, the disclosure provides the antibody-drug conjugate of the second embodiment, wherein a is an integer from 1 to 8, 1 to 6, 1 to 4, or a is 1 or 2, optionally wherein a is determined by liquid chromatography-mass spectrometry (LC-MS). The definitions of the remaining variables are provided in the second embodiment or any embodiment described herein. In some embodiments, a is an integer from 1 to 6 or from 1 to 4, or a is 1 or 2, or a is determined by liquid chromatography-mass spectrometry (LC-MS).

[0023] In a fourth embodiment, the present disclosure provides the antibody-drug conjugate of the second or third embodiment, wherein L 2’ and L 3’ Each of L comprises a cleavable group, optionally wherein at least one cleavable group comprises a glucuronide group, a pyrophosphate group, a peptide group and / or a self-immolative group. 2’ and L3’ Each of comprises a cleavable group, 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 herein.

[0024] In a fifth embodiment, the present disclosure provides the antibody-drug conjugate of the second embodiment, wherein the antibody-drug conjugate is represented by formula (B):

[0025]

[0026] in:

[0027] Ab is an antibody or its antigen-binding fragment;

[0028] R 1 is an attachment group;

[0029] L 1 is a bridging spacer;

[0030] W is N or CR w ; where R w Is H or C 1-6 alkyl;

[0031] L 2 and L 3 each independently a linker spacer;

[0032] E 1 and E 2 Each is independently an enzymatic cleavage element or a hydrophilic moiety;

[0033] 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;

[0034] D 1 and D 2 are each independently an antitumor compound, wherein D 1 and D 2 At least one of the proteins is a BH3 mimetic.

[0035] Definitions of the remaining variables are provided in the second embodiment or any embodiment described herein. In some embodiments, V 1 and V 2 Each is independently i) a self-immolative group or ii) an enzymatic cleavage element; and D 1 and D 2 Each is independently a BH3 mimetic.

[0036] In a sixth embodiment, the present disclosure provides the antibody-drug conjugate of the fifth embodiment, wherein (i) V 1 and V 2 Each independently comprises a phosphate, a pyrophosphate and / or a self-immolative group; (ii) V 1 and V 2 Each independently contains a self-decomposing group; (iii) V 1 and V 2 each independently comprises a self-immolative group comprising -CH2-O-, -OC(=O)-, -NH-CH2-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or iv) V 1 and V 2 Each independently comprises a group containing p-aminobenzyl-phosphate or p-aminobenzyl-pyrophosphate. Definitions of the remaining variables are provided in the fifth embodiment or any embodiment described herein.

[0037] In some embodiments, for the antibody-drug conjugate of the fifth embodiment, V 1 and V 2 Defined as: (i) V 1 and V 2 Each independently comprises a phosphate, a pyrophosphate and / or a self-immolative group; (ii) V 1 and V 2 each independently contains a self-immolative group; or (iii) V 1 and V 2 Each independently comprises a self-immolative group comprising -CH2-O-, -OC(=O)-, -NH-CH2-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0038] In a seventh embodiment, the present disclosure provides the antibody-drug conjugate of the fifth embodiment, wherein the antibody-drug conjugate is represented by formula (C):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein

[0041] Ab is an antibody or its antigen-binding fragment;

[0042] R 1 is an attachment group;

[0043] L 1 is a bridging spacer;

[0044] W is N or CR w ; where R w Is H or C 1-6 alkyl;

[0045] L 2 and L 3 each independently a linker spacer;

[0046] E 1 and E 2 each independently a peptide group comprising 1 to 6 amino acids, wherein the peptide group is optionally substituted with a hydrophilic group;

[0047] A 1 and A 2 are each independently a bond, -OC(=O)-*, -OC(=O)NH-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[0048] Each R a are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 or A 2 * indicates that the 1 or D 2 attachment points;

[0049] D 1 and D 2 are each independently an antitumor compound, wherein D 1 and D 2 at least one of which is a BH3 mimetic;

[0050] L 4 and L 5 each independently a spacer moiety;

[0051] R 2 and R 3 Each independently is a hydrophilic group or an enzymatic cleavage element; and

[0052] m and n are each independently 0 or 1.

[0053] Definitions for the remaining variables are provided in the fifth embodiment or any embodiment described herein. In some embodiments, D 1 and D 2 Each is independently a BH3 mimetic.

[0054] In an eighth embodiment, the present disclosure provides the antibody-drug conjugate of the seventh embodiment, wherein the antibody-drug conjugate is represented by formula (D1), (D2) or (D3):

[0055]

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein for formula (D2), D 1 and D 2 are each independently an antitumor compound, wherein D 1 and D 2 At least one of R 2 and R 3 are each independently an enzymatic cleavage element; and for formula (D3), R 2 Is a hydrophilic group and R 3 is an enzymatic cleavage element. Definitions of the remaining variables are provided in the seventh embodiment or any embodiment described herein. In some embodiments, D 1 and D 2 Each is independently a BH3 mimetic.

[0058] In a ninth embodiment, the present disclosure provides the antibody-drug conjugate of the eighth embodiment, wherein for formula (D1), R 2 and R 3 Each is independently a hydrophilic group. Definitions for the remaining variables are provided in the eighth embodiment or any embodiment described herein.

[0059] In a tenth embodiment, the disclosure provides the antibody-drug conjugate of any one of the second to ninth embodiments, wherein the attachment group is formed by a reaction comprising at least one reactive group. The definitions of the remaining variables are provided in any one of the second to ninth embodiments or any embodiment described herein.

[0060] In an eleventh embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to tenth embodiments, wherein the attachment group is formed by reacting:

[0061] a first reactive group, which is attached to the linker, and

[0062] A second reactive group that is attached to the antibody or is an amino acid residue of the antibody, wherein optionally,

[0063] (i) at least one of the reactive groups comprises:

[0064] thiols,

[0065] Maleimide,

[0066] Haloacetamide,

[0067] Azide,

[0068] Alkynes,

[0069] Cyclooctene,

[0070] Triarylphosphine,

[0071] Oxanorbornadiene,

[0072] Cyclooctyne,

[0073] Diaryltetrazine,

[0074] Monoaryl tetrazines,

[0075] Norbornene,

[0076] aldehyde,

[0077] Hydroxylamine,

[0078] Hydrazine,

[0079] NH2-NH-C(=O)-,

[0080] ketone,

[0081] Vinyl sulfone,

[0082] Aziridine,

[0083] amino acid residues,

[0084] -ONH2, -NH2, -N3, -SH, -SR 11 、-SSR 12 , -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NHC(=O)CH2Br, -NHC(=O)CH2I, -C(O)NHNH2,

[0085] in:

[0086] Each R 11 Independently selected from H and C1-C6 alkyl;

[0087] Each R 12 is 2-pyridyl or 4-pyridyl;

[0088] Each R 13 Independently selected from H, C1-C6 alkyl, F, Cl and -OH;

[0089] Each R 14 Independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH;

[0090] Each R 15 independently selected from H, C1-C6 alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1-4 Alkoxy and C substituted by -C(=O)OH 1-4 Alkyl; and / or

[0091] (ii) the first reactive group and the second reactive group comprise:

[0092] Thiol and maleimide,

[0093] Thiols and haloacetamides,

[0094] Thiol and vinyl sulfone,

[0095] Thiols and aziridines,

[0096] Azides and alkynes,

[0097] Azide and cyclooctyne,

[0098] Azide and cyclooctene,

[0099] Azide and triarylphosphine,

[0100] Azide and oxa-norbornadiene,

[0101] Diaryltetrazine and cyclooctene,

[0102] Monoaryl tetrazines and norbornene,

[0103] Aldehydes and hydroxylamines,

[0104] Aldehydes and hydrazines,

[0105] Aldehyde and NH2-NH-C(=O)-,

[0106] Ketones and hydroxylamines,

[0107] Ketones and hydrazines,

[0108] Ketone and NH2-NH-C(=O)-,

[0109] Hydroxylamine and

[0110] Amine and or

[0111] CoA or a CoA analog and a serine residue.

[0112] Definitions for the remaining variables are provided in any of the second through tenth embodiments, or any embodiment described herein.

[0113] In a twelfth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to eleventh embodiments, wherein the attachment group is selected from:

[0114]

[0115]

[0116]

[0117]

[0118] amide;

[0119]

[0120]

[0121] and

[0122] disulfide,

[0123] in:

[0124] R 16 It is H, C 1-4 Alkyl, phenyl, pyrimidine or pyridine;

[0125] R 18 It is H, C 1-6 Alkyl, phenyl or C substituted by 1 to 3 -OH groups 1-4 alkyl;

[0126] Each R 15 Independently selected from H, C 1-6Alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1-4 Alkoxy and C substituted by -C(=O)OH 1-4 alkyl;

[0127] R 17 independently selected from H, phenyl and pyridine;

[0128] q is 0, 1, 2, or 3;

[0129] R 19 is H or methyl; and

[0130] R 20 It is H, -CH3 or phenyl.

[0131] Definitions for the remaining variables are provided in any of the second through eleventh embodiments, or any embodiment described herein.

[0132] In a thirteenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to twelfth embodiments, wherein the attachment group is Definitions for the remaining variables are provided in any of the second through twelfth embodiments, or any embodiment described herein.

[0133] In a fourteenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to thirteenth embodiments, wherein:

[0134] (1)L 1 Include:

[0135] or *-CH(OH)CH(OH)CH(OH)CH(OH)-**,

[0136] wherein each n is an integer from 1 to 12, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point;

[0137] (2)L 1 yes and n is an integer from 1 to 12 or n is 1 or n is 2, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point;

[0138] (3)L 1 yes and n is an integer from 1 to 12, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point;

[0139] (4)L 1 Include Among them L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point;

[0140] (5)L 1 is a bridging spacer comprising:

[0141] *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;

[0142] *-C(=O)NH((CH2) m O) t (CH2) n -**;

[0143] *-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;

[0144] *-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;

[0145] *-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;

[0146] *-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;

[0147] *-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;

[0148] *-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;

[0149] *-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;

[0150] *-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-**or

[0151] *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point;

[0152] X1 is and

[0153] Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0154] Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

[0155] 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; and

[0156] Each R L1 Independently selected from H and C1-C6 alkyl.

[0157] Definitions for the remaining variables are provided in any of the second through thirteenth embodiments, or any embodiment described herein.

[0158] In a fifteenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to fourteenth embodiments, wherein L 1 Contains the parts represented by

[0159]

[0160] Where n is an integer from 1 to 12, where L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 Definitions for the remaining variables are provided in any of the second through fourteenth embodiments, or any embodiment described herein.

[0161] In the sixteenth embodiment, the present disclosure provides the antibody-drug conjugate of the fifteenth embodiment, wherein L 1 It is expressed by the following formula

[0162]

[0163] in

[0164] n is an integer from 1 to 12;

[0165] x is an integer from 0 to 6;

[0166] y is 0 or 1;

[0167] z is an integer from 0 to 6;

[0168] u is 0 or 1; and

[0169] Among them L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point.

[0170] Definitions for the remaining variables are provided in the fifteenth embodiment or any embodiment described herein.

[0171] In a seventeenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to sixteenth embodiments, wherein L 1 Selected from the following:

[0172]

[0173] Definitions for the remaining variables are provided in any of the second through sixteenth embodiments, or any embodiment described herein.

[0174] In an eighteenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the fifth to seventeenth embodiments, wherein L 2 and L 3 Each is independently a linker spacer comprising a moiety represented by:

[0175]

[0176] in

[0177] k is an integer from 0 to 6;

[0178] r is 0 or 1;

[0179] o is an integer from 0 to 6;

[0180] p is an integer from 0 to 6; and

[0181] Among them L 2 or L 3 The # indicates direct or indirect attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates a point directly or indirectly attached to W.

[0182] Definitions for the remaining variables are provided in the second through seventeenth embodiments, or any embodiment described herein.

[0183] In the nineteenth embodiment, the present disclosure provides the antibody-drug conjugate of the eighteenth embodiment, wherein L 2 and L 3 Each is independently a linker spacer selected from the following

[0184]

[0185]

[0186] in

[0187] k is independently at each occurrence an integer from 0 to 4;

[0188] r is independently 0 or 1 at each occurrence;

[0189] o is independently at each occurrence an integer from 0 to 10;

[0190] p is independently at each occurrence an integer from 0 to 4;

[0191] R L23 is hydrogen or C 1-6 alkyl;

[0192] R L is hydrogen or -C(O)-R H ;

[0193] R H is a hydrophilic group; and

[0194] L 2 or L 3 The # indicates direct attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates the point directly attached to W;

[0195] The condition is that when W is N, L 2 and L 3 Not (L2c), (L2d), (L2f), or (L2k).

[0196] Definitions for the remaining variables are provided in the eighteenth embodiment or any embodiment described herein.

[0197] In the twentieth embodiment, the present disclosure provides the antibody-drug conjugate of the nineteenth embodiment, wherein L 2 and L 3 Each is independently a linker spacer selected from the following

[0198]

[0199]

[0200] in

[0201] k is independently at each occurrence an integer from 1 to 3;

[0202] o is independently at each occurrence an integer from 1 to 9;

[0203] p is independently at each occurrence an integer from 1 to 3;

[0204] R L23 is hydrogen or C 1-3 alkyl;

[0205] R L is hydrogen or -C(O)-R H ;

[0206] R H is a hydrophilic group; and

[0207] L 2 or L 3 The # indicates direct attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates a point directly attached to W; provided that when W is N, L 2 and L 3 Not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

[0208] Definitions for the remaining variables are provided in the nineteenth embodiment or any embodiment described herein.

[0209] In the twenty-first embodiment, the present disclosure provides the antibody-drug conjugate of the fifth to twentieth embodiments, wherein:

[0210] L 2 and L 3 are independently linking spacers selected from the following

[0211]

[0212]

[0213] Among them L 2 or L 3 The # indicates direct attachment to E 1 or E 2 Point, L 2 or L 3 The ## indicates the point directly attached to W; R L is hydrogen or -C(O)-R H ;and

[0214] R H yes and d is an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

[0215] Definitions for the remaining variables are provided in the fifth through twentieth embodiments, or any embodiment described herein.

[0216] In the twenty-second embodiment, the disclosure provides the antibody-drug conjugate of the twenty-first embodiment, wherein d is 25. Definitions of the remaining variables are provided in the twenty-first embodiment or any embodiment described herein.

[0217] In the twenty-third embodiment, the 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. The definitions of the remaining variables are provided in the seventh to twenty-second embodiments or any embodiment described herein.

[0218] In the 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-cysteine ​​(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). The definitions of the remaining variables are provided in the twenty-third embodiment or any embodiment described herein.

[0219] 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. The definitions of the remaining variables are provided in the first to twenty-third embodiments or any embodiment described herein.

[0220] In the twenty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the twenty-third to twenty-fifth embodiments, wherein E 1 or E 2 The peptide group represented is an enzymatic cleavage element. Definitions for the remaining variables are provided in the twenty-third through twenty-fifth embodiments, or any embodiment described herein.

[0221] In the twenty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of any one of the twenty-third to twenty-fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2The peptide group represented by is the hydrophilic moiety. Definitions for the remaining variables are provided in the twenty-third through twenty-fifth embodiments, or any embodiment described herein.

[0222] In the twenty-eighth embodiment, the present disclosure provides the antibody-drug conjugate of the twenty-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2 is independently an enzymatic cleavage element selected from the group consisting of

[0223]

[0224] Among them E 1 or E 2 The ^ represents a direct attachment to V in formula (B) 1 or V 2 or the point of direct attachment to the -NH- group in formulas (C) and (D); and E 1 or E 2 The ^^ respectively indicate direct attachment to L 2 or L 3 Definitions for the remaining variables are provided in the twenty-sixth embodiment or any embodiment described herein.

[0225] In the twenty-ninth embodiment, the present disclosure provides the antibody-drug conjugate of the twenty-seventh embodiment, or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2 is independently a hydrophilic moiety represented by

[0226]

[0227] where R E is a hydrophilic group R H Definitions for the remaining variables are provided in the twenty-seventh embodiment or any embodiment described herein.

[0228] In the thirtieth embodiment, the present disclosure provides the antibody-drug conjugate of the twenty-ninth embodiment, or a pharmaceutically acceptable salt thereof, wherein in E 1 or E 2 Each hydrophilic group R H Independently wherein e is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30). Definitions of the remaining variables are provided in the twenty-ninth embodiment or any embodiment described herein.

[0229] In the thirty-first embodiment, the disclosure provides the antibody-drug conjugate of the thirtieth embodiment, wherein e is 24. Definitions of the remaining variables are provided in the thirtieth embodiment or any embodiment described herein.

[0230] In the thirty-second embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 are independently a bond, -OC(=O)-* or Where * indicates attachment to D 1 or D 2 The definitions of the remaining variables are provided in the seventh to thirty-first embodiments or any embodiment described herein. In some embodiments, A 1 and A 2 independently a key or Where * indicates attachment to D 1 or D 2 In some embodiments, A 1 and A 2 is independently a bond or -OC(=O)-*, where * represents attachment to D 1 or D 2 In some embodiments, A 1 and A 2 The definition of is: (i) A 1 and A 2 Yes-OC(=O)-*; (ii)A 1 and A 2 yes (iii)A 1 is -OC(=O)-* and A 2 is a key; (iv) A 1 is -OC(=O)-* and A 2 yes (v)A 1 It is a key and A 2 yes or (vi) A 1 It is a key and A 2 is -OC(=O)-*, where * indicates attachment to D 1 or D 2 point.

[0231] In the thirty-third embodiment, the present disclosure provides the antibody-drug conjugates of the seventh to thirty-second embodiments, wherein A 1 and A 2 Definitions for the remaining variables are provided in the seventh through thirty-second embodiments, or any embodiment described herein.

[0232] In the thirty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-third embodiments, wherein

[0233] i)L 4 and L 5 Each is independently a spacer moiety having the structure in:

[0234] Z is -O-, -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and

[0235] X is a bond, triazolyl or -CH2-triazolyl-,

[0236] Where X is connected to R 2 or R 3 ;or

[0237] (ii)L 4 and L 5 is independently a spacer moiety having the structure

[0238] in:

[0239] Z is -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NRb -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and

[0240] X is -CH2-triazolyl-C 1-4 Alkylene-OC(O)NHS(O)2NH-, -C 4-6 Cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -, -CH2-triazolyl-C 1-4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4-6 Cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -, wherein each n is independently 1, 2 or 3,

[0241] Where X is connected to R 2 or R 3 .

[0242] Definitions for the remaining variables are provided in the seventh through thirty-third embodiments, or any embodiment described herein.

[0243] In the thirty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of the thirty-fourth embodiment, or a pharmaceutically acceptable salt thereof, wherein Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazolyl or -CH2-triazolyl-; and R L45 is independently H or C at each occurrence 1-3 Definitions for the remaining variables are provided in the thirty-fourth embodiment or any embodiment described herein.

[0244] In a thirty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein L 4 and L 5 Each is independently a spacer moiety selected from the following

[0245] Among them L 4 or L 5 The @ indicates the point of direct attachment to the phenyl group, and L 4 or L 5 @@ indicates a direct attachment to R 2 or R 3 Definitions for the remaining variables are provided in the seventh to thirty-fifth embodiments, or any embodiment described herein.

[0246] In the thirty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-sixth embodiments, wherein R 2 and R 3 The hydrophilic groups represented by each independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 Substituted C2-C6 alkyl or C2-C6 alkyl substituted by 1 to 2 substituents independently selected from the following: -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1-4 Alkylene -P(O)(OCH2CH3)2 and -COOH groups. Definitions for the remaining variables are provided in the seventh through thirty-sixth embodiments, or any embodiment described herein.

[0247] In the thirty-eighth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-seventh embodiments, wherein R 2 or R 3 Independently where n is an integer between 1 and 6,

[0248] Definitions for the remaining variables are provided in the seventh through thirty-seventh embodiments, or any embodiment described herein.

[0249] In the thirty-ninth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-eighth embodiments, wherein R 2 or R 3 The hydrophilic groups represented by each independently comprise:

[0250] (i) Polysarcosine having the following moieties:

[0251] in

[0252] f is an integer between 3 and 25; and

[0253] R 23 is H, -CH3 or -CH2CH2C(=O)OH; or

[0254] (ii) polyethylene glycol of the formula: in

[0255] g and h are independently integers between 2 and 30.

[0256] In some embodiments, R 2 or R 3 The hydrophilic groups represented by each independently comprise:

[0257] Polysarcosine having the following moieties:

[0258] in:

[0259] f is an integer between 3 and 25; and

[0260] R 23 It is H, -CH3 or -CH2CH2C(=O)OH.

[0261] Definitions for the remaining variables are provided in the seventh through thirty-eighth embodiments, or any embodiment described herein.

[0262] In the 40th embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-sixth embodiments, wherein R 2 or R 3 The enzymatic cleavage elements represented each independently comprise:

[0263]

[0264] Definitions for the remaining variables are provided in the seventh through thirty-sixth embodiments, or any embodiment described herein.

[0265] In the forty-first embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventh to thirty-sixth embodiments, wherein R 2 or R 3 Each independently selected from the following: wherein g and h are independently integers between 20 and 30.

[0266] Definitions for the remaining variables are provided in the seventh through thirty-sixth embodiments, or any embodiment described herein.

[0267] In the forty-second embodiment, the present disclosure provides the antibody-drug conjugate of the thirty-ninth to forty-first embodiments, wherein

[0268] g is 23, 24, or 25; and

[0269] h is 23, 24, or 25.

[0270] Definitions for the remaining variables are provided in the thirty-ninth through forty-first embodiments, or any embodiment described herein.

[0271] In the forty-third embodiment, the present disclosure provides the antibody-drug conjugate of the seventh embodiment, wherein the dual linker is represented by the following formula:

[0272]

[0273]

[0274]

[0275] in:

[0276] A 1 and A 2 are each independently a bond, -OC(=O)-* or Among them A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point;

[0277] g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30);

[0278] o is independently at each occurrence an integer between 1 and 9 (e.g., an integer between 2 and 5);

[0279] n is an integer between 1 and 12 (e.g., an integer between 2 and 5);

[0280] ** - indicates the point of attachment to Ab; and

[0281] Indicates direct attachment to D 1 or D 2 point.

[0282] Definitions for the remaining variables are provided in the seventh embodiment or any embodiment described herein. In some embodiments, A 1 and A 2 are each independently a bond or -OC(=O)-*, wherein A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 One of them is a bond and the other is OC(=O)-*.

[0283] In the forty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of the seventh embodiment, wherein the dual linker is represented by formula (D5):

[0284]

[0285] in:

[0286] A 1 and A 2 are each independently a bond, -OC(=O)-* or Among them A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point;

[0287] g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30);

[0288] o is independently at each occurrence an integer between 1 and 9 (e.g., an integer between 1 and 3);

[0289] n is an integer between 1 and 12 (e.g., an integer between 5 and 10);

[0290] ** - indicates the point of attachment to Ab; and

[0291] Indicates direct attachment to D 1 or D 2 The definitions of the remaining variables are provided in the seventh embodiment or any embodiment described herein. In some embodiments, A 1 and A 2are each independently a bond or -OC(=O)-*, wherein A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point.

[0292] In the forty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the dual linker is represented by the following formula:

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] Each of A 1 or A 2 are independently a bond, -OC(=O)-* or Where * indicates attachment to D 1 or D 2 ** indicates the point of attachment to Ab; and Indicates direct attachment to D 1 or D 2 point

[0303] Definitions of the remaining variables are provided in the first embodiment. In some embodiments, A 1 and A 2 Each is independently a bond or -OC(=O)-*. In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 One of them is a bond and the other is OC(=O)-*.

[0304] In the forty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to forty-fifth embodiments, D 1 and D 2 Each is independently a BH3 mimetic. Alternatively, D 1 and D 2 One of the compounds is a BH3 mimetic selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other is an anti-tumor non-BH3 mimetic selected from a topoisomerase 1 inhibitor or an anti-mitotic drug. The definitions of the remaining variables are provided in the second to forty-fifth embodiments or any embodiment described herein. In some embodiments, D 1 is a BH3 mimetic and D 2 is an anti-tumor non-BH3 mimetic; and the definitions of the remaining variables are provided in the second to forty-fifth embodiments or any embodiment described herein. In some embodiments, D 1 selected from the group consisting of a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and D 2 is a topoisomerase 1 inhibitor or an antimitotic drug. In some embodiments, D 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 It is an antimitotic drug.

[0305] In some embodiments, D 1 and / or D 2 Each is independently selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor.

[0306] In the forty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to forty-sixth embodiments, wherein D 1 and D 2 Both are (i) a Mcl-1 inhibitor; (ii) a Bcl-2 inhibitor; or (iii) a Bcl-xL inhibitor. Definitions of the remaining variables are provided in the second through forty-sixth embodiments, or any embodiment described herein.

[0307] In a forty-eighth embodiment, the present disclosure provides an embodiment of any one of the second to forty-seventh embodiments, wherein D 1 and D 2 The definitions of the remaining variables are provided in the second through forty-sixth embodiments, or any embodiment described herein.

[0308] In the forty-ninth embodiment, the present disclosure provides an embodiment of any one of the second to forty-seventh embodiments, wherein D 1 and D 2 Definitions for the remaining variables are provided in the second through forty-seventh embodiments, or any embodiment described herein.

[0309] In a fiftieth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the second to forty-seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein (i) D 1 and D 2 One of them is a Mcl-1 inhibitor and the other is a Bcl-2 inhibitor; (ii) D 1 and D 2 one of which is a Mcl-1 inhibitor and the other is a Bcl-xL inhibitor; or (iii) D 1 and D 2 One of the compounds is a Bcl-2 inhibitor and the other is a Bcl-xL inhibitor. The definitions of the remaining variables are provided in the second to forty-seventh embodiments or any of the embodiments described herein. Alternatively, the disclosure provides the antibody-drug conjugate of any one of the second to forty-seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: (i) D 1 is a Mcl-1 inhibitor and D 2 is a Mcl-1 inhibitor; (ii) D 1 is a 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 a Mcl-1 inhibitor; or (vi) D 1 is a Mcl-1 inhibitor and D 2 is a Bcl-xL inhibitor. Definitions for the remaining variables are provided in the second through forty-seventh embodiments, or any embodiment described herein.

[0310] In the fifty-first embodiment, the present disclosure provides the antibody-drug conjugate of any one of the forty-sixth to fiftieth embodiments, or a pharmaceutically acceptable salt thereof, wherein the Mcl-1 inhibitor is represented by formula (I):

[0311]

[0312] in:

[0313] Ring D0 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

[0314] Ring E0 is a furyl, thienyl or pyrrolyl ring,

[0315] X 01 、X 03 、X 04 and X 05 are independently a carbon atom or a nitrogen atom,

[0316] X 02 It's CR 026 group or nitrogen atom,

[0317] Meaning that the ring is aromatic,

[0318] Y0 is a nitrogen atom or CR 03 Group,

[0319] Z0 is a nitrogen atom or CR 04 Group,

[0320] R 01 is a halogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, a straight chain or branched chain (C1-C6) haloalkyl group, a hydroxyl group, a hydroxyl (C1-C6) alkyl group, a straight chain or branched chain (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -C 08 、-(C0-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 'or -SO2-(C1-C6)alkyl,

[0321] R 02 、R03 、R 04 and R 05 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a hydroxyl (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 031 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 'or -SO2-(C1-C6)alkyl,

[0322] 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, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, straight or branched (C1-C6)alkyl, (C0-C6)alkyl-NR 011 R 011 '、-NR 013 R013’ 、-(C0-C6)alkyl-Cy 01 or oxo,

[0323] R 06 and R 07 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 'or -SO2-(C1-C6)alkyl,

[0324] or (R 06 ,R 07 ) pairs, when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a straight or branched (C1-C6)alkyl group, a -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 or oxo-substituted,

[0325] W0 is a -CH2- group, a -NH- group or an oxygen atom,

[0326] R08 is a hydrogen atom, a straight-chain or branched (C1-C8) alkyl group, -CHR 0a R 0b group, an aryl group, a heteroaryl group, an aryl(C1-C6)alkyl group or a heteroaryl(C1-C6)alkyl group,

[0327] R 09 is a hydrogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, -Cy 02 、-(C1-C6)alkyl-Cy 02 、-(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 、-Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 、-Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 03 , halogen atoms, cyano groups, -C(O)-R 014 or -C(O)-NR 014 R 014 ',

[0328] R 010 is a hydrogen atom, a straight or branched (C1-C6) alkyl group, a straight or branched (C2-C6) alkenyl group, a straight or branched (C2-C6) alkynyl group, an aryl (C1-C6) alkyl group, a (C1-C6) cycloalkylalkyl group, a straight or branched (C1-C6) haloalkyl group or -(C1-C6) alkyl-O-C 04 ,

[0329] or (R 09 ,R 010 ) pair, when fused to 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, which optionally contains 1 to 3 heteroatoms selected from O, S and N,

[0330] R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 ,

[0331] or (R 011 ,R 011') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted by 1 or 2 groups selected from linear or branched (C1-C6)alkyl groups, and wherein one or more carbon atoms of the linear or branched (C1-C6)alkyl group are optionally deuterated,

[0332] R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 06 、-Cy 05 -(C0-C6)alkyl-Cy 06 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 06 、-Cy 05 -Cy 06 -O-(C0-C6)alkyl-Cy 07 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 09 、-Cy 05 -(C0-C6)alkyl-Cy 09 、-NH-C(O)-NH-R 011 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 09 、-C(O)-NR 011 R 011 '、-NR 011 R 011 '、-OR 011 、-NR 011 -C(O)-R 011 ', -O-(C1-C6)alkyl-OR 011 、-SO2-R 011 、-C(O)-OR 011 ,

[0333] R 013 、R 013 '、R 014 and R 014 ' are independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group,

[0334] R 0a is a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0335] R 0b Yes-OC(O)-OR 0c Group, -OC(O)-NR 0c R 0c 'group or -OP(O)(OR 0c )2 group,

[0336] R 0c and R 0c 'are independently a hydrogen atom, a linear or branched (C1-C8)alkyl group, a cycloalkyl group, a (C1-C6)alkoxy (C1-C6)alkyl group or a (C1-C6)alkoxycarbonyl (C1-C6)alkyl group,

[0337] or (R 0c ,R 0c ') pair together with the nitrogen atom to which it is attached forms a non-aromatic ring consisting of 5 to 7 ring members, which in addition to the nitrogen atom may also contain 1 to 3 heteroatoms selected from oxygen and nitrogen, wherein the nitrogen atom is optionally substituted by a linear or branched (C1-C6) alkyl group,

[0338] Cy 01 、Cy 02 、Cy 03 、Cy 04 、Cy 05 、Cy 06 、Cy 07 、Cy 08 and Cy 010 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted,

[0339] Cy 09 yes

[0340] or Cy 09 is a heteroaryl group substituted by a group selected from: -OP(O)(OR 020 )2;-OP(O)(O - M + )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ; Hydroxyl; Hydroxyl (C1-C6) alkyl; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R021 ',

[0341] R 015 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; Straight or branched (C1-C6) alkoxy (C1-C6) alkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U0-(CH2) s0 - a heterocycloalkyl group,

[0342] R 016 is a hydrogen atom; a hydroxyl group; a hydroxy(C1-C6)alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0-V0-OP(O)(OR 020 )2 group; -OP(O)(O - M + )2 group; -OS(O)2OR 020 Group; -S(O)2OR 020 Group; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; -(CH2) p0 -OC(O)-NR 022 R 023 group; or -U0-(CH2) q0 -NR 021 R 021 'Group,

[0343] R 017 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; -CH2-P(O)(OR 020 )2 group, -OP(O)(OR 020 )2 group; -OP(O)(O - M +)2 group; hydroxyl group; hydroxy(C1-C6)alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or aldonic acid,

[0344] M + is a pharmaceutically acceptable monovalent cation,

[0345] U0 is a bond or oxygen atom,

[0346] V0 is -(CH2) s0 - group or -C(O)- group,

[0347] R 018 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group,

[0348] R 019 is a hydrogen atom or a hydroxy(C1-C6)alkyl group,

[0349] R 020 is a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0350] R 021 and R 021 'are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a hydroxy (C1-C6) alkyl group,

[0351] or (R 021 ,R 021 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom or a straight-chain or branched (C1-C6)alkyl group,

[0352] R 022 is a (C1-C6)alkoxy(C1-C6)alkyl group, -(CH2) p0 -NR 024 R 024 ' group or -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 20 Group,

[0353] R 023 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group,

[0354] or (R 022 ,R 023 ) form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 18 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom, a straight-chain or branched (C1-C6)alkyl group or a heterocycloalkyl group,

[0355] R 024 and R 024 'are independently a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0356] or (R 024 ,R 024 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring consisting of 5 to 7 ring members, which, in addition to the nitrogen atom, may contain 1 to 3 heteroatoms selected from O, S and N, and wherein the resulting ring is optionally substituted with a hydrogen atom or a linear or branched (C1-C6)alkyl group,

[0357] R 025 is a hydrogen atom, a hydroxyl group or a hydroxy(C1-C6)alkyl group,

[0358] R 026 is a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group or a cyano group,

[0359] R 027 is a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0360] R 028 Yes-OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 030 ) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -O-SO2-O - Group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-OR 030 Group, -Cy 010 、-(CH2) p0 -SO2-OR 030 Group, -OC(O)-R 029 Group, -OC(O)-OR 029Group or -OC(O)-NR 029 R 029 'group;

[0361] R 029 and R 029 'are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched amino (C1-C6) alkyl group,

[0362] R 030 and R 030 'are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or an aryl (C1-C6) alkyl group,

[0363] R 031 yes

[0364]

[0365] wherein ammonium is optionally present as a zwitterion or with a monovalent anionic counterion,

[0366] n0 is an integer equal to 0 or 1,

[0367] p0 is an integer equal to 0, 1, 2 or 3,

[0368] q0 is an integer equal to 1, 2, 3 or 4,

[0369] r0 and s0 are independently integers equal to 0 or 1;

[0370] Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker, and

[0371] wherein the valence of an atom is not exceeded by one or more substituents bonded thereto,

[0372] or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

[0373] Definitions for the remaining variables are provided in the forty-sixth through fiftieth embodiments, or any embodiment described herein.

[0374] In the fifty-second embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-first embodiment, wherein Cy 01 、Cy 02 、Cy 03 、Cy 04 、Cy 05 、Cy 06、Cy 07 、Cy 08 and Cy 010 are independently a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted by one or more groups selected from the group consisting of: halogen; -(C1-C6)alkoxy; -(C1-C6)haloalkyl; -(C1-C6)haloalkoxy; -(CH2) p0 -O-SO2-OR030; -(CH2)p0-SO2-OR 030 ;-OP(O)(OR 020 )2;-OP(O)(O - M + )2;-CH2-P(O)(OR 020 )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ; Hydroxyl; Hydroxyl (C1-C6) alkyl; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; or -U0-(CH2) q0 -NR 021 R 021 '.

[0375] Definitions for the remaining variables are provided in the fifty-first embodiment or any embodiment described herein.

[0376] In the fifty-third embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-first embodiment, wherein the Mcl-1 inhibitor is represented by formula (IA):

[0377]

[0378] in:

[0379] Z0 is a nitrogen atom or CR 04 Group,

[0380] R 01 is a halogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, a straight chain or branched chain (C1-C6) haloalkyl group, a hydroxyl group, a straight chain or branched chain (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, -C 08 、-NR 011 R 011 ',

[0381] R02 、R 03 and R 04 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 031 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 'or -SO2-(C1-C6)alkyl,

[0382] or (R 02 ,R 03 ) or (R 03 ,R 04 ) together with the carbon atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the ring is optionally substituted with a group selected from the group consisting of: straight or branched (C1-C6) alkyl, -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 and oxo,

[0383] R 06 and R 07are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 'or -SO2-(C1-C6)alkyl,

[0384] or (R 06 ,R 07 ) pair, when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, and wherein the resulting ring is optionally substituted with a group selected from the group consisting of a straight or branched (C1-C6) alkyl group, a -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 and oxo,

[0385] R 08 is a hydrogen atom, a linear or branched (C1-C8)alkyl group, an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl (C1-C6)alkyl group,

[0386] R 09 is a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, -Cy 02、-(C1-C6)alkyl-Cy 02 、-(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 、-Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 、-Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 03 , halogen atoms, cyano groups, -C(O)-R 014 、-C(O)-NR 014 R 014 ',

[0387] R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 , or (R 011 ,R 011 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom is optionally substituted by a linear or branched (C1-C6) alkyl group, and wherein one or more carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated,

[0388] R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-Cy 06 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 06 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 06 、-Cy 05 -Cy 06 -O-(C0-C6)alkyl-Cy 07 、-Cy 05 -(C0-C6)alkyl-Cy 09 、-NH-C(O)-NH-R 011 、-C(O)-NR 011 R 011 '、-NR 011 R 011 '、-OR 011 、-NR 011-C(O)-R 011 ', -O-(C1-C6)alkyl-OR 011 、-SO2-R 011 OR-C(O)-OR 011 ,

[0389] R 013 、R 013 '、R 014 and R 014 ' are independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group,

[0390] Cy 01 、Cy 02 、Cy 03 、Cy 05 、Cy 06 、Cy 07 and Cy 08 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted,

[0391] Cy 09 yes where R 015 、R 016 and R 017 As defined for formula (I),

[0392] R 031 yes where R 027 and R 028 As defined for formula (I),

[0393] Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker,

[0394] or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

[0395] Definitions for the remaining variables are provided in the fifty-first embodiment or any embodiment described herein.

[0396] In the fifty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-first embodiment, wherein the Mcl-1 inhibitor is represented by formula (IB):

[0397]

[0398] in:

[0399] R 01 is a linear or branched (C1-C6) alkyl group,

[0400] R 03 is -O-(C1-C6)alkyl-NR 011 R 011 'or

[0401] where R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 ;

[0402] or (R 011 ,R 011 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted by 1 or 2 groups selected from the group consisting of a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0403] And R 027 is a hydrogen atom and R 028 Yes - (CH2) p0 -O-SO2-O- group or -(CH2) p0 -SO2-OR 030 group;

[0404] R 09 is a straight chain or branched (C2-C6) alkynyl group or -Cy 02 ,

[0405] R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-Cy 06 or -Cy 05 -(C0-C6)alkyl-Cy 09 ,

[0406] Cy 01 、Cy 02 、Cy 05 and Cy 06 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted,

[0407] Cy 09 yes

[0408] R 015 、R016 and R 017 is as defined for formula (I),

[0409] Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker,

[0410] or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

[0411] Definitions of the remaining variables are provided in the fifty-first embodiment.

[0412] In the fifty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein R 01 is methyl or ethyl. Definitions for the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0413] In the fifty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein R 03 Yes -O-CH2-CH2-NR 011 R 011 ', where R 011 and R 011 Together with the nitrogen atom carrying it, it forms a piperazinyl group, which may be substituted with a hydrogen atom or a linear or branched (C1-C6) alkyl group. The definitions of the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0414] In the fifty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein R 03 Contains the following formula: where R 027 is a hydrogen atom and R 028 Yes - (CH2) p0 -SO2-OR 030 Definitions for the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0415] In the fifty-eighth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein R 03 Contains the following formula:

[0416] wherein -* is a bond to a linker. Definitions of the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0417] In the fifty-ninth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein R 09 It's Cy 02 Definitions for the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0418] In the sixtieth embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-ninth embodiment, wherein Cy 02 is an optionally substituted aryl group. Definitions for the remaining variables are provided in the fifty-ninth embodiment or any embodiment described herein.

[0419] In the sixty-first embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein Cy 05 Contains a heteroaryl group selected from the group consisting of a pyrazolyl group and a pyrimidinyl group. Definitions of the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0420] In the sixty-second embodiment, the present disclosure provides the antibody-drug conjugate of the fifty-fourth embodiment, wherein Cy 05 is a pyrimidinyl group. Definitions of the remaining variables are provided in the fifty-fourth embodiment or any embodiment described herein.

[0421] In the sixty-third embodiment, the present disclosure provides the antibody-drug conjugate of any one of the fifty-fourth to sixty-second embodiments, wherein the Mcl-1 inhibitor is covalently attached to R of formula (I), (IA) or (IB) 03 ; or is covalently attached to R of formula (I), (IA) or (IB) 09 Definitions for the remaining variables are provided in the fifty-fourth through sixty-second embodiments, or any embodiment described herein.

[0422] In the sixty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the fifty-fourth to sixty-third embodiments, wherein the Mcl-1 inhibitor is represented by any one of the following formulae:

[0423] Table A1

[0424]

[0425]

[0426]

[0427] or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing. Definitions of the remaining variables are provided in the fifty-fourth to sixty-third embodiments or any embodiment described herein.

[0428] In the sixty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the forty-sixth to fiftieth embodiments, wherein the Bcl-xL inhibitor is represented by formula (II) or formula (III):

[0429]

[0430] or any enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0431] R1 and R2 independently of one another represent a group selected from the group consisting of: hydrogen; a straight-chain or branched C1-C6 alkyl group, which is optionally substituted by a hydroxyl group or a C1-C6 alkoxy group; a C3-C6 cycloalkyl group; a trifluoromethyl group; and a straight-chain or branched C1-C6 alkylene-heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by a straight-chain or branched C1-C6 alkyl group;

[0432] or R1 and R2 together with the carbon atoms carrying them form a C3-C6 cycloalkylene group,

[0433] R3 represents a group selected from the following: hydrogen; C3-C6 cycloalkyl; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-COOR c ;-X1-PO(OH)2;-X1-SO2(OH);-X1-N3 and

[0434] R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O-; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR d R e ; C1-C6 alkylene-N + R dR e R f ; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a C1-C6 alkoxy group; and the following groups:

[0435]

[0436] or R a and R b Together with the nitrogen atom carrying it, it forms ring B1;

[0437] or R a 、R b and R c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0438] R c 、R d 、R e 、R f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0439] or R d and R e Together with the nitrogen atom carrying it, it forms ring B2,

[0440] or R d 、R e and R f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0441] Het1 represents a group selected from the following:

[0442]

[0443] Het2 represents a group selected from the following:

[0444]

[0445] A1 is -NH-, -N(C1-C3 alkyl), O, S or Se,

[0446] A2 is N, CH or C(R5),

[0447] G is selected from:

[0448] -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 G1R 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)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1 )NR G1 R G2 , -C1-C6 alkyl optionally substituted by hydroxyl groups, halogen, -NO2 and -CN, wherein:

[0449] -R G1 and R G2 is independently selected at each occurrence from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl;

[0450] R G3 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; or R G1 and R G2 and their respective atoms to which they are attached to form a C3-C8 heterocycloalkyl; or in the alternative, G is selected from:

[0451]

[0452] where R G4is selected from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl,

[0453] and R G5 represents a hydrogen atom or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms,

[0454] R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group,

[0455] R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; halogen; and -CN,

[0456] R6 represents a group selected from the following:

[0457] hydrogen;

[0458] a linear or branched-C1-C6 alkylene-R8 group;

[0459] -C2-C6 alkenyl;

[0460] -X2-O-R7;

[0461]

[0462] -X2-NSO2-R7;

[0463] -C=C(R9)-Y1-O-R7;

[0464] C3-C6 cycloalkyl;

[0465] C3-C6 heterocycloalkyl optionally substituted by a hydroxy group;

[0466] C3-C6 cycloalkylene-Y2-R7;

[0467] C3-C6 heterocycloalkylene-Y2-R7 group, and

[0468] a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group,

[0469] R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8;

[0470]

[0471] wherein Cy represents a C3-C8 cycloalkyl group,

[0472] R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and

[0473] R9 represents a group selected from the group consisting of a linear or branched C1-C6 alkyl group, a trifluoromethyl group, a hydroxyl group, a halogen group, and a C1-C6 alkoxy group,

[0474] R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl,

[0475] R 11 represents a group selected from the group consisting of hydrogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8,

[0476] R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group,

[0477] R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group,

[0478] R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0479] X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy,

[0480] X'2 represents a straight or branched C1-C6 alkylene group,

[0481] R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' e R' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl group or a C1-C6 alkoxy group; and the following groups:

[0482]

[0483] or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3,

[0484] or R' a , R' b and R' c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0485] R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0486] or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4,

[0487] or R' d , R' e and R'f Together with the nitrogen atom carrying it, it forms a bridging C3-C 8D Heterocycloalkyl,

[0488] Y1 represents a straight or branched C1-C4 alkylene group,

[0489] Y2 represents bond, -O-, -O-CH2-, -O-CO-, -O-SO2-, -CH2-, -CH2-O, -CH2-CO-, -CH2-SO2-, -C2H5-, -CO-, -CO-O-, -CO-CH2-, -CO-NH-CH2-, -SO2-, -SO2-CH2-, -NH-CO- or -NH-SO2-,

[0490] m=0, 1 or 2,

[0491] B1, B2, B3 and B4 independently represent a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain one or two heteroatoms independently selected from oxygen, sulfur and nitrogen in addition to the nitrogen atom, (iii) be substituted by one or two groups selected from the group consisting of fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl,

[0492] wherein one of the R3 and R8 groups, if present, is covalently attached to the linker, and wherein the compound of atoms is not exceeded by one or more substituents bonded thereto; or

[0493]

[0494] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0495] n=0, 1 or 2,

[0496] ------ indicates a single bond or a double bond,

[0497] A4 and A5 independently represent a carbon or nitrogen atom,

[0498] Z1 represents a bond, -N(R)- or -O-, wherein R represents hydrogen or a linear or branched C1-C6 alkyl group,

[0499] R1 represents a group selected from the following: hydrogen; a straight or branched C1-C6 alkyl group optionally substituted by a hydroxyl or C1-C6 alkoxy group; a C3-C6 cycloalkyl group; a trifluoromethyl group; and a straight or branched C1-C6 alkylene-heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by a straight or branched C1-C6 alkyl group;

[0500] R2 represents hydrogen or methyl;

[0501] R3 represents a group selected from the following: hydrogen; linear or branched C1-C4 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-COOR c ; -X1-PO(OH)2; -X1-SO2(OH); -X1-N3 and:

[0502]

[0503] R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O-; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR d R e ; C1-C6 alkylene-N + R d R e R f ; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a C1-C6 alkoxy group; and the following groups:

[0504]

[0505] or R a and R b Together with the nitrogen atom carrying it, it forms ring B1;

[0506] or R a 、R b and R c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0507] R c 、R d 、R e 、R f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0508] or R d and R e Together with the nitrogen atom carrying it, it forms ring B2,

[0509] or R d 、R e and R f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0510] Het1 represents a group selected from the following:

[0511]

[0512] Het2 represents a group selected from the following:

[0513]

[0514] A1 is -NH-, -N(C1-C3 alkyl), O, S or Se,

[0515] A2 is N, CH or C(R5),

[0516] G is selected from:

[0517] -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)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1)NR G1 R G2 , -C1-C6 alkyl optionally substituted by hydroxyl groups, halogen, -NO2 and -CN, wherein:

[0518] -R G1 and R G2 is independently selected at each occurrence from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl;

[0519] -R G3 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are each attached to form a C3-C8 heterocycloalkyl; or in the alternative, G is selected from:

[0520]

[0521] where R G4 is selected from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl,

[0522] and R G5 represents a hydrogen atom or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms,

[0523] R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group,

[0524] R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; halogen; and -CN,

[0525] R6 represents a group selected from the following:

[0526] hydrogen;

[0527] a linear or branched-C1-C6 alkylene-R8 group;

[0528] -C2-C6 alkenyl;

[0529] -X2-O-R7;

[0530]

[0531] -X2-NSO2-R7;

[0532] -C=C(R9)-Y1-O-R7;

[0533] C3-C6 cycloalkyl;

[0534] C3-C6 heterocycloalkyl, which is optionally substituted with a hydroxy group;

[0535] C3-C6 cycloalkylene-Y2-R7;

[0536] C3-C6 heterocycloalkylene-Y2-R7 group, and

[0537] a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group,

[0538] R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8;

[0539]

[0540] wherein Cy represents a C3-C8 cycloalkyl group,

[0541] R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and:

[0542]

[0543] R9 represents a group selected from the group consisting of a linear or branched C1-C6 alkyl group, a trifluoromethyl group, a hydroxyl group, a halogen group, and a C1-C6 alkoxy group,

[0544] R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl,

[0545] R 11 represents a group selected from the group consisting of hydrogen, halogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8,

[0546] R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group,

[0547] R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group,

[0548] R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0549] X1 represents a linear or branched C1-C4 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy,

[0550] X2 represents a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy,

[0551] X'2 represents a straight or branched C1-C6 alkylene group,

[0552] R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group, which is optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O -; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' e R' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl group or a C1-C6 alkoxy group; and the following groups:

[0553]

[0554] or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3,

[0555] or R' a , R' b and R' c together with the nitrogen atom carrying it, forms a bridged C3-C8 heterocycloalkyl group,

[0556] R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0557] or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4,

[0558] or R' d , R' e and R' f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0559] Y1 represents a straight or branched C1-C4 alkylene group,

[0560] Y2 represents bond, -O-, -O-CH2-, -O-CO-, -O-SO2-, -CH2-, -CH2-O, -CH2-CO-, -CH2-SO2-, -C2H5-, -CO-, -CO-O-, -CO-CH2-, -CO-NH-CH2-, -SO2-, -SO2-CH2-, -NH-CO- or -NH-SO2-,

[0561] m=0, 1 or 2,

[0562] B1, B2, B3 and B4 independently represent a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen in addition to the nitrogen atom, (iii) be substituted by one or two groups selected from the group consisting of fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl,

[0563] wherein one of the R3, R8, and G groups, if present, is covalently attached to the linker, and wherein the compound of atoms is not exceeded by one or more substituents bonded thereto. Definitions of the remaining variables are provided in the forty-sixth to fiftieth embodiments, or any embodiment described herein.

[0564] In the sixty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of the sixty-fifth embodiment, wherein the Bcl-xL inhibitor is represented by formula (IIA) or (IIIA):

[0565]

[0566] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0567] Z1 represents a bond or -O-,

[0568] R3 represents a group selected from the following: hydrogen; C3-C6 cycloalkyl; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-N3 and

[0569] R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; and a C1-C6 alkylene group -SO2O - ,

[0570] R c represents hydrogen or a linear or branched C1-C6 alkyl group,

[0571] Het2 represents a group selected from the following:

[0572]

[0573] A1 is -NH-, -N(C1-C3 alkyl), O, S or Se,

[0574] A2 is N, CH or C(R5),

[0575] G is selected from:

[0576] -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 G1 C(O)OR G3 、-C(=NOR G1 )NR G1 R G2 、-NR G1 C(=NCN)NR G1 R G2 、-NR G1 S(O)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1 )NR G1 R G2 , -C1-C6 alkyl optionally substituted by a hydroxyl group, -C(O)NR G5 S(O)2R G4 , halogen, -NO2 and -CN, among which:

[0577] -R G1 、R G2 、R G4 and R G5 is independently at each occurrence a group selected from the group consisting of hydrogen and C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms;

[0578] -RG3 is a C1-C6 alkyl group which is optionally substituted by 1 to 3 halogen atoms; or

[0579] R G1 and R G2 are combined with the atoms to which they are each attached to form a C3-C8 heterocycloalkyl;

[0580] R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group,

[0581] R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; halogen and -CN,

[0582] R6 represents a group selected from the following:

[0583] a linear or branched-C1-C6 alkylene-R8 group;

[0584] -X2-O-R7; and

[0585] a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group,

[0586] R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8;

[0587]

[0588] wherein Cy represents a C3-C8 cycloalkyl group,

[0589] R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and:

[0590]

[0591] R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl,

[0592] R 11 represents a group selected from the group consisting of hydrogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8,

[0593] R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group,

[0594] R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group,

[0595] R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0596] X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy,

[0597] X'2 represents a straight or branched C1-C6 alkylene group,

[0598] R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group, which is optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' eR' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl group or a C1-C6 alkoxy group; and the following groups:

[0599]

[0600] or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3,

[0601] or R' a , R' b and R' c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0602] R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0603] or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4,

[0604] or R' d , R' e and R' f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group,

[0605] m=0, 1 or 2,

[0606] p = 1, 2, 3 or 4,

[0607] B3 and B4 independently represent a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) in addition to the nitrogen atom, may contain one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, (iii) be substituted by one or two groups selected from the following: fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl.

[0608] Definitions for the remaining variables are provided in the sixty-fifth embodiment or any embodiment described herein.

[0609] In the sixty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of the sixty-sixth embodiment, wherein G is selected from: -C(O)OH, -C(O)OR G3 、-C(O)NR G1R 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)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、C(=NR G1 )NR G1 R G2 , halogen, -NO2, and -CN. Definitions of the remaining variables are provided in the sixty-sixth embodiment or any embodiment described herein.

[0610] In the sixty-eighth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to sixty-seventh embodiments, wherein R7 represents a group selected from the group consisting of: a linear or branched C1-C6 alkyl group; (C3-C6)cycloalkylene-R8;

[0611]

[0612] wherein Cy represents a C3-C8 cycloalkyl group. Definitions of the remaining variables are provided in the sixty-fifth to sixty-seventh embodiments, or any embodiment described herein.

[0613] In the sixty-ninth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to sixty-seventh embodiments, wherein R7 represents a group selected from:

[0614]

[0615] Definitions for the remaining variables are provided in the sixty-fifth through sixty-seventh embodiments, or any embodiment described herein.

[0616] In the seventieth embodiment, the present disclosure provides the antibody-drug conjugate of the sixty-fifth embodiment, wherein the Bcl-xL inhibitor is represented by formula (IIB), (IIC), (IIIB) or (IIIC):

[0617]

[0618]

[0619] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0620] For formula (IIB) or (IIC), R3 represents a group selected from the following: hydrogen; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ; and-X1-OR c ;

[0621] For formula (IIIB) or (IIIC), Z1 represents a bond, and R3 represents hydrogen; or Z1 represents -O-, and R3 represents -X1-NR a R b ,

[0622] R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; and a C1-C6 alkylene group -SO2O - ,

[0623] R c represents hydrogen or a linear or branched C1-C6 alkyl group

[0624] R6 represents -X2-O-R7 or a heteroarylene-R7 group optionally substituted by a linear or branched C1-C6 alkyl group,

[0625] R7 represents a group selected from the following:

[0626]

[0627]

[0628] R8 represents a group selected from the following: -NR' a R' b ;-O-X'2-NR' a R' b ; and -X'2-NR' a R' b ,

[0629] R 10 represents fluorine,

[0630] R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group,

[0631] R 14 and R 15 independently of one another represent hydrogen or a methyl group,

[0632] X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen, C1-C6 alkoxy,

[0633] X'2 represents a straight or branched C1-C6 alkylene group,

[0634] R' a and R' b independently of one another represent a group selected from the following: hydrogen; linear or branched C1-C6 alkyl optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-NR' d R' e ;

[0635] or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3,

[0636] R' d , R' e independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group,

[0637] B3 represents a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain one or two heteroatoms independently selected from oxygen and nitrogen in addition to the nitrogen atom, (iii) be substituted by one or two groups selected from the following: fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl and oxo.

[0638] Definitions for the remaining variables are provided in the sixty-fifth embodiment or any embodiment described herein.

[0639] In the seventy-first embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to seventieth embodiments, wherein R7 represents the following group:

[0640]

[0641] Definitions for the remaining variables are provided in the sixty-fifth through seventieth embodiments, or any embodiment described herein.

[0642] In the seventy-second embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to seventieth embodiments, wherein R7 represents a group selected from:

[0643]

[0644] Definitions for the remaining variables are provided in the sixty-fifth through seventieth embodiments, or any embodiment described herein.

[0645] In the seventy-third embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to seventy-second embodiments, wherein R8 represents a group selected from the following:

[0646]

[0647] Wherein -* represents the bond to the linker.

[0648] Definitions for the remaining variables are provided in the sixty-fifth through seventy-second embodiments, or any embodiment described herein.

[0649] In the seventy-fourth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the sixty-fifth to seventy-third embodiments, wherein B3 represents a C3-C8 heterocycloalkyl group selected from the following: a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group. The definitions of the remaining variables are provided in the sixty-fifth to seventy-third embodiments or any embodiment described herein.

[0650] In the seventy-fifth embodiment, the present disclosure provides the antibody-drug conjugate of the sixty-fifth embodiment, wherein the Bcl-xL inhibitor is represented by any one of the following:

[0651] Table A2

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.Definitions of the remaining variables are provided in the sixty-fifth embodiment or any embodiment described herein.

[0664] In the seventy-sixth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the forty-sixth to fiftieth embodiments, or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is represented by formula (IV) or formula (V):

[0665]

[0666] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0667] A1 represents a hydrogen or halogen atom, a linear or branched (C1-C6) polyhalogenated alkyl group, a linear or branched (C1-C6) alkyl group or a cycloalkyl group,

[0668] A2 represents a linear or branched (C1-C6) alkyl group, which is optionally substituted by a group selected from the group consisting of halogen, hydroxy, linear or branched (C1-C6) alkoxy, NR'R" and morpholine, or A2 represents a linear or branched (C1-C6) polyhalogenated alkyl group or a cyclopropyl group,

[0669] It is understood that R' and R" each independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0670] T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a (C1-C4)alkyl-NR1R2 group or a (C1-C4)alkyl-OR6 group,

[0671] R1 and R2 each independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0672] or R1 and R2 form a heterocycloalkyl group with the nitrogen atom carrying it,

[0673] R3 represents an aryl or heteroaryl group, it being understood that one or more carbon atoms of the aforementioned groups or their possible substituents may be deuterated,

[0674] R4 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 aforementioned groups or their possible substituents may be deuterated,

[0675] R5 represents a hydrogen or halogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched (C1-C6) alkoxy group,

[0676] R6 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0677] R a and R d Each represents a hydrogen atom and (R b ,R c ) together with the carbon atom carrying it forms 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,

[0678] or R a and R d Each represents a hydrogen atom, R b represents a hydrogen or halogen atom and R c represents a hydroxyl or methoxy group, or: R a and R d Each represents a hydrogen atom, R b represents a hydroxyl or methoxy group and R c represents a halogen atom, or

[0679]

[0680] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein:

[0681] Z1 and Z2 both represent methyl groups, or they form together with the atoms carrying them a fused piperidine group,

[0682] T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a (C1-C4)alkylene-NR1R2 group, a (C1-C4)alkylene-OR i Group,

[0683] R1 and R2 independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0684] or R1 and R2 together with the nitrogen atom carrying them form a heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups and halogen atoms,

[0685] R3 represents a group selected from the following:

[0686]

[0687] R4 represents a group selected from the following:

[0688]

[0689] R5 represents a hydrogen atom, a halogen atom or a hydroxyl group,

[0690] R6 represents hydrogen, a linear or branched (C1-C6) alkyl group or a halogen atom,

[0691] Alk represents a linear or branched (C1-C6) alkyl group,

[0692] A1 represents C-Y4 or a nitrogen atom,

[0693] A2 represents CH or a nitrogen atom,

[0694] Cy1 represents a phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group, wherein the phenyl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxyl group, a cycloalkyl group and a halogen atom, and a heterocycloalkyl group is optionally further substituted by an oxo group,

[0695] Cy2 represents a phenyl or heteroaryl group, wherein the phenyl and heteroaryl groups are optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxyl group and a halogen atom,

[0696] X represents a bond, -O-, -S- or NR k ,

[0697] Y1 and Y5 independently represent a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched (C1-C6) alkyl group and a linear or branched (C1-C6) alkoxy group,

[0698] Y2 and Y4 independently represent a group selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group and a heterocycloalkyl group optionally substituted by a linear or branched (C1-C6) alkyl group,

[0699] Y3 represents a group selected from the following: a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkynyl group, -(C1-C4) alkylene group, l , linear or branched (C1-C6) alkoxy group, -O-phenyl, -S-phenyl, -O-(C1-C4) alkylene-Cy3, -O-(C1-C4) alkylene-Cy4, -O-Cy3, -O-(C1-C4) alkylene-NR g R h , -(C1-C4)alkylene-Cy3, -(C1-C4)alkylene-Cy4, Cy3, Cy4, and:

[0700]

[0701] The alkylene portion of the aforementioned group may be straight chain or branched,

[0702] Cy3 represents a heterocycloalkyl group optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group, a hydroxyl group, a cycloalkyl group, a heterocycloalkyl group and a halogen atom optionally substituted by 1 to 3 halogen atoms,

[0703] Cy4 represents a cycloalkyl group optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group, a hydroxyl group, a cycloalkyl group, a heterocycloalkyl group and a halogen atom optionally substituted by 1 to 3 halogen atoms,

[0704] R a and R b independently of one another represent a hydrogen atom or a halogen atom,

[0705] R c represents a group selected from the group consisting of hydrogen, linear or branched (C1-C6)alkyl optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NR d R e 、(C1-C6)alkylene-OR j , cycloalkyl, heterocycloalkyl and (C1-C6)alkylene-heterocycloalkyl groups,

[0706] R' c and R” c independently of one another represent a hydrogen atom or a linear or branched (C1-C6) alkyl group,

[0707] R d and R e independently of one another represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, a cycloalkyl group or a heterocycloalkyl group,

[0708] R f represents a hydrogen atom, a halogen atom or a cyano group,

[0709] R' f represents a hydrogen atom or a halogen atom,

[0710] R g and R h independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a cycloalkyl group, a heterocycloalkyl group or a -(C1-C6)alkylene-heterocycloalkyl group,

[0711] R i 、R j and R k independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or a -(C1-C6)alkylene-cycloalkyl group,

[0712] R l represents a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched (C1-C6) alkylene-heterocycloalkyl group,

[0713] R m represents hydrogen or a linear or branched (C1-C6) alkyl group.

[0714] Definitions for the remaining variables are provided in the forty-sixth through fiftieth embodiments, or any embodiment described herein.

[0715] In some embodiments, it is understood that:

[0716] "Aryl" means phenyl, naphthyl, biphenyl or indenyl,

[0717] "Heteroaryl" means any monocyclic or bicyclic radical consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogen),

[0718] "Cycloalkyl" means any monocyclic or bicyclic, non-aromatic carbocyclic group containing from 3 to 10 ring members.

[0719] "Heterocycloalkyl" means any monocyclic or bicyclic, non-aromatic, fused or spirocyclic group consisting of 3 to 10 ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur, SO, SO2 and nitrogen, and

[0720] Aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be defined as such, and the groups alkyl, alkenyl, alkynyl and alkoxy may be substituted by 1 to 3 groups selected from the group consisting of linear or branched (C1-C6)alkyl, (C3-C6)spirocycle, 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.

[0721] In the seventy-seventh embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is represented by formula (IV), or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing. Definitions of the remaining variables are provided in the seventy-sixth embodiment or any embodiment described herein.

[0722] In the seventy-eighth embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth or seventy-seventh embodiment, wherein, in formula (IV), (i) A1 represents a hydrogen atom or a methyl group; or (ii) A1 and A2 both represent methyl groups. The definitions of the remaining variables are provided in the seventy-sixth or seventy-seventh embodiment, or any embodiment described herein.

[0723] In the seventy-ninth embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth to seventy-eighth embodiments, wherein in formula (IV), T represents a 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 trifluoromethyl group. The definitions of the remaining variables are provided in the seventy-sixth to seventy-eighth embodiments or any embodiment described herein.

[0724] In the eightieth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the seventy-sixth to seventy-ninth embodiments, wherein, in formula (IV), R3 represents a group selected from the group consisting of 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, Pyridine, 5H-pyrrolo[3,2-d]pyrimidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole and pyrazolo[1,5-a]pyrimidine, these groups optionally have one or more substituents selected from the following: halogen, linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, -CO-O-CH3, trideuteromethyl, 2-(morpholin-4-yl)ethyl and 2-(morpholin-4-yl)ethoxy. The definitions of the remaining variables are provided in the seventy-sixth to seventy-ninth embodiments or any embodiment described herein.

[0725] In the eighty-first embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, wherein the Bcl-2 inhibitor is represented by formula (V), or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing. Definitions of the remaining variables are provided in the seventy-sixth embodiment or any embodiment described herein.

[0726] In the eighty-second embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, wherein the Bcl-2 inhibitor is represented by formula (Va):

[0727]

[0728] or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.Definitions of the remaining variables are provided in the seventy-sixth embodiment or any embodiment described herein.

[0729] In the eighty-third embodiment, the present disclosure provides the antibody-drug conjugate of the eighty-first or eighty-second embodiment, wherein R3 in formula (V) or (Va) represents the following group:

[0730]

[0731] and R c represents a group selected from the group consisting of hydrogen, linear or branched (C1-C6)alkyl optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NR d Re 、(C1-C6)alkylene-OR j , cycloalkyl, heterocycloalkyl, and (C1-C6)alkylene-heterocycloalkyl groups. Definitions of the remaining variables are provided in the eighty-first or eighty-second embodiment, or any embodiment described herein.

[0732] In the eighty-fourth embodiment, the present disclosure provides the antibody-drug conjugate of the eighty-third embodiment, wherein R c represents a methyl group. Definitions for the remaining variables are provided in the eighty-third embodiment or any embodiment described herein.

[0733] In the eighty-fifth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the eighty-first to eighty-third embodiments, wherein R4 in formula (V) or (Va) represents the following group:

[0734]

[0735] Definitions for the remaining variables are provided in the eighty-first through eighty-third embodiments, or any embodiment described herein.

[0736] In the eighty-sixth embodiment, the present disclosure provides the antibody-drug conjugate of the eighty-first embodiment, wherein the Bcl-2 inhibitor is represented by formula (Vb):

[0737]

[0738] or an enantiomer, diastereomer, and / or pharmaceutically acceptable salt of any of the foregoing.Definitions of the remaining variables are provided in the eighty-first embodiment or any embodiment described herein.

[0739] In the eighty-seventh embodiment, the present disclosure provides the antibody-drug conjugate of the eighty-sixth embodiment, wherein R in formula (Vb) c represents a methyl group. Definitions for the remaining variables are provided in the eighty-sixth embodiment or any embodiment described herein.

[0740] In the eighty-eighth embodiment, the present disclosure provides the antibody-drug conjugate of the eighty-first embodiment, wherein the Bcl-2 inhibitor is represented by formula (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj):

[0741]

[0742]

[0743]

[0744] or an enantiomer, diastereomer, and / or pharmaceutically acceptable salt of any of the foregoing.Definitions of the remaining variables are provided in the eighty-first embodiment or any embodiment described herein.

[0745] In the eighty-ninth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the eighty-first to eighty-eighth embodiments, wherein in Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj):

[0746] (i) X represents a bond;

[0747] (ii) A1 represents C-Y4;

[0748] (iii)R a and R b All represent hydrogen atoms;

[0749] (iv) R5 represents a hydrogen atom, a hydroxyl group or a fluorine atom, preferably a hydroxyl group;

[0750] (v) R6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom;

[0751] (vi) A1 represents CH and Y2 represents a hydrogen atom;

[0752] (vii) Y1 and Y5 both represent a hydrogen atom, or: Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively;

[0753] (viii) Y3 represents an -O-(C1-C6)alkylene-heterocycloalkyl group or an -O-(C1-C4)alkylene-Cy3 group;

[0754] (ix) Y3 represents a group selected from the group consisting of 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]hept-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]dec-9-yl}ethoxy ethoxy, 2-{4-oxa-7-azaspiro[2.5]oct-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)prop-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy, 2-(3-methylmorpholin-4-yl)ethoxy, 2-(1,4-dioxan-2-yl)ethoxy;

[0755] (x) Group:

[0756]

[0757] (xi) T represents a linear or branched (C1-C6)alkyl group or a (C1-C4)alkylene-NR1R2 group; and / or

[0758] (xii) T represents a group selected from the group consisting of a methyl group, a (piperidin-1-yl)methyl group, a (morpholin-4-yl)methyl group, a (piperidin-1-yl)ethyl group, a [(3R)-3-fluoropyrrolidin-1-yl]methyl group, a (4-fluoropiperidin-1-yl)methyl group, a [methyl(propan-2-yl)amino]methyl group, a (azepan-1-yl)methyl group, a (pyrrolidin-1-yl)methyl group, a [(3S)-3-methylpiperidin-1-yl]methyl group, a [(3R)-3-methylpiperidin-1-yl]methyl group, a [(1RS,5SR)-3-azabicyclo[3.1.0]hexan-3-yl]methyl group, a [(2S)-2-methylpiperidin-1-yl]methyl group, a {6-azaspiro[2.5] ]heptan-2-ylmethyl, 2-azaspiro[3.3]hept-2-ylmethyl, and aminomethyl. The definitions of the remaining variables are provided in the eighty-first to eighty-eighth embodiments or any embodiment described herein.

[0759] In some embodiments, for the antibody-drug conjugate of the eighty-eighth embodiment, the Bcl-2 inhibitor is represented by Formula (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj), wherein:

[0760] (i) X represents a bond;

[0761] (ii) A1 represents C-Y4;

[0762] (iii)R a and R b All represent hydrogen atoms;

[0763] (iv) R5 represents a hydrogen atom, a hydroxyl group or a fluorine atom, preferably a hydroxyl group;

[0764] (v) R6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom;

[0765] (vi) A1 represents CH and Y2 represents a hydrogen atom;

[0766] (vii) Y1 and Y5 both represent a hydrogen atom, or: Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively;

[0767] (viii) Y3 represents an -O-(C1-C6)alkylene-heterocycloalkyl group;

[0768] (ix) Y3 represents a group selected from the group consisting of 2-(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]dec-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, 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)prop-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy and [(oxan-4-yl)methoxy]methyl;

[0769] (x) Group:

[0770]

[0771] (xi) T represents a linear or branched (C1-C6)alkyl group or a (C1-C4)alkylene-NR1R2 group; and / or

[0772] (xii) T represents a group selected from the group consisting of 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]hexan-3-yl]methyl, [(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.

[0773] In some embodiments, in Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj), R5 represents a hydroxyl group and R6 represents a hydrogen atom. In some embodiments, in Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj), Y3 represents an -O-(C1-C4)alkylene-Cy3 group.

[0774] In the ninetieth embodiment, the present disclosure provides the antibody-drug conjugate of the seventy-sixth embodiment, wherein the Bcl-2 inhibitor is represented by any one of the following or a pharmaceutically acceptable salt thereof:

[0775] Table A3

[0776]

[0777]

[0778]

[0779] Definitions for the remaining variables are provided in the seventy-sixth embodiment or any embodiment described herein.

[0780] In some embodiments, the present disclosure provides the antibody-drug conjugate described in any one of the first to forty-sixth, forty-ninth, fifty-first to ninetieth embodiments, wherein the topoisomerase 1 inhibitor is represented by any one of the following formulae or a pharmaceutically acceptable salt thereof:

[0781] Table A4

[0782]

[0783] Definitions for the remaining variables are provided in any of the first to forty-sixth, forty-ninth, fifty-first, or ninetieth embodiments, or any embodiment described herein.

[0784] In some embodiments, the present disclosure provides the antibody-drug conjugate of any one of the first to forty-sixth, forty-ninth, fifty-first to ninetyth embodiments, wherein the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane. The definitions of the remaining variables are provided in any one of the first to forty-sixth, forty-ninth, fifty-first, or ninetieth embodiments, or any embodiment described herein. In some embodiments, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

[0785] In the ninety-first embodiment, the disclosure provides the antibody-drug conjugate of any one of the first to ninetieth embodiments, wherein the antibody or antigen-binding fragment thereof binds to a target antigen on a cancer cell. The definitions of the remaining variables are provided in the first to ninetieth embodiments or any embodiment described herein.

[0786] In the ninety-second embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein:

[0787] (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;

[0788] (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

[0789] (iii) The target antigen is MET, CD48, CD74, EphA2, PCAD, TROP2, B7-H3, or 5T4 or HER2.

[0790] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0791] In the ninety-third embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment having the CDR sequence is selected from those in Tables D3 and D8, or the antibody or antigen-binding fragment having the variable region is selected from those in Tables D2 and D8, or the antibody or antigen-binding fragment having the full length is selected from those in Tables D4, D5, and D7. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0792] In the ninety-fourth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0793] 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, and 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;

[0794] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and 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;

[0795] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, and 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;

[0796] 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and 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;

[0797] 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, and 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;

[0798] 6) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174;

[0799] 7) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 267, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and

[0800] 8) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174.

[0801] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0802] In the ninety-fifth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 variables are provided in the ninety-first embodiment.

[0803] In the ninety-sixth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD74 antibody comprising:

[0804] (a) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237;

[0805] (b) the heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence at least 95% identical to SEQ ID NO: 236, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; or

[0806] (c) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 239, or a sequence at least 95% identical to SEQ ID NO: 239.

[0807] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0808] In the ninety-seventh embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0809] 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;

[0810] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 274, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 275, and 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;

[0811] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 276, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, and 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;

[0812] 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

[0813] 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:51, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:52, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:53; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:54, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:55, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:56.

[0814] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0815] In the ninety-eighth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 variables are provided in the ninety-first embodiment.

[0816] In the ninety-ninth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 243 or a sequence 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 at least 95% identical to SEQ ID NO: 242, and a light chain amino acid sequence of SEQ ID NO: 243 or a sequence at least 95% identical to SEQ ID NO: 243; (c) a heavy chain amino acid sequence of SEQ ID NO: 240 or a sequence at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 69 or a sequence at least 95% identical to SEQ ID NO: 70. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0817] In the one hundredth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the following:

[0818] 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, and 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;

[0819] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 292, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, and 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;

[0820] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 293, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 294, and 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

[0821] 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:39, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:40, and 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.

[0822] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0823] In the one hundred and first embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 variables are provided in the ninety-first embodiment.

[0824] In the one hundred and second embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 having at least 95% identity with SEQ ID NO: 245, and a light chain amino acid sequence of SEQ ID NO: 66 or a sequence having at least 95% identity with SEQ ID NO: 66. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0825] In the one hundred and third embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0826] 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, and 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;

[0827] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 307, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, and 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;

[0828] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 309, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, and 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

[0829] 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 310, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, and 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.

[0830] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0831] In the one hundred and fourth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 variables are provided in the ninety-first embodiment.

[0832] In the one hundred and fifth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 at least 95% identical to SEQ ID NO: 248, and a light chain amino acid sequence of SEQ ID NO: 250, or a sequence at least 95% identical to SEQ ID NO: 250. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0833] In the one hundred and sixth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0834] 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 319, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 320, and 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;

[0835] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 322, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, and 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;

[0836] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 325, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 326, and 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

[0837] 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; 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.

[0838] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0839] In the one hundred and seventh embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 variables are provided in the ninety-first embodiment.

[0840] In the one hundred and eighth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first 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 at least 95% identical to SEQ ID NO: 252, and a light chain amino acid sequence of SEQ ID NO: 254, or a sequence at least 95% identical to SEQ ID NO: 254. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0841] In the one hundred and ninth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0842] 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 349, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 350, and 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;

[0843] 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 355, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 356, and 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

[0844] 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 361, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 362, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 363; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 364, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 365, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 366. Definitions of the remaining variables are provided in the ninety-first embodiment.

[0845] In the one hundred and tenth embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising a heavy chain variable region and a light chain variable region selected from the group consisting of:

[0846] 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;

[0847] 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

[0848] 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.

[0849] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0850] In the one hundred eleventh embodiment, the present disclosure provides the antibody-drug conjugate of the ninety-first embodiment, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising a heavy chain and a light chain selected from the group consisting of:

[0851] 1) a heavy chain amino acid sequence of SEQ ID NO: 367, or a sequence at least 95% identical to SEQ ID NO: 367, and a light chain amino acid sequence of SEQ ID NO: 368, or a sequence at least 95% identical to SEQ ID NO: 368;

[0852] 2) the heavy chain amino acid sequence of SEQ ID NO: 369, or a sequence at least 95% identical to SEQ ID NO: 369, and the light chain amino acid sequence of SEQ ID NO: 370, or a sequence at least 95% identical to SEQ ID NO: 370;

[0853] 3) the heavy chain amino acid sequence of SEQ ID NO: 371, or a sequence at least 95% identical to SEQ ID NO: 371, and the light chain amino acid sequence of SEQ ID NO: 372, or a sequence at least 95% identical to SEQ ID NO: 372;

[0854] 4) the heavy chain amino acid sequence of SEQ ID NO: 373, or a sequence at least 95% identical to SEQ ID NO: 373, and the light chain amino acid sequence of SEQ ID NO: 374, or a sequence at least 95% identical to SEQ ID NO: 374;

[0855] 5) the heavy chain amino acid sequence of SEQ ID NO: 375, or a sequence at least 95% identical to SEQ ID NO: 375, and the light chain amino acid sequence of SEQ ID NO: 370, or a sequence at least 95% identical to SEQ ID NO: 370; and

[0856] 6) the heavy chain amino acid sequence of SEQ ID NO: 376, or a sequence at least 95% identical to SEQ ID NO: 376, and the light chain amino acid sequence of SEQ ID NO: 372, or a sequence at least 95% identical to SEQ ID NO: 372.

[0857] Definitions of the remaining variables are provided in the ninety-first embodiment.

[0858] In the one hundred twelfth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the one hundred ninth to one hundred eleventh embodiments, wherein both anti-tumor payloads are Bcl-xL inhibitors.

[0859] In the 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 of the heavy chain of the antibody or antigen-binding fragment thereof, wherein positions are numbered according to the EU system. Definitions of the remaining variables are provided in the 94th to 112th embodiments.

[0860] In the one hundred and fourteenth embodiment, the present disclosure provides the antibody-drug conjugate of any one of the ninety-fourth to one hundred and twelfth embodiments, wherein the antibody or antigen-binding fragment thereof comprises one or more Fc silent mutations. The definitions of the remaining variables are provided in the ninety-fourth to one hundred and twelfth embodiments.

[0861] In some embodiments, the present disclosure provides, in part, novel antibody-drug conjugate (ADC) compounds with biological activity against cancer cells. The compounds can delay, inhibit and / or reverse tumor growth in mammals, and / or can be used to treat human cancer patients. In some embodiments, the present disclosure is more specifically directed to ADC compounds that can bind to and kill cancer cells. In some embodiments, the ADC compounds disclosed herein comprise a dual linker that attaches two BH3 mimetics to a full-length antibody or antigen-binding fragment. In some embodiments, the ADC compound can also be internalized into a target cell after binding.

[0862] In some embodiments, in the ADC compounds disclosed herein (e.g., ADCs of Formula (A), (B), (C), (D1), (D2), or (D3) in the present disclosure), D 1 and / or D 2 Independently comprising a formula selected from any one of the formulas in Table A1a, or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

[0863] Table A1a

[0864]

[0865]

[0866]

[0867] Wherein -* represents a bond to a linker.

[0868] In some embodiments, in the ADC compounds disclosed herein (e.g., ADCs of Formula (A), (B), (C), (D1), (D2), or (D3) in the present disclosure), D 1 and / or D 2 Independently comprising a formula selected from any one of the formulas in Table A2a, or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any one of the foregoing.

[0869] Table A2a

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] Wherein -* represents a bond to a linker.

[0882] In some embodiments, in the ADC compounds disclosed herein (e.g., ADCs of Formula (A), (B), (C), (D1), (D2), or (D3) in the present disclosure), D 1 and / or D 2 Independently comprising a formula selected from any one of the formulas in Table A3a, or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any one of the foregoing.

[0883] Table A3a

[0884]

[0885]

[0886]

[0887]

[0888] Wherein -* represents a bond to a linker.

[0889] In some embodiments, in the ADC compounds disclosed herein (e.g., ADCs of Formula (A), (B), (C), (D1), (D2), or (D3) in the present disclosure), D 1 and / or D 2 Independently comprising a formula selected from any one of the formulas in Table A4a, or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any one of the foregoing.

[0890] Table A4a

[0891]

[0892] Wherein -* represents a bond to a linker.

[0893] In some embodiments, It is formed from a compound selected from Table B or an enantiomer, diastereomer and / or pharmaceutically acceptable salt thereof. In some embodiments, the maleimide group in the compound of Table B with an antibody or its antigen-binding fragment (Ab) to form a Part of the ADC compound of formula (A), wherein * represents the point of attachment to Ab. For the compounds in Table A1, Table A2, Table A3, Table B and Table C, these compounds may contain a pharmaceutically acceptable monovalent anionic counterion M1 according to their charge. - In some embodiments, the monovalent anionic counterion M1 - M1 can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, formate, etc. In some embodiments, the monovalent anionic counterion M1 - It is trifluoroacetate or formate.

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944] The ADCC described above can also be expressed as follows:

[0945]

[0946] in represents an antibody or antigenic fragment thereof covalently linked to a linker-payload (L / P) as described 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).

[0947] In some embodiments, for the ADCs described in Table C, the antibody is an antibody described herein or an antigenic fragment thereof. In some embodiments, the antibody is an anti-HER2 antibody (e.g., trastuzumab, vedicizumab, or Ab T). In some embodiments, the antibody is an anti-CD74 antibody (e.g., VHmil x VK1aNQ or miratumumab). 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., dedabotulinumab). 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.

[0948] As used herein, "PLP" refers to a linker-payload, a linker-drug, or a linker-compound disclosed herein and the term "P#-L#-P#" refers to a specific dual linker-drug disclosed herein, wherein each code "P#" refers to a specific anti-tumor compound (e.g., a BH3 mimetic) unless otherwise indicated, and L# refers to a specific dual linker unless otherwise indicated. The two "P#" codes can be the same or different, i.e., refer to the same or different anti-tumor compounds (e.g., BH3 mimetics). 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, diastereomers, atropisomers, deuterated derivatives, and / or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, for example, when the linker L1 is asymmetric, the terms "P1-L1-P2" and "P2-L1-P1" refer to two different linker-drugs. In the present disclosure, "L#-P#" refers to a specific single linker-drug disclosed herein. For example, "L1-P1" refers to a linker-payload compound having a single linker L1 attached to one P1 payload.

[0949] 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, α-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, SPAPIB, SPAP IC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP 1, STEAP2, STMP, prostate cancer associated gene 1, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M member 4), TWEAK-R, TYRP 1 (glycoprotein 75), VEGF, VEGF-A, EGFR-1, 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.

[0950] 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. WO2018 / 098306, WO2016 / 179257, WO2011 / 097627, WO2017 / 214282, WO2017 / 214301, WO2017 / 214233, WO2013 / 126810, WO2008 / 056833, WO2020 / 236817, WO2017 / 214335, and WO2012147713, and in U.S. Patent No. US6870034B2, the entire contents of which are incorporated by reference.

[0951] 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 antibodies or antigen binding fragments comprising one or more SEQ IDs listed in Tables D2-D5, D7, and D8 disclosed herein.

[0952] In some embodiments, the present invention also provides a composition comprising multiple copies of an antibody-drug conjugate (e.g., any exemplary antibody-drug conjugate described herein). In some embodiments, the average p of the antibody-drug conjugate in the composition is from about 2 to about 4.

[0953] Also provided herein, in some embodiments, are pharmaceutical compositions comprising an antibody-drug conjugate (e.g., any exemplary antibody-drug conjugate described herein) or a composition (e.g., any exemplary composition described herein) and a pharmaceutically acceptable carrier.

[0954] In some embodiments, the present disclosure further provides methods for treating cancer (e.g., cancers expressing antigens targeted by antibodies or antigen-binding fragments of ADCs, such as PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4). In some embodiments, the present disclosure provides methods for reducing or slowing the proliferation of cancer cell populations in subjects. In some embodiments, the present disclosure provides methods for determining whether a subject suffering from or suspected of having cancer will respond to treatment with an ADC compound or composition disclosed herein.

[0955] An exemplary embodiment is a method for treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition 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, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, BrevicanBCAN, 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 subtype), 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 (episome receptor type B), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAPIC), fibronectin extradomain B, frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 hematological 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0956] Another exemplary embodiment is a method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition 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 subtype), 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, SPAP IB, SPAP II), SPAP IIIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCAhlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP 1, STEAP2, STMP, prostate cancer associated gene 1, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M member 4), TWEAK-R, TYRP 1 (glycoprotein 75), VEGF, VEGF-A, EGFR-1, 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, gastric cancer, colon cancer, head and neck cancer, or spleen cancer. In some embodiments, the tumor is gastric cancer. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0957] Another exemplary embodiment is a method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition 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, α-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, BrevicanBCAN, 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 subtype), 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, SPAPIB, SPAPIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 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, 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, gastric 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 an antibody-drug conjugate, composition, or pharmaceutical composition reduces cancer cell populations by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, administration of an antibody-drug conjugate, composition, or pharmaceutical composition reduces cancer cell population expansion 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%.

[0958] Another exemplary embodiment is an antibody-drug conjugate, composition or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition or pharmaceutical composition disclosed herein) for treating a subject suffering from 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 subtype), 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, SPAP IB, SPAP II), SPAP IIIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 hematological 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0959] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition disclosed herein) in treating a subject suffering from 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 subtype), 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, SPAP IB, SPAP II), SPAP IIIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 hematological 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0960] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition disclosed herein) in a method for preparing a drug for treating a subject suffering from 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 subtype), 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, SPAPIB, SPAPIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, SemaSb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 hematological 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0961] Another exemplary embodiment is a method of determining whether a subject having or suspected of having cancer will respond to treatment with an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any exemplary antibody-drug conjugate, composition, or pharmaceutical composition disclosed herein) by providing a biological sample from the subject; contacting the sample with an antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample. In some embodiments, 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, α-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 subtype), 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, SPAPIB, SPAPIC), fibronectin extradomain 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, prostaglandin-specific membrane antigen, PSCA (prostaglandin stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, SemaSb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer-related genes I, TAG-72, TEMI, tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, 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 hematological cancer. In some embodiments, 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, lymphatic system malignancy in 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, cancer is lymphoma or gastric cancer. In some embodiments, sample is tissue biopsy sample, blood sample or bone marrow sample.

[0962] The present invention also discloses methods for producing the ADC compounds and compositions. One exemplary embodiment is a method for producing an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a dual linker that is linked or covalently attached to two anti-tumor compounds, wherein at least one anti-tumor compound is a BH3 mimetic (e.g., two BH3 mimetics or one BH3 mimetic and one non-BH3 mimetic (e.g., a topoisomerase 1 inhibitor)) under permissive conjugation conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0963] Figure 1 Shown are the tumor volumes (mm) of H929-implanted female SCID mice after treatment with IgG1-CysmAb Fc-silencing_P1-L19-P2, anti-CD48MEM_CysmAb Fc-silencing, and anti-CD48MEM_CysmAb Fc-silencing_P1-L19-P2, administered once IV at 30 mg / kg. 3 )(n=8).

[0964] Figure 2Shown are the % body weight loss of H929-engrafted female SCID mice (n=8) after treatment with IgG1-CysmAb Fc-silencing_P1-L19-P2, anti-CD48MEM_CysmAb Fc-silencing, anti-CD48MEM_CysmAb Fc-silencing_P1-L19-P2, administered once IV at 30 mg / kg.

[0965] Figure 3 Shown are the tumor volumes (mm) of H929-engrafted female SCID mice after treatment with IgG1-CysmAb Fc WT_P1-L19-P2, anti-CD48MEM_CysmAb Fc WT_P1-L19-P2, anti-CD48MEM_CysmAb Fc WT_P1-L29-P2, anti-CD48MEM_CysmAb Fc WT_P2-L29-P1, anti-CD48MEM_CysmAb Fc WT_P1-L31-P2, anti-CD48MEM_CysmAb Fc WT_P1-L32-P2, and anti-CD48MEM_CysmAb Fc WT_P1-L30-P2, administered once at 30 mg / kg IV. 3 )(n=6).

[0966] Figure 4 Shown are the body weights of H929-engrafted female SCID mice (n=6) after treatment with IgG1-CysmAb Fc WT_P1-L19-P2, anti-CD48MEM_CysmAb Fc WT_P1-L19-P2, anti-CD48MEM_CysmAb Fc WT_P1-L29-P2, anti-CD48MEM_CysmAb Fc WT_P2-L29-P1, anti-CD48MEM_CysmAb Fc WT_P1-L31-P2, anti-CD48MEM_CysmAb Fc WT_P1-L32-P2, and anti-CD48MEM_CysmAb Fc WT_P1-L30-P2, administered once IV at 30 mg / kg.

[0967] Figure 5 Shown are the tumor volumes (mm) of KMS-21-BM-transplanted female NSG mice after treatment with IgG1-CysmAb Fc-silenced_P1-L29-P2, anti-CD48MEM_CysmAb Fc-silenced, and anti-CD48MEM_CysmAb Fc-silenced_P1-L29-P2, administered once IV. 3 )(n=6).

[0968] Figure 6Shown are the body weights of KMS-21-BM transplanted female NSG mice (n=6) after treatment with IgG1-CysmAb Fc-silencing_P1-L29-P2, anti-CD48MEM_CysmAb Fc-silencing, and anti-CD48MEM_CysmAb Fc-silencing_P1-L29-P2, administered once IV.

[0969] Figure 7 Shown are tumor volumes (mm) of KMS27-implanted female NSG mice after treatment with IgG1-CysmAb Fc-silencing_P1-L19-P2, anti-CD48MEM102-CysmAb Fc-silencing, and anti-CD48MEM102-CysmAb Fc-silencing_P1-L19-P2, administered once IV at 10 and / or 30 mg / kg. 3 )(n=6).

[0970] Figure 8 Shown are body weights of KMS27-transplanted female NSG mice (n=6) after treatment with IgG1-CysmAb Fc-silencing_P1-L19-P2, anti-CD48MEM102_CysmAb Fc-silencing, and anti-CD48MEM102_CysmAb Fc-silencing_P1-L19-P2, administered once IV at 10 and / or 30 mg / kg.

[0971] Figure 9 is a graph showing dose response curves of three ADCs - datubulumab-P5-L12-P7, datubulumab-mono-L1-P5, and datubulumab-mono-L3-P8 - in the NCI-H441 cell line.

[0972] Figure 10A is a graph showing dose response curves of 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.

[0973] Figure 10B is a graph showing dose response curves of four ADCs - trastuzumab-mono-L3-P8, dicetuzumab-mono-L1-P5, dicetuzumab-mono-L3-P8, and dicetuzumab-P5-L12-P7 - in the UACC-812 cell line.

[0974] Figure 11 is a graph showing dose response curves of three ADCs - NY920-P5-L12-P4, NY920-mono-L1-P4 and NY920-mono-L2-P5 - in the KMS-27 cell line.

[0975] Figure 12 is a graph showing dose response curves of three ADCs - VHmil xVK1aNQ-P5-L12-P4, VHmil xVK1aNQ-mono-L1-P4 and VHmil xVK1aNQ-mono-L2-P5 - in the EOL-1 cell line. DETAILED DESCRIPTION

[0976] The disclosed compositions and methods may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure.

[0977] Herein, descriptions relate to compositions and methods of using the compositions. When this disclosure describes or claims features or embodiments relating to compositions, such features or embodiments also apply to methods of using the compositions. Similarly, when this disclosure describes or claims features or embodiments relating to methods of using a composition, such features or embodiments also apply to the composition.

[0978] When expressing a range of values, it includes embodiments using any specific value within the range. In addition, references to values ​​specified in a range include each value within the range. All ranges are inclusive and combinable. When a value is expressed as an approximation by using the antecedent "about," it will be understood that the specific value forms another embodiment. Unless the context clearly indicates otherwise, references to a specific numerical value include at least that specific value. Unless the specific context of its use provides otherwise, the use of "or" will mean "and / or." For all purposes, all references cited herein are incorporated by reference. When a reference conflicts with the specification, the specification will prevail.

[0979] Unless the context of the description indicates otherwise, e.g., without a symbol indicating a particular point of attachment, when a structure or fragment of a structure is drawn, it may be used alone or attached to other components of the ADC, and it may do so in any orientation, e.g., an antibody attached to a chemical moiety, such as a linker-drug, at any suitable point of attachment. However, at designated locations, the components of the ADC are attached in the orientation shown in a given formula. For example, if formula (1) is described as And the group Described as Then the detailed structure of formula (1) is It is not Not really

[0980] It should be understood that certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments for purposes of clarity may also be provided in combination in a single embodiment. Conversely, different features of the disclosed compositions and methods that are described in the context of a single embodiment for purposes of brevity may also be provided separately or in any subcombination.

[0981] As used throughout this application, antibody-drug conjugates can be identified using the naming convention of the general formula "target antigen / antibody-payload-dual linker-payload". By way of example only, if an antibody drug conjugate is referred to as "target X-P1-L1-P2", such conjugate will contain 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 conjugate will contain 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 conjugate will contain 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 comprising a nonspecific isotype control antibody may be referred to as "isotype control IgG1-P1-L1-P2" or "IgG1-P1-L1-P2."

[0982] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 3 H. 11 C, 13 C. 14 C. 15 N. 18 F and 36 Cl. Thus, it is to be understood that the present disclosure encompasses the incorporation of one or more of any of the foregoing isotopes (including, for example, radioisotopes (e.g. 3 H and 14 C)) or compounds in which non-radioactive isotopes (e.g. 2 H and 13 C). Such isotope-labeled compounds can be used for metabolic studies (using 14 C), reaction kinetics studies (e.g. 2 H or 3H), 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 therapy for patients. In particular, 18 Compounds labeled with F or 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 an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0983] definition

[0984] Various terms related to various aspects of this specification are used throughout the specification and claims. Unless otherwise indicated, such terms shall have their ordinary meanings in the art. Other specifically defined terms will be interpreted in a manner consistent with the definitions provided herein.

[0985] As used herein, the singular forms "a," "an," and "the" include plural forms unless the context clearly indicates otherwise. Unless otherwise indicated, the terms "comprising," "having," and "having a chemical formula" are to be interpreted as open terms (i.e., meaning "including but not limited to"). In addition, whenever "comprising" or another open term is used in an embodiment, it should be understood that the intermediate term "consisting essentially of" or the closed term "consisting of" may be used to more narrowly claim the same embodiment.

[0986] When used in the context of numerical values ​​and ranges, the term "about" or "approximately" refers to a value or range that is approximately or close to the value or range described, so that the embodiment can be performed as expected, as will be apparent to those skilled in the art from the teachings contained herein. In some embodiments, approximately refers to a numerical value plus or minus 20%, 15%, 10%, 5%, 1%, 0.5% or 0.1%. In one embodiment, the term "about" refers to a value range that is 10% more or less than a specified value. In another embodiment, the term "about" refers to a value range that is 5% more or less than a specified value. In another embodiment, the term "about" refers to a value range that is 1% more or less than a specified value.

[0987] 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-tumor payload such as 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 is defined by the following general formula: Where Ab = antibody or antigen-binding fragment, L = double linker moiety, D 1 and D 2 = drug moiety (e.g., Mcl-1 inhibitor, Bcl-2 inhibitor, Bcl-xL inhibitor drug moiety), and a = each antibody or antigen-binding fragment has a D attached 1 and D 2 In ADCs comprising an anti-tumor payload (e.g., a BH3 mimetic moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug), "2a" refers to the number of anti-tumor payloads (e.g., a BH3 mimetic moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug) attached to the antibody or antigen-binding fragment.

[0988] 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 thereof, through at least one antigen recognition site within its variable region. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and can be derived from natural or recombinant sources. An "intact" antibody is a glycoprotein that typically comprises 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 comprises 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 hypervariable regions, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: 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 region of an 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 a complete antibody or an antigen-binding fragment thereof.

[0989] In some embodiments, antibodies or antibody fragments disclosed herein include modified or engineered amino acid residues, for example, one or more cysteine ​​residues, as sites for conjugation to a drug moiety (Junutula JR et al., Nat Biotechnol 2008, 26: 925-932). In one embodiment, the disclosure provides a modified antibody or antibody fragment comprising a substitution of one or more amino acids with cysteine ​​at a position as described herein. The cysteine ​​substitution site is located in the constant region of the antibody or antibody fragment and is therefore suitable for use in a variety of antibodies or antibody fragments, and these sites are selected to provide stable and uniform conjugates. The modified antibody or fragment may have one, two or more cysteine ​​substitutions, and these substitutions may be used in combination with other modifications and conjugation methods as described herein. Methods for inserting cysteine ​​at specific positions of antibodies are known in the art, see, for example, 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 substitution of one or more amino acids on its constant region with cysteine ​​selected from the group consisting of: 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 heavy chain of the antibody, and wherein these 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 ​​on its constant region selected from the following positions: 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, wherein positions are numbered according to the EU system, and wherein 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 ​​on its constant region, wherein the combination comprises 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, and wherein these 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, wherein the substitution is at position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, position 107 of the antibody light chain, position 165 of the antibody light chain, or position 159 of the antibody light chain, and wherein the positions are numbered according to the EU system, and wherein the light chain is a kappa chain. In a specific embodiment, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two amino acids with cysteine ​​in its constant region, wherein the combination comprises substitutions at position 375 of the antibody heavy chain and position 152 of the antibody heavy chain, wherein the positions are numbered according to the EU system. In a specific embodiment, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​at position 360 of the antibody heavy chain, wherein 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 cysteine ​​at position 107 of the antibody light chain, wherein the positions are numbered according to the EU system, and wherein the light chain is a kappa chain.

[0990] As used herein, the term "antibody fragment" or "antigen binding fragment" or "functional antibody fragment" refers to at least a portion of an antibody that retains the ability to specifically interact with an antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3 or 5T4) epitope (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution). The antigen binding fragment may also retain the ability to be internalized into antigen-expressing cells. In some embodiments, the antigen binding fragment also retains immune effector activity. The terms antibody, antibody fragment, antigen binding fragment, etc. are intended to cover the use of binding domains from antibodies 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 full-length antibodies. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fv (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (VL or VH), Camelidae VHH domains, multispecific antibodies formed from antibody fragments (e.g., a bivalent fragment comprising two Fab fragments linked by a disulfide bond 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 transplanted into scaffolds based on polypeptides such as type III fibronectin (Fn3) (see U.S. Patent No. 6,703,199, which describes fibronectin polypeptide miniantibodies). The term "scFv" refers to a fusion protein comprising at least one antigen binding fragment comprising a light chain variable region and at least one antigen binding fragment comprising a heavy chain variable region, wherein the light chain and heavy chain variable regions are continuously connected, for example, via a synthetic linker (e.g., a short flexible polypeptide linker) and can be expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the complete antibody from which it is derived. Unless otherwise indicated, scFv can have VL and VH variable regions in any order (e.g., relative to the N-terminus and C-terminus of the polypeptide), and the scFv can comprise VL-linker-VH or can comprise VH-linker-VL. Antigen binding fragments are obtained using conventional techniques known to those skilled in the art, and the utility of the binding fragments (e.g., binding affinity, internalization) is screened in the same manner as for complete antibodies. For example, antigen binding fragments can be prepared by cleavage of the complete protein, for example, by protease or chemical cleavage.

[0991] As used herein, the term "complementarity determining region" or "CDR" refers to the amino acid sequence within the variable region of an antibody that confers antigen specificity and binding affinity. For example, typically, there are 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 in Kabat et al., (1991) "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) J Mol Biol. 273(4):927-48 ("Chothia" numbering scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al., (2003) Dev Comp Immunol. 27(1):55-77 ("IMGT" numbering scheme); or a combination thereof. In 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 CDR corresponds to amino acid residues defined as part of a Kabat CDR and amino acid residues defined as part of a Chothia CDR. As used herein, CDRs defined according to the "Chothia" numbering scheme are sometimes also referred to as "hypervariable loops."

[0992] In some embodiments, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1) (e.g., one or more insertions after position 35), 50-65 (HCDR2), and 95-102 (HCDR3); the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) (e.g., one or more insertions after position 27), 50-56 (LCDR2), and 89-97 (LCDR3). In some embodiments, under Chothia, the CDR amino acid residues in VH are numbered 26-32 (HCDR1) (e.g., one or more insertions after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., one or more insertions after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, in some embodiments, the CDR comprises or consists of, for example, amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH or 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 as approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered as approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the program IMGT / DomainGap Align can be used to determine the CDR regions of an antibody.

[0993] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, that is, the individual antibodies comprising the population are consistent except for possible naturally occurring mutations present in trace amounts. Monoclonal antibodies are highly specific, directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include multiple antibodies directed against (or specifically against) different epitopes. The modifier "monoclonal" indicates the characteristics of an antibody obtained from a substantially homogeneous antibody population and should not be interpreted as requiring antibodies to be produced by any particular method. For example, the monoclonal antibody to be used according to the present disclosure can be prepared by the hybridoma method described first by Kohler et al., (1975) Nature 256:495, or by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques such as Clackson et al., (1991) Nature 352:624-8 and Marks et al., (1991) J Mol Biol. 222:581-97. The term also includes preparations of antibody molecules of single molecular composition.A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0994] The monoclonal antibodies described herein can be non-human, human or humanized. The term specifically includes "chimeric" antibodies, in which a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence derived from a particular class of antibodies or belonging to a particular antibody class or subclass, while the remainder of the chain or chains is identical or homologous to a corresponding sequence in an antibody derived from another class of antibodies or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as it specifically binds to the target antigen and / or exhibits the desired biological activity.

[0995] As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human. The term includes antibodies having variable regions in which both the framework and CDR regions are derived from human sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences, or mutated forms of human germline sequences or antibodies containing consensus framework sequences derived from analysis of human framework sequences, e.g., as described in Knappik et al., (2000) J Mol Biol. 296(1):57-86. The structure and position of immunoglobulin variable domains, e.g., CDRs, can be defined using well-known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and / or the ImMunoGenTics (IMGT) numbering scheme. 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 conservative substitution to improve stability or production). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, e.g., a mouse, have been grafted into human framework sequences.

[0996] As used herein, the term "recombinant human antibody" refers to a human antibody prepared, expressed, produced or isolated by recombinant means, such as an antibody isolated from an animal (e.g., a mouse) (the animal is transgenic or transchromosomal for human immunoglobulin genes) or a hybridoma prepared therefrom; an antibody isolated from a host cell transformed to express human antibodies (e.g., from a transfectoma); an antibody isolated from a recombinant combinatorial human antibody library; and an antibody prepared, expressed, produced or isolated by any other means (which involves splicing of all or part of human immunoglobulin genes, other DNA sequences). Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when a transgenic animal of a human Ig sequence is used, in vivo somatic mutagenesis is performed), and therefore, the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from and related to human germline VH and VL sequences, may not naturally occur in the human antibody germline library in vivo.

[0997] As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some cases, the variable regions of the heavy and light chains correspond to those 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., humans) to minimize the immune response in the latter species.

[0998] As used herein, the term "humanized antibody" refers to an antibody form comprising sequences from non-human (e.g., mouse) antibodies and human antibodies. Such antibodies are chimeric antibodies of a type, which contain the minimum sequence derived from non-human immunoglobulin (NII). Generally, humanized antibodies will include substantially all of at least one and typically two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin (NII), and all or substantially all of the framework (FR) regions are those of human immunoglobulin sequences. Humanized antibodies also optionally include at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin (HIG). Humanized antibodies can be further modified by replacing residues in the Fv framework region and / or in the non-human residues replaced to improve and optimize antibody specificity, affinity and / or activity.

[0999] As used herein, the term "Fc region" refers to a polypeptide comprising the CH3, CH2, and at least a portion of the hinge region of an antibody constant domain. Optionally, the Fc region may include the CH4 domain present in some antibody classes. The Fc region may comprise the entire hinge region of an antibody constant domain. In some embodiments, an antibody or antigen-binding fragment comprises the Fc region and CH1 region of an antibody. In some embodiments, an antibody or antigen-binding fragment comprises the CH3 region of the Fc region of an antibody. In some embodiments, an antibody or antigen-binding fragment comprises the Fc region, CH1 region, and kappa / lambda regions from an antibody constant domain. In some embodiments, an antibody or antigen-binding fragment comprises a constant region, such as a heavy chain constant region and / or a light chain constant region. In some embodiments, such constant regions are modified compared to wild-type constant regions. That is, a polypeptide may comprise alterations or modifications to one or more of the three heavy chain constant regions (CH1, CH2, or CH3) and / or the light chain constant region (CL). Exemplary modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such alterations may be included to optimize effector function, half-life, etc.

[1000] As used herein for antibodies or antigen binding fragments, "internalization" refers to that the antibody or antigen binding fragment can enter the internal compartment (i.e., "internalization") through the lipid bilayer membrane of the cell after binding to the cell, preferably into the degradation compartment in the cell. For example, internalization anti-HER2 antibodies are antibodies that can be taken into cells after binding to HER2 on the cell membrane. In some embodiments, the antibody or antigen binding fragment used in the ADC disclosed herein targets cell surface antigens (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) and is an internalization antibody or internalization antigen binding fragment (i.e., after antigen binding, ADC transfers through the cell membrane). In some embodiments, the internalization antibody or antigen binding fragment binds to receptors on the cell surface. Internalization antibodies or internalization antigen binding fragments targeting receptors on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalization antibody or internalization antigen binding fragment is taken into the cell by receptor-mediated endocytosis.

[1001] As used herein for antibodies or antigen-binding fragments, "non-internalizing" refers to antibodies or antigen-binding fragments that remain on the cell surface after binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADC disclosed herein targets cell surface antigens and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., ADC remains on the cell surface and does not transfer 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).

[1002] As used herein, the term "EPH receptor A2" or "EphA2" refers to any naturally occurring 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) as well as any form of human EphA2 that can be processed by cells. 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., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). EphA2 can be isolated from humans or produced recombinantly or by synthetic methods.

[1003] As used herein, the term "anti-EphA2 antibody" or "antibody that binds to EphA2" refers to any form of an antibody or antigen-binding fragment thereof that binds (e.g., specifically binds) to EphA2. 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 EphA2. WO 2007 / 030642 provides exemplary EphA2 binding sequences (including exemplary anti-EphA2 antibody sequences) and is incorporated herein by reference. In some embodiments, the anti-EphA2 antibody used in the ADC disclosed herein is an internalizing antibody or internalizing antibody binding fragment. 1C1 (WO 2007 / 030642) is an exemplary anti-EphA2 antibody.

[1004] As used herein, the term "P-cadherin" or "PCAD" 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), as well as any form of human PCAD that can be processed by cells. 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., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). PCAD can be isolated from humans or produced recombinantly or by synthetic methods.

[1005] As used herein, the term "anti-PCAD antibody" or "antibody that binds to PCAD" refers to any form of an 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 incorporated herein by reference. In some embodiments, the anti-PCAD antibody used in the ADC disclosed herein is an internalizing antibody or internalizing antibody binding fragment. NOV169N31Q (WO 2016 / 203432) is an exemplary anti-PCAD antibody.

[1006] As used herein, the term "human epidermal growth factor receptor 2," "HER2," or "HER2 / NEU" 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), as well as any form of human HER2 that can be processed by cells. 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., unless the context indicates that the term is used to refer only to wild-type protein, variants and fragments are encompassed). HER2 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[1007] As used herein, the term "anti-HER2 antibody" or "antibody that is bound to HER2" refers to any form of an antibody or antigen-binding fragment thereof that is bound (e.g., specifically bound) to HER2. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, as long as they are bound (e.g., specifically bound) 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. In some embodiments, the anti-HER2 antibody used in the ADC disclosed herein is an internalizing antibody or an internalizing antibody binding fragment. NOV169N31Q (WO 2016 / 203432) is an exemplary anti-PCAD antibody. Trastuzumab (U.S. Patent Nos. 5,821,337 and 6,870,034; see also Molina et al., (2001) Cancer Res. 61(12):4744-9) is an exemplary anti-HER2 antibody.

[1008] As used herein, "cluster of differentiation 48" or "CD48" 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), as well as any form of human CD48 that can be processed by cells. 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., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). CD48 can be isolated from humans or produced recombinantly or by synthetic methods.

[1009] As used herein, the term "anti-CD48 antibody" or "antibody that binds to CD48" refers to any form of an 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, as long as they bind (e.g., specifically bind) to CD48. International patent application numbers 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. In some embodiments, the anti-CD48 antibody used in the ADC disclosed herein is an internalizing antibody or an internalizing antibody binding fragment. SGN-CD48A (MEM102) and NY920 are exemplary anti-CD48 antibodies.

[1010] As used herein, "cluster of differentiation 74" or "CD74" refers to any native form of human CD74 (also known as the HLA class II histocompatibility antigen gamma chain or the HLA-DR antigen-associated constant chain). The term encompasses full-length human CD74 (e.g., NCBI Reference Sequence: NP_001020330.1; SEQ ID NO: 140), as well as any form of human CD74 that can be processed by cells. 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., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). CD74 can be isolated from humans or can be produced recombinantly or by synthetic methods.

[1011] As used herein, the term "anti-CD74 antibody" or "antibody that binds to CD74" refers to any form of an 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, as long as they bind (e.g., specifically bind) to CD74. WO2020 / 236817 provides exemplary CD74 binding sequences (including exemplary anti-CD74 antibody sequences), and is incorporated herein by reference. In some embodiments, the anti-CD74 antibody used in the ADC disclosed herein is an internalizing antibody or an internalizing antibody binding fragment. Milatumumab (WO2003 / 074567) and VHmil x VK1aNQ (WO2020 / 236817) are exemplary anti-CD74 antibodies.

[1012] As used herein, the term "binding specificity" refers to the ability of individual antibodies or Fabs to preferentially react with an antigenic determinant relative to different antigenic determinants. The degree of specificity represents that an antibody or fragment preferentially binds to an antigenic determinant relative to different antigenic determinants. In addition, as used herein, the terms "specificity," "specific binding," and "specifically bind" refer to the binding reaction between the target antigen (e.g., HER2) in the heterogeneous population of an antibody or Fab (e.g., anti-HER2 antibodies) and protein and other biological products. The binding specificity of an antibody can be tested by comparing the binding to an appropriate antigen and the binding to an unrelated antigen or antigen mixture under a given set of conditions. If the binding affinity of an antibody to an appropriate antigen is at least 2, 5, 7, 10 or more times higher than the affinity to an unrelated antigen or antigen mixture, it is considered to be specific. A "specific antibody" or "target-specific antibody" is an antibody that binds only to a target antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4) but does not bind (or exhibits 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) has a specificity of less than 1×10 -6 M, less than 1×10 -7 M, less than 1×10 -8 M, less than 1×10 -9 M, less than 1×10 -10 M, less than 1×10 -11 M, less than 1×10 -12 M, or less than 1×10 -13 M's K D In some embodiments, K DIn some embodiments, K D Between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[1013] As used herein, the term "affinity" 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 regions of the antibody "arms" interact with the antigen at multiple sites through weak non-covalent forces; the more interactions, the stronger the affinity, generally. The binding affinity of an antibody is the sum of the attractive and repulsive forces acting between the antigenic determinant and the antibody binding site.

[1014] The term "k on ” or “k a ” refers to the association rate constant for the association of an antibody with an antigen to form an antibody / antigen complex. This rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[1015] The term "k off ” or “k d ” refers to the dissociation rate constant for the dissociation of the antibody from the antibody / antigen complex. This rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[1016] The term "K D ” refers to the equilibrium dissociation constant of a specific antibody-antigen interaction. K D By k a / k d Calculation. The rate can be determined using standard assays, such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[1017] The term "epitope" refers to the part of an antigen that can be recognized and specifically bound by an antibody (or antigen binding fragment). Epitope determinants are typically composed of chemically active surface groups of molecules (e.g., amino acids or carbohydrates or sugar side chains) and may have specific three-dimensional structural characteristics as well as specific charge characteristics. When the antigen is a polypeptide, the epitope may be formed by continuous amino acids or non-continuous amino acids juxtaposed by the tertiary folding of the polypeptide. An epitope may be "linear" or "conformational." The difference between a conformational epitope and a linear epitope is that the binding to the former, rather than the latter, is lost in the presence of a denaturing solvent. The epitope to which an antibody (or antigen binding fragment) binds can be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct observation of the antigen-antibody complex, and monitoring the binding of the antibody to the antigen fragment or mutant variant, or monitoring the solvent accessibility of different parts of the antibody and antigen. Exemplary strategies for mapping antibody epitopes include, but are not limited to, array-based oligopeptide 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).

[1018] Competitive binding and epitope binning can also be used to determine antibodies that share the same or overlapping epitopes. Competitive binding can be assessed using cross-blocking assays, such as the assay described in "Antibodies, A Laboratory Manual," Cold Spring Harbor Laboratory, Harlow and Lane (1st Edition 1988, 2nd Edition 2014). In some embodiments, competitive binding is determined when the test antibody or binding protein reduces the binding of the reference antibody or binding protein to a target antigen such as PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3, or 5T4 (e.g., a binding protein comprising CDRs and / or variable domains selected from those identified in Tables 3-5) by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% or more, or any percentage therebetween), and / or vice versa. In some embodiments, competitive binding may be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance, where the antibody or binding protein binds at a nearby epitope (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 ranked 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 in a separate group of binding proteins that do not have overlapping or nearby epitopes.

[1019] 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 comprising two or more amino acids joined to each other by peptide bonds, wherein one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as applicable to naturally occurring amino acid polymers 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.

[1020] A "recombinant" protein refers to a protein (eg, an antibody) that is produced using recombinant techniques (eg, by expression of a recombinant nucleic acid).

[1021] An "isolated" protein is one that is free from at least some of the materials with which it is normally associated in its native 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 the living organism, is isolated. This definition includes production of antibodies in a variety of organisms and / or host cells known in the art.

[1022] As used herein, an "isolated antibody" is an antibody that has been identified and separated from one or more (e.g., a majority) of the components (by weight) of its source environment, such as from components of a hybridoma cell culture or a different cell culture used for its production. In some embodiments, separation is performed to fully remove components that might otherwise interfere with the suitability of the antibody for a 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.

[1023] As used herein, the term "variant" refers to a nucleic acid sequence or amino acid sequence that is different from a reference nucleic acid sequence or amino acid sequence, respectively, but retains one or more biological properties of the reference sequence. The variant may contain one or more amino acid substitutions, deletions and / or insertions (or corresponding codon substitutions, deletions and / or insertions) 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 an amino acid sequence identical to the amino acid sequence encoded by the unmodified nucleic acid, or encode a modified amino acid sequence that retains one or more functional properties of the unmodified amino acid sequence. The changes in the peptide variant sequence are generally limited or conservative, so the sequences of the unmodified peptide and the variant are very similar overall and are identical in many regions. In some embodiments, the peptide variant retains one or more functional properties of the unmodified peptide sequence. The variant and the unmodified peptide may differ in amino acid sequence by one or more substitutions, additions, or deletions in any combination.

[1024] The variant of nucleic acid or peptide can be a naturally occurring variant or an unknown naturally occurring variant. The variant of nucleic acid and peptide can be prepared by mutagenesis technology, by direct synthesis or by other technologies known in the art. Variant does not necessarily need to physically manipulate the reference sequence. As long as the sequence comprises different nucleic acids or amino acids compared to the reference sequence, no matter how it is synthesized, it is considered to be a "variant". In some embodiments, compared to the reference sequence, the variant has a high sequence identity (i.e., 60% nucleic acid or amino acid sequence identity or higher). In some embodiments, peptide variants encompass polypeptides with amino acid substitutions, deletions and / or insertions, as 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 to the corresponding fragment (e.g., functional fragment) of the reference sequence or the reference sequence (e.g., variants that also retain one or more functions of the reference sequence). In some embodiments, nucleic acid variants encompass polynucleotides having amino acid substitutions, deletions and / or insertions, so long as the polynucleotides have 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%, or at least 99% nucleic acid sequence identity to a reference sequence or a corresponding fragment (e.g., a functional fragment) of a reference sequence.

[1025] The term "conservatively modified variant" applies to both amino acid and nucleic acid sequences. For nucleic acid sequences, conservatively modified variants refer to those nucleic acids that encode the same or substantially the same amino acid sequence. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Therefore, at each 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 type of conservatively modified variation. Each nucleic acid sequence encoding a polypeptide herein also describes every possible silent variation of the nucleic acid. Those skilled in the art will recognize that every codon in a nucleic acid (except AUG, which is typically the only codon for methionine, and TGG, which is typically the only codon for tryptophan) can be modified to produce functionally identical molecules. Therefore, every silent variation of a nucleic acid encoding a polypeptide is implicit in each described sequence. For polypeptide sequences, conservatively modified variants include a single substitution, deletion, or addition to the polypeptide sequence, resulting in the substitution of an amino acid with a chemically similar amino acid. Conservative substitutions providing functionally similar amino acids are well known in the art.

[1026] As used herein, the term "conservative sequence modification" refers to amino acid modifications that do not significantly affect or change, for example, the binding characteristics of 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 site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are substitutions in which an amino acid residue is replaced by an amino acid residue with a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with the following side chains: 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), non-polar 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.

[1027] As used herein, the term "homologous" or "identity" refers to the subunit sequence identity between two polymeric molecules, such as between two nucleic acid molecules (such as two DNA molecules or two RNA molecules) or between two polypeptide molecules. When the subunit position in the two molecules is occupied by the same monomeric subunit; for example, 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 direct function of the number of matching positions or homologous positions. For example, if half of the positions in the two sequences (e.g., five positions in a polymer that is ten subunits in length) are matched or homologous, then the two sequences are 50% homologous; if 90% of the positions (e.g., 9 out of 10) are matched or homologous, then the two sequences are 90% homologous.

[1028] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the fragment of the amino acid sequence in the comparison window can comprise an addition or deletion (e.g., a gap or overhang) compared to a reference sequence (which does not comprise an addition or deletion) so that the two sequences are optimally aligned. This percentage can be calculated by the following method: the number of positions at which the identical amino acid residues occur in the two sequences is measured to produce a matching number of positions, the matching number of positions is divided by the total number of positions in the comparison window, and the result is multiplied by 100, thereby obtaining the percentage of sequence identity. The output is the percentage identity of the subject sequence relative to the query sequence. The percentage identity between the two sequences is a function of the number of identical positions that the two sequences have in common, taking into account the number of gaps, the length of each gap, which needs to be introduced to carry out the optimal comparison of the two sequences. In general, the amino acid identity or homology between the proteins disclosed herein, and variants thereof, including variants of the target antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, MET, TROP2, B7-H3 or 5T4) and variants of the antibody variable domain (including individual variant CDRs), is at least 80%, e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, almost 100% or 100% identical or homologous to the sequences described herein.

[1029] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J Mol Biol. 48:444-53) algorithm, which has been incorporated into the GAP program in the GCG software package, using a Blossum 62 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 the 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 Blossum 62 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 can also be determined using the algorithm of Meyers and Miller ((1989) CABIOS 4:11-17), which has been 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.

[1030] As used herein, the term "pharmaceutical agent" refers to a compound, a mixture of compounds, a biomacromolecule, an extract made from a biological material, or a combination of two or more thereof. The term "therapeutic agent" or "drug" refers to an agent that modulates a biological process and / or has biological activity. As described herein, Bcl-xL inhibitors and ADCs containing the same are exemplary therapeutic agents.

[1031] As used herein, the term "chemotherapeutic agent" or "anticancer agent" refers to all agents that are effective in treating cancer, regardless of the mechanism of action. Inhibition of metastasis or angiogenesis is generally a characteristic of chemotherapeutic agents. Chemotherapeutic agents include antibodies, biomolecules, and small molecules, and encompass Mcl-xL inhibitors and ADCs comprising the same as described herein. Chemotherapeutic agents can be cytotoxic agents or cytostatic agents. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or cell proliferation. The term "cytotoxic agent" refers to a substance that causes cell death primarily by interfering with the expression activity and / or function of a cell.

[1032] As used herein, the term "anti-tumor payload" or "anti-tumor compound" refers to one or more compounds that slow down or inhibit cancer cell division or kill cancer cells. Non-limiting examples of anti-tumor payloads include BH3 mimetic compounds (e.g., MCl-1 inhibitors, Bcl-xL inhibitors, or Bcl-2 inhibitors), topoisomerase 1 inhibitors (e.g., topotecan, exitecan, derunotecan, or SN-38), or anti-mitotic drugs (e.g., monomethyl auristatin E (MMAE) or taxanes). In one embodiment, the anti-tumor payload is a BH3 mimetic compound. In one embodiment, the anti-tumor payload is a topoisomerase 1 inhibitor. In one embodiment, the anti-tumor payload is an anti-mitotic drug.

[1033] As used herein, the term "anti-tumor non-BH3 mimetic" refers to one or more compounds that are non-BH3 mimetics and slow or inhibit cancer cell division or kill cancer cells. Non-limiting examples of anti-tumor non-BH3 mimetics include topoisomerase 1 inhibitors (e.g., topotecan, exotecan, derunotecan, or SN-38) or anti-mitotic drugs (e.g., monomethyl auristatin E (MMAE) or taxanes). In one embodiment, the anti-tumor non-BH3 mimetic is a topoisomerase 1 inhibitor. In one embodiment, the anti-tumor non-BH3 mimetic is an anti-mitotic drug.

[1034] As used herein, the term "BH3 mimetic" refers to an agent that disrupts the interaction between pro-apoptotic and anti-apoptotic members of the Bcl-2 family and is a potent inducer of apoptosis. Exemplary BH3 mimetics include inhibitors of Bcl-2, Bcl-xL, Bcl-w, and Mcl-1.

[1035] As used herein, the term "myeloid cell leukemia 1" or "Mcl-1" refers to any native form of human Mcl-1, which is 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 can be produced by 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 also encompassed 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 can be produced recombinantly or by synthetic methods.

[1036] As used herein, the term "inhibit" or "inhibition" or "inhibiting" means to reduce a biological activity or process by a measurable amount and may include but does not require complete prevention or inhibition. In some embodiments, "inhibition" means to reduce the expression and / or activity of Bcl-xL and / or one or more of its upstream regulators or downstream targets.

[1037] As used herein, the term "Mcl-1 inhibitor" refers to an agent that is capable of reducing the expression and / or activity of Mcl-1 and / or one or more of its upstream regulators or downstream targets. Exemplary Mcl-1 modulators (including exemplary Mcl-1 inhibitors) 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 / 035927, US 2019 / 0055264, WO 2016 / 033486, WO 2017 / 147410, WO 2018 / 183418, and WO 2017 / 182625, each of which is incorporated herein by reference as an exemplary Mcl-1 modulator (including exemplary Mcl-1 inhibitors that can be included as a drug moiety in the disclosed ADCs). For example, exemplary Mcl-1 inhibitors that can be included as a drug moiety in the disclosed ADCs are those of the formula:

[1038] 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,

[1039]

[1040]

[1041] Each compound as a drug payload can be conjugated to an antibody or linker via the N-methyl nitrogen atom of the piperazinyl functional group of the compound. As used herein, when referring to Mcl-1 inhibitors, etc., the terms "derivative" and "analog" refer to any such compound that retains substantially the same, similar, or enhanced biological function or activity as the original compound, but has an altered chemical or biological structure.

[1042] As used herein, "Mcl-1 inhibitor drug moiety," "Mcl-1 inhibitor," and the like refer to a component of an ADC or composition that provides the structure of a Mcl-1 inhibitor compound or a compound modified to be attached to an ADC that retains substantially the same, similar, or enhanced biological function or activity as 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 represented by the formula (I) described herein. In some embodiments, the Mcl-1 inhibitor is a compound described in any one of the fiftieth to sixty-third embodiments in the Summary of the Invention section of this disclosure.

[1043] As used herein, the term "B-cell lymphoma-ultra large" or "Bcl-xL" refers to any naturally occurring 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 can be produced by cellular processing. The term also encompasses functional variants or fragments of human Bcl-xL, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Bcl-xL (i.e., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). Bcl-xL can be isolated from humans or produced recombinantly or by synthetic methods.

[1044] As used herein, the term "Bcl-xL inhibitor" refers to an agent that is capable of reducing the expression and / or activity of Bcl-xL and / or one or more of its upstream regulators or downstream targets. Exemplary Bcl-xL modulators (including exemplary Bcl-xL inhibitors) are described in WO2010 / 080503, WO2010 / 080478, WO2013 / 055897, WO2013 / 055895, WO2016 / 094509, WO2016 / 094517, WO2016 / 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 (2014), 5(10), 1088-109 and Wang et al., ACS Medicinal Chemistry Letters (2014), 5(10), 1088-109. Letters (2020), 11(10), 1829-1836, each of which is incorporated herein by reference as an exemplary Bcl-xL modulator, including exemplary Bcl-xL inhibitors, which can be included as a drug moiety in the disclosed ADCs.

[1045] As used herein, "Bcl-xL inhibitor drug moiety," "Bcl-xL inhibitor," and the like refer to a component of an ADC or composition that provides the structure of a Bcl-xL inhibitor compound or a compound modified for attachment to an ADC that retains substantially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, the Bcl-xL inhibitor drug moiety is a component (D) in an ADC of formula (A) 1 and / or D 2 In some embodiments, the Bcl-xL inhibitor is a compound of formula (II) or formula (III) as described herein. In some embodiments, the Bcl-xL inhibitor is a compound described in any one of the sixty-fourth to seventy-fourth embodiments in the Summary of the Invention section of this disclosure.

[1046] As used herein, the term "B-cell lymphoma 2" or "Bcl-2" refers to any native form of human Bcl-2, which is 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) as well as any form of human Bcl-2 that can be processed and produced by cells. 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., unless the context indicates that the term is used to refer only to the wild-type protein, variants and fragments are encompassed). Mcl-1 can be isolated from humans or produced recombinantly or by synthetic methods.

[1047] As used herein, the term "Bcl-2 inhibitor" refers to an agent that can reduce the expression and / or activity of Bcl-2 and / or one or more of its upstream regulators or downstream targets. Exemplary Bcl-2 modulators (including exemplary Bcl-2 inhibitors) are described in WO 2013 / 110890, WO 2015 / 011400, WO 2015 / 011399, WO 2015 / 011397, WO 2015 / 011396, WO 2015 / 011164, and WO 2019081559, each of which is incorporated herein by reference as an exemplary Bcl-2 modulator, including exemplary Bcl-2 inhibitors, which can be included as a drug moiety in the disclosed ADCs.

[1048] As used herein, "Bcl-2 inhibitor drug moiety," "Bcl-2 inhibitor," and the like refer to a component of an ADC or composition that provides a Bcl-2 inhibitor compound or a structure of a compound modified for attachment to an ADC that retains substantially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, the 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 a compound of formula (IV) or formula (V) as described herein. In some embodiments, the Bcl-2 inhibitor is a compound described in any one of embodiments seventy-fifth to eighty-ninth in the Summary of the Invention section of this disclosure.

[1049] As used herein, the term "topoisomerase 1 inhibitor" refers to one or more compounds that interfere with the action of the enzyme topoisomerase 1. In one embodiment, such agents include but are not limited to topotecan, exitecan, delutecan, or SN-38.

[1050] As used herein, the term "antimitotic drug" refers to one or more compounds that target mitotic regulatory enzymes, such as microtubule-regulated enzymes, Polo-like kinases (PLKs), kinesin-spindle proteins (KSPs), Aurora kinases, and the like. In one embodiment, the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane. In some embodiments, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

[1051] As used herein, the term "cancer" refers to the presence of cells with the typical characteristics of oncogenic cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological characteristics. Typically, cancer cells can be in the form of a tumor or mass, but such cells can be present alone in a subject, or can 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 hematologic cancers, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Hematologic cancers can include B cell malignancies, hematologic cancers (leukemias), plasma cell cancers (myeloma, such as multiple myeloma), or lymph node cancers (lymphomas). Exemplary B cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B cell lymphoma. Leukemia can include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. The terms "acute lymphoblastic leukemia" and "acute lymphoblastic leukemia" can be used interchangeably to describe ALL. Lymphoma can include Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc. Other blood cancers can include myelodysplastic syndrome (MDS). Solid tumors can include cancers, such as adenocarcinomas, such as breast cancer, pancreatic cancer, prostate cancer, colon cancer or colorectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, glioma, melanoma, etc. 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, gastric cancer, colon cancer or head and neck cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[1052] As used herein, the term "tumor" refers to any tissue mass resulting from excessive cell growth or proliferation, whether benign or malignant, including precancerous lesions. In some embodiments, the tumor is breast cancer, stomach cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, pancreatic cancer, stomach cancer, colon cancer, head and neck cancer, or spleen cancer. In some embodiments, the tumor is stomach cancer.

[1053] The terms "tumor cell" and "cancer cell" are used interchangeably herein and refer to individual cells or populations of cells derived from a tumor or cancer, including non-tumorigenic cells and cancer stem cells. The terms "tumor cell" and "cancer cell" are modified by the term "non-tumorigenic" when referring only to those cells that lack the capacity to renew and differentiate, to distinguish these cells from cancer stem cells.

[1054] As used herein, the terms "target negative," "target antigen negative," or "antigen negative" refer to the absence of target antigen expression in 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 the target antigen can be described as target negative, while a cell or cell line that expresses the target antigen can be described as target positive.

[1055] The terms "subject" and "patient" are used interchangeably herein and refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[1056] As used herein, the term "a subject in need of treatment" 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).

[1057] As used herein, the terms "treat," "treating," or "treatment" refer to any improvement in any consequence of a disease, disorder, or condition, such as prolonged survival, reduced morbidity, and / or reduced side effects, resulting from alternative treatment modalities. In some embodiments, treatment comprises delaying or ameliorating a disease, disorder, or condition (i.e., slowing or preventing or reducing the development of a disease or at least one clinical symptom thereof). In some embodiments, treatment comprises delaying, alleviating, or improving at least one physical parameter of a disease, disorder, or condition, including those that may not be discernible by the patient. In some embodiments, treatment comprises regulating a disease, disorder, or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In some embodiments, treatment comprises administering the ADC compound or composition to a subject (e.g., a patient) to obtain the therapeutic benefits listed herein. Treatment can be curing, healing, alleviating, delaying, preventing, alleviating, altering, remedying, ameliorating, alleviating, improving, or affecting a disease, disorder, or condition (e.g., cancer), a symptom of a disease, disorder, or condition (e.g., cancer), or susceptibility to a disease, disorder, or condition (e.g., cancer). In some embodiments, in addition to treating a subject with a disease, disorder, or condition, the compositions disclosed herein can also be provided prophylactically to prevent or reduce the likelihood of developing a disease, disorder, or condition.

[1058] As used herein, the terms "prevent," "preventing," or "prevention" of a disease, disorder, or condition refer to prophylactic treatment of; or delaying the onset or progression of; a disease, disorder, or condition.

[1059] As used herein, "pharmaceutical composition" refers to a formulation of a composition, such as an ADC compound or composition, and at least one other (and optionally more than one other) component suitable for administration to a subject, such as a pharmaceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical compositions provided herein are in such a form that allows administration and subsequent provision of the intended biological activity of the active ingredient and / or achievement of a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that are unacceptably toxic to the subject to which the formulation is to be administered.

[1060] As used herein, the terms "pharmaceutically acceptable carrier" and "physiologically acceptable carrier" are used interchangeably and refer to a carrier or diluent that does not cause significant irritation to the subject and does not eliminate the biological activity and properties of the administered ADC compound or composition and / or any other therapeutic agent in the composition. Pharmaceutically acceptable carriers can enhance or stabilize the composition or can be used to promote the preparation of the composition. Pharmaceutically acceptable carriers may include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, adhesives, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, etc. and combinations thereof, which are as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical compositions is considered. The carrier may be selected to minimize adverse side effects in the subject, and / or to minimize degradation of the active ingredient.An adjuvant may also be included in any of these formulations.

[1061] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the active ingredient. Formulations for parenteral administration may, for example, contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalene. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, including, for example, polysorbate 20.

[1062] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that does not abrogate the biological activity and properties of the compounds of the invention and does not cause significant irritation to a subject to which it is administered. Examples of such salts include, but are not limited to: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed with elemental anions such as chloride, bromide, and iodide. 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.

[1063] In some embodiments, the antibody-drug conjugates (ADCs), linkers, payloads, and linker-payloads described herein may contain a monovalent anionic counterion M1, depending on their charge. - Any suitable anionic counterion may be used. In certain embodiments, the monovalent anionic counterion is a pharmaceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M1 - M1 can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, formate, etc. In some embodiments, the monovalent anionic counterion M1 - It is trifluoroacetate or formate.

[1064] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of a compound as described herein (e.g., an ADC compound or composition as described herein) that is capable of achieving the desired therapeutic outcome (i.e., reduction or inhibition of enzyme or protein activity, improvement of symptoms, alleviation of symptoms or condition, delay in disease progression, reduction in tumor size, inhibition of tumor growth, prevention of metastasis). In some embodiments, the therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, the therapeutically effective amount induces or causes side effects, but only those side effects that are acceptable to the treating clinician in view of the patient's condition. In some embodiments, the therapeutically effective amount is effective for detectably killing, reducing and / or inhibiting the growth or spread of cancer cells, the size or number of tumors, and / or other measurements of the level, stage, progression and / or severity of cancer. The term also applies to doses that induce a specific response in target cells, such as a reduction, slowing or inhibition of cell growth. A therapeutically effective amount can be determined by first administering a low dose and then incrementally 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 condition being treated, such as the subject's weight and age, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific amount may vary depending on, for example, the specific pharmaceutical composition, the subject and their age and existing health condition or the risk of a health condition, the dosing regimen to be followed, the severity of the disease, whether to be administered in combination with other agents, the timing of administration, the tissue to be administered, and the physical delivery system to carry it. In the case of cancer, a therapeutically effective amount of ADC can reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow down or stop) tumor metastasis, inhibit (e.g., slow down or stop) tumor growth, and / or alleviate one or more symptoms.

[1065] 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 to achieve the desired prophylactic effect at the necessary dosage and time period. Typically, a prophylactic dose will be less than a therapeutically effective amount because the prophylactic dose is used in subjects before or at an early stage of disease. In some embodiments, the prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with cancer.

[1066] The term "p" or "drug loading" or "drug:antibody ratio" or "drug to antibody ratio" or "DAR" refers to the number of drug moieties per antibody or antigen-binding fragment, i.e., drug loading, or the number of BH3 mimetic moieties per antibody or antigen-binding fragment (Ab) in an ADC of formula (1). In an ADC comprising an anti-tumor compound (e.g., a BH3 mimetic drug moiety, a topoisomerase 1 inhibitor, or an anti-mitotic drug), "p" refers to the number of anti-tumor compounds (e.g., BH3 mimetic drug moieties, topoisomerase 1 inhibitors, or anti-mitotic drugs) attached to the antibody or antigen-binding fragment. In the present disclosure, one dual linker allows two anti-tumor 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 be attached to an antibody or antigen-binding fragment, and thus, if the antibody or antigen-binding fragment is linked to only one dual linker to which two anti-tumor 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)) are attached, then p is 2. In a composition comprising multiple copies of an ADC of formula (1), "average p" refers to the average number of anti-tumor 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 "average drug loading."

[1067] 1. Antibody-drug conjugates

[1068] The antibody-drug conjugate (ADC) compounds of the present disclosure include those with anticancer activity. Specifically, the ADC compounds include antibodies or antigen-binding fragments conjugated (i.e., covalently attached via a dual linker) to two anti-tumor compounds, such as BH3 mimetic drug moieties (e.g., Mcl-1 inhibitors, Bcl-2 inhibitors, or Bcl-xL inhibitors, or combinations thereof), topoisomerase 1 inhibitors (e.g., topotecan, exitecan, derutecan, or SN-38), or anti-mitotic drugs (e.g., monomethyl auristatin E (MMAE) or taxanes), wherein at least one of the anti-tumor compounds is a BH3 mimetic drug moiety, and wherein the anti-tumor compound has a cytotoxic or cytostatic effect when not conjugated to the antibody or antigen-binding fragment. In some embodiments, the BH3 mimetic drug moiety, when not conjugated to the antibody or antigen-binding fragment, is capable of reducing the expression and / or activity of a Bcl-2 family protein (e.g., Mcl-1, Bcl-2, and / or Bcl-xL) and / or one or more upstream regulators or downstream targets thereof. Without being bound by theory, in some embodiments, by targeting the expression and / or activity of Bcl-2 family proteins (e.g., Mcl-1, Bcl-2, and / or Bcl-xL), the ADCs disclosed herein can provide effective anticancer agents. Moreover, without being bound by theory, by conjugating an anti-tumor compound to an antibody that binds to an antigen associated with expression in tumor cells or cancer, the ADC can provide improved activity, better cytotoxic specificity, and / or reduced off-target killing, as compared to the anti-tumor compound when administered alone.

[1069] Thus, in some embodiments, the components of the ADC are selected to (i) retain one or more therapeutic properties exhibited by the antibody and anti-tumor compound individually, (ii) maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) optimize drug loading and drug-to-antibody ratio; (iv) allow delivery (e.g., intracellular delivery) of the anti-tumor compound via stable attachment to the antibody or antigen-binding fragment; (v) preserve the stability of the ADC as a complete conjugate until transport or delivery to the target site; (vi) minimize aggregation of the ADC before or after administration; (vii) allow for the therapeutic effect (e.g., cytotoxic effect) of the anti-tumor compound following cleavage or other release mechanism in the cellular environment; (viii) exhibit in vivo anti-cancer therapeutic efficacy similar to or better than that of the isolated antibody and anti-tumor compound; (ix) minimize off-target killing by the anti-tumor compound; and / or (x) exhibit desired pharmacokinetic and pharmacodynamic properties, formulatability, and toxicological / immunological characteristics. Each of these properties may provide improved ADCs for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[1070] The ADC compounds of the present disclosure can selectively deliver effective doses of cytotoxic or cytostatic agents to cancer cells or tumor tissues. In some embodiments, the cytotoxic and / or cytostatic activity of the ADC depends on the expression of the target antigen in the cell. In some embodiments, the disclosed ADCs are particularly effective in 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.

[1071] Exemplary BCMA-expressing cancers include, but are not limited to, multiple myeloma (Cho et al. (2018) Front Immunol. 9:1821).

[1072] Exemplary CD33-expressing cancers include, but are not limited to, colorectal cancer, pancreatic cancer, lymphoma, and leukemia (eg, acute myeloid leukemia) (Human Protein Atlas; Walter (2014) Expert Opin Ther Targets 18(7):715-8).

[1073] 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).

[1074] Exemplary HER-2 expressing cancers include, but are not limited to, breast cancer, gastric cancer, bladder cancer, urothelial cancer, esophageal cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial carcinoma), salivary duct carcinoma, cervical cancer, endometrial cancer, and ovarian cancer (English et al. (2013) Mol Diagn Ther. 17:85-99).

[1075] In certain aspects, provided herein are ADC compounds comprising two anti-tumor payloads, such as a BH3 mimetic, a topoisomerase 1 inhibitor, or an anti-mitotic drug (D) covalently linked via a dual linker (L). 1 and D 2) or its antigen-binding fragment (Ab), wherein at least one anti-tumor payload is a BH3 mimetic, and wherein the dual linker has one attachment point connected to the antibody and two attachment points connected to two anti-tumor payloads (such as BH3 mimetic), and the two anti-tumor payloads can be the same or different. In some embodiments, for the ADC compounds provided herein, the antibody or its antigen-binding fragment (Ab) targets cancer cells. In some embodiments, the antibody or antigen-binding fragment is capable of binding to a tumor-associated antigen (e.g., CD74, CD48, EphA2, PCAD, or HER2) with high specificity and high affinity, for example. In some embodiments, the antibody or antigen-binding fragment is internalized into the target cell after binding, for example, internalized into a degradation compartment in the cell. In some embodiments, the ADC is internalized after binding to the target cell, undergoes degradation, and releases the Bcl-xL inhibitor drug portion to kill the cancer cells. The anti-tumor payload, such as a BH3 mimetic, a topoisomerase 1 inhibitor, or an anti-mitotic drug, can be released from the antibody and / or linker portion of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[1076] An exemplary ADC has formula (1):

[1077]

[1078] Where Ab = antibody or antigen-binding fragment, L = double linker moiety, D 1 and D 2 = anti-tumor payload, such as a BH3 mimetic, topoisomerase 1 inhibitor, or anti-mitotic drug, where D 1 and D 2 At least one of which is a BH3 mimetic, and a = the number of anti-tumor payloads attached to each antibody or antigen-binding fragment D 1 and D 2 The number of

[1079] A. Antibodies

[1080] The antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. In some embodiments, the antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. The antibody or antigen-binding fragment may have a dissociation constant (K) of ≤1 mM, ≤100 nM, or ≤10 nM, or any amount therebetween. D ) binds to the target antigen, such as by e.g. In some embodiments, K D In some embodiments, K DBetween 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[1081] In some embodiments, the antibody or antigen-binding fragment is a four-chain antibody (also known as an immunoglobulin or full-length or intact antibody) comprising two heavy chains and two light chains. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment of an immunoglobulin that retains the ability to bind to a target cancer antigen and / or provides at least one function of an immunoglobulin.

[1082] In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof binds to a target cancer antigen expressed on the cell surface and enters the cell after binding. In some embodiments, after the ADC enters and is present in a cell expressing the target cancer antigen (i.e., after the ADC is internalized), the Bcl-xL inhibitor drug portion of the ADC is released from the antibody or antigen-binding fragment of the ADC, for example, by cleavage, by degradation of the antibody or antigen-binding fragment, or by any other suitable release mechanism.

[1083] In some embodiments, the antibody comprises a mutation that mediates reduced or no antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, these mutations are referred to as Fc silencing (Fc Silencing, Fc Silent, or Fc Silenced) mutations. In some embodiments, the amino acid residues L234 and L235 of the IgG1 constant region are replaced with A234 and A235 (also referred to as "LALA"). In some embodiments, the amino acid residue N297 of the IgG1 constant region is replaced with A297 (also referred to as "N297A"). In some embodiments, the amino acid residues D265 and P329 of the IgG1 constant region are replaced with A265 and A329 (also referred to as "DAPA"). Other antibody Fc silent mutations can also be used. In some embodiments, Fc silent mutations are used in combination, such as D265A, N297A, and P329A (also referred to as "DANAPA").

[1084] As described herein, if an antibody is modified, it is further designated by that modification. For example, if selected amino acids in the antibody have been changed to cysteine ​​(e.g., E152C, S375C according to EU numbering of the antibody heavy chain to facilitate conjugation to a linker-drug moiety), it is named "CysMab"; or if the antibody is modified with the Fc silent mutations D265A, N297A, and P329A of the IgG1 constant region according to EU numbering, "DANAPA" is added to the antibody name, or if the antibody is modified with the Fc silent mutations D265A and P329A of the IgG1 constant region according to EU numbering, "DAPA" is added to the antibody name.

[1085] In addition to exemplary antigenic targets, the amino acid sequences of exemplary antibodies of the present disclosure are shown in Tables D1-D8.

[1086] Table D1: Exemplary Antibodies

[1087]

[1088]

[1089] Table D2: Amino acid sequences of mAb variable regions

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] Table D2a: Nucleotide sequences corresponding to the amino acid sequences of the variable domain heavy and light chains (VH and VL) of HER2 dicetuzumab and 8902 antibodies

[1097]

[1098]

[1099] Table D3: Amino acid sequences of mAb CDRs (combination)

[1100]

[1101]

[1102]

[1103] Table D4: Amino acid sequences of full-length mAb Ig chains

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117] Table D5: Amino acid sequences of full-length mAb Ig chains

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131] Table D6: Exemplary Bcl-xL and target antigen amino acid sequences

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150] Table D7: Exemplary Antibody Sequences

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169] Table D8: Exemplary Antibody CDR and Variable Region Sequences

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177] In some embodiments, the antibodies or antigen-binding fragments of the ADCs 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 antibodies or antigen-binding fragments of the ADCs disclosed herein may comprise conservative modifications and / or amino acid sequences homologous to the sequences listed in the table above, as long as the ADC retains binding to its target cancer antigen (e.g., wherein K D Less than 1x10 -8 M), and retain one or more functional properties of the ADC disclosed herein (e.g., internalization, ability to bind to an antigen target, e.g., an antigen expressed on a tumor or other cancer cell, etc.).

[1178] 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 ADCs described herein 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 ADCs described herein comprise a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain and a human Ig kappa light chain constant domain.

[1179] In some embodiments, the target cancer antigen of the ADC is PCAD.

[1180] 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, and 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.

[1181] 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, and 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.

[1182] 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, and 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.

[1183] 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, and 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.

[1184] 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, and 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.

[1185] 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 sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises 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.

[1186] 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 sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof comprises 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.

[1187] In some embodiments, the anti-PCAD antibody or antigen-binding fragment thereof is an internalizing antibody or internalizing antigen-binding fragment. In some embodiments, the anti-PCAD antibody comprises a human IgG1 heavy chain constant domain or a modified IgG1 heavy chain constant domain. In some embodiments, the IgG1 heavy chain constant domain comprises a cysteine ​​residue (C) at amino acid positions corresponding to 152 and 375 in a wild-type (unmodified) IgG1 heavy chain constant domain numbered according to the EU numbering system.

[1188] In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 63, or a sequence at least 95% identical to SEQ ID NO: 63, and a light chain amino acid sequence of SEQ ID NO: 64, or a sequence at least 95% identical to SEQ ID NO: 64. In some embodiments, the anti-PCAD antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 63 and a light chain amino acid sequence of SEQ ID NO: 64, or a sequence at least 95% identical to the disclosed sequences. In some embodiments, the anti-PCAD antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 63 and a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 64. In some embodiments, the anti-PCAD antibody is NOV169N31Q (WO 2016 / 203...

Claims

1. An antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof covalently linked to two anti-tumor payloads via a dual linker, wherein at least one anti-tumor payload is a BH3 mimetic, and wherein the dual linker has one attachment point to the antibody and two attachment points to the two anti-tumor payloads, and wherein the two anti-tumor payloads can be the same or different.

2. The antibody-drug conjugate of claim 1, wherein one anti-tumor payload is a BH3 mimetic and the other anti-tumor payload is an anti-tumor non-BH3 mimetic.

3. The antibody-drug conjugate of claim 2, wherein the anti-tumor non-BH3 mimetic is a topoisomerase 1 inhibitor or an antimitotic drug.

4. The antibody-drug conjugate of claim 3, wherein the topoisomerase 1 inhibitor is selected from topotecan, exitecan, delutecan and SN-38. 5 . The antibody-drug conjugate of claim 3 , wherein the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane. The antibody-drug conjugate of claim 5 , wherein the taxane is docetaxel, paclitaxel, or cabazitaxel.

7. The antibody-drug conjugate of claim 1, wherein the two anti-tumor payloads are two BH3 mimetics.

8. The antibody-drug conjugate of any one of claims 1 to 7, wherein the BH3 mimetic is selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor.

9. The antibody-drug conjugate of any one of claims 7 to 8, wherein the BH3 mimetics of the two anti-tumor payloads are identical.

10. The antibody-drug conjugate of any one of claims 7 to 8, wherein the BH3 mimetics of the two anti-tumor payloads are different.

11. The antibody-drug conjugate of any one of claims 7, 8, and 10, wherein (i) one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a Bcl-2 inhibitor; (ii) one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a Bcl-xL inhibitor; or (iii) one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is a Bcl-xL inhibitor.

12. The antibody-drug conjugate of any one of claims 1 to 3, wherein one anti-tumor payload is a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other anti-tumor payload is a topoisomerase 1 inhibitor or an antimitotic drug.

13. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Bcl-xL inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor.

14. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Bcl-xL inhibitor and the other anti-tumor payload is an anti-mitotic drug.

15. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor.

16. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Mcl-1 inhibitor and the other anti-tumor payload is an anti-mitotic drug.

17. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is a topoisomerase 1 inhibitor.

18. The antibody-drug conjugate of any one of claims 1 to 3 and 12, wherein one anti-tumor payload is a Bcl-2 inhibitor and the other anti-tumor payload is an anti-mitotic drug.

19. The antibody-drug conjugate according to claim 1, wherein the antibody-drug conjugate is represented by formula (A): in: Ab is an antibody or its antigen-binding fragment; R 1 is an attachment group; L 1 is a bridging spacer; W is the branch part; L 2’ and L 3’ Each independently is a joint; D 1 and D 2 Each is independently an anti-tumor payload, wherein D 1 and D 2 At least one of is a BH3 mimetic; and a is an integer from 1 to 16.

20. The antibody-drug conjugate of claim 19, wherein D 1 and D 2 Each is independently a BH3 mimetic.

21. The antibody-drug conjugate of claim 16, wherein a is an integer from 1 to 6 or from 1 to 4, or a is 1 or 2, or a is determined by liquid chromatography-mass spectrometry (LC-MS).

22. The antibody-drug conjugate according to any one of claims 19 to 21, wherein L 2’ and L 3’ Each of the comprises a cleavable group, optionally wherein at least one cleavable group comprises a glucuronide group, a pyrophosphate group, a peptide group and / or a self-immolative group.

23. The antibody-drug conjugate according to any one of claims 19 to 22, wherein L 2’ and L 3’ Each of the comprises a cleavable group, optionally wherein at least one of the cleavable groups comprises a pyrophosphate group, a peptide group and / or a self-immolative group.

24. The antibody-drug conjugate according to claim 1 or 19, wherein the antibody-drug conjugate is represented by formula (B): in: Ab is an antibody or its antigen-binding fragment; R 1 is an attachment group; L 1 is a bridging spacer; W is N or CR w ; where R w Is H or C 1-6 alkyl; L 2 and L 3 each independently a linker spacer; E 1 and E 2 Each is 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 Each is independently an anti-tumor payload, wherein D 1 and D 2 At least one of is a BH3 mimetic; and a is an integer from 1 to 16.

25. The antibody-drug conjugate of claim 24, wherein V 1 and V 2 Each is independently i) a self-immolative group or ii) an enzymatic cleavage element; and D 1 and D 2 Each is independently a BH3 mimetic.

26. The antibody-drug conjugate of claim 24 or 25, wherein (i) V 1 and V 2 Each independently comprises a phosphate, a pyrophosphate and / or a self-immolative group; (ii) V 1 and V 2 Each independently contains a self-decomposing group; (iii) V 1 and V 2 each independently comprises a self-immolative group comprising -CH2-O-, -OC(=O)-, -NH-CH2-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or iv) V 1 and V 2 Each independently comprises a group containing p-aminobenzyl-phosphate or p-aminobenzyl-pyrophosphate.

27. The antibody-drug conjugate of claim 26, wherein (i) V 1 and V 2 Each independently comprises a phosphate, a pyrophosphate and / or a self-immolative group; (ii) V 1 and V 2 each independently contains a self-immolative group; or (iii) V 1 and V 2 Each independently comprises a self-immolative group comprising -CH2-O-, -OC(=O)-, -NH-CH2-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

28. The antibody-drug conjugate according to any one of claims 1, 19 and 24, wherein the antibody-drug conjugate is represented by formula (C): or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or its antigen-binding fragment; R 1 is an attachment group; L 1 is a bridging spacer; W is N or CR w ; where R w Is H or C 1-6 alkyl; L 2 and L 3 each independently a linker spacer; E 1 and E 2 each independently a peptide group comprising 1 to 6 amino acids, wherein the peptide group is optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, -OC(=O)NH-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or -OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 or A 2 * indicates that the 1 or D 2 attachment points; D 1 and D 2 Each is independently an anti-tumor payload, wherein D 1 and D 2 at least one of which is a BH3 mimetic; L 4 and L 5 each independently a spacer moiety; R 2 and R 3 Each independently is a hydrophilic group or an enzymatic cleavage element; m and n are each independently 0 or 1; and a is an integer from 1 to 16.

29. The antibody-drug conjugate of claim 28, wherein D 1 and D 2 Each is independently a BH3 mimetic.

30. The antibody-drug conjugate according to any one of claims 1, 19, 24 and 28, wherein the antibody-drug conjugate is represented by formula (D1), (D2) or (D3): or a pharmaceutically acceptable salt thereof, wherein D 1 and D 2 Each is independently an anti-tumor payload, wherein D 1 and D 2 At least one of is a BH3 mimetic; for formula (D2), R 2 and R 3 are each independently an enzymatic cleavage element; and for formula (D3), R 2 Is a hydrophilic group and R 3 It is an enzymatic cleavage element.

31. The antibody-drug conjugate of claim 30, wherein D 1 and D 2 Each is independently a BH3 mimetic.

32. The antibody-drug conjugate of claim 30 or 31, wherein for formula (D1), R 2 and R 3 Each is independently a hydrophilic group.

33. The antibody-drug conjugate of any one of claims 19 to 32, wherein a is an integer from 1 to 8, 1 to 6, 1 to 4, or a is 1 or 2, optionally wherein a is determined by liquid chromatography-mass spectrometry (LC-MS).

34. The antibody-drug conjugate of any one of claims 19 to 33, wherein the attachment group is formed by a reaction involving at least one reactive group.

35. The antibody-drug conjugate of any one of claims 19 to 34, wherein the attachment group is formed by reacting: a first reactive group, which is attached to the linker, and A second reactive group is attached to the antibody or is an amino acid residue of the antibody, wherein optionally, (i) at least one of the reactive groups comprises: thiols, Maleimide, Haloacetamide, Azide, Alkynes, Cyclooctene, Triarylphosphine, Oxanorbornadiene, Cyclooctyne, Diaryltetrazine, Monoaryl tetrazines, Norbornene, aldehyde, Hydroxylamine, Hydrazine, NH2-NH-C(=O)-, ketone, Vinyl sulfone, Aziridine, amino acid residues, -ONH2、-NH2、 -N3、 -SH、-SR 11 ,-SSR 12 ,-S(=O)2(CH=CH2)、-(CH2)2S(=O)2(CH=CH2)、-NHS(=O)2(CH=CH2)、-NHC(=O)CH2Br、-NHC(=O)CH2I、 -C(O)NHNH2, in: Each R 11 Independently selected from H and C1-C6 alkyl; Each R 12 is 2-pyridyl or 4-pyridyl; Each R 13 Independently selected from H, C1-C6 alkyl, F, Cl and -OH; Each R 14 Independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH; Each R 15 independently selected from H, C1-C6 alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1-4 Alkoxy and C substituted by -C(=O)OH 1-4 Alkyl; and / or (ii) the first reactive group and the second reactive group comprise: Thiol and maleimide, Thiols and haloacetamides, Thiol and vinyl sulfone, Thiols and aziridines, Azides and alkynes, Azide and cyclooctyne, Azide and cyclooctene, Azide and triarylphosphine, Azide and oxa-norbornadiene, Diaryltetrazine and cyclooctene, Monoaryl tetrazines and norbornene, Aldehydes and hydroxylamines, Aldehydes and hydrazines, Aldehyde and NH2-NH-C(=O)-, Ketones and hydroxylamines, Ketones and hydrazines, Ketone and NH2-NH-C(=O)-, Hydroxylamine and Amine and Alternatively, CoA or a CoA analog and a serine residue.

36. The antibody-drug conjugate of any one of claims 19 to 35, wherein the attachment group is selected from: amide; disulfide, in: R 16 It is H, C 1-4 Alkyl, phenyl, pyrimidine or pyridine; R 18 It is H, C 1-6 Alkyl, phenyl or C substituted by 1 to 3 -OH groups 1-4 alkyl; Each R 15 Independently selected from H, C 1-6 Alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1-4 Alkoxy and C substituted by -C(=O)OH 1-4 alkyl; R 17 independently selected from H, phenyl and pyridine; q is 0, 1, 2, or 3; R 19 is H or methyl; and R 20 It is H, -CH3 or phenyl.

37. The antibody-drug conjugate of any one of claims 19 to 36, wherein the attachment group is 38. The antibody-drug conjugate of any one of claims 19 to 37, wherein: (1)L 1 Include: or *-CH(OH)CH(OH)CH(OH)CH(OH)-**, wherein each n is an integer from 1 to 12, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point; (2)L 1 yes and n is an integer from 1 to 12 or n is 1 or n is 2, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point; (3)L 1 yes and n is an integer from 1 to 12, wherein L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point; (4)L 1 Include Among them L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point; (5)L 1 is a bridging spacer comprising: *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**; *-C(=O)NH((CH2) m O) t (CH2) n -**; *-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**; *-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**; *-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**; *-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**; *-C(=O)((CH2) m Oh) t (CH2) n NHC(=O)(CH2) n -**; *-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**; *-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**; *-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-**or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point; X1 is 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; and 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; and Each R L1 Independently selected from H and C1-C6 alkyl.

39. The antibody-drug conjugate of any one of claims 19 to 38, wherein L 1 Contains the parts represented by Where n is an integer from 1 to 12, where L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point.

40. The antibody-drug conjugate of claim 39, wherein L 1 It is expressed by the following formula in 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; and Among them L 1 The * indicates a point directly or indirectly attached to W, and L 1 The ** indicates direct or indirect attachment to R 1 point.

41. The antibody-drug conjugate of any one of claims 19 to 40, wherein L 1 Selected from the following:

42. The antibody-drug conjugate of any one of claims 24 to 41, wherein L 2 and L 3 Each is independently a linker spacer comprising a moiety represented by: in 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; and Among them L 2 or L 3 The # indicates direct or indirect attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates a point directly or indirectly attached to W.

43. The antibody-drug conjugate of claim 42, wherein L 2 and L 3 Each is independently a linker spacer selected from the following in k is independently at each occurrence an integer from 0 to 4; r is independently 0 or 1 at each occurrence; o is independently at each occurrence an integer from 0 to 10; p is independently at each occurrence an integer from 0 to 4; R L23 is hydrogen or C 1-6 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # indicates direct attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates the point directly attached to W; The condition is that when W is N, L 2 and L 3 Not (L2c), (L2d), (L2f), or (L2k).

44. The antibody-drug conjugate of claim 43, wherein L 2 and L 3 Each is independently a linker spacer selected from the following in k is independently at each occurrence an integer from 1 to 3; o is independently at each occurrence an integer from 1 to 9; p is independently at each occurrence an integer from 1 to 3; R L23 is hydrogen or C 1-3 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # indicates direct attachment to E 1 or E 2 point, and L 2 or L 3 The ## indicates a point directly attached to W; provided that when W is N, L 2 and L 3 Not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

45. The antibody-drug conjugate of any one of claims 24 to 44, wherein L 2 and L 3 are independently linking spacers selected from the following Among them L 2 or L 3 The # indicates direct attachment to E 1 or E 2 Point, L 2 or L 3 The ## indicates the point directly attached to W; R L is hydrogen or -C(O)-R H ;and R H yes and d is an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

46. ​​The antibody-drug conjugate of claim 45, wherein d is 25.

47. The antibody-drug conjugate of any one of claims 28 to 46, wherein the peptide group comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

48. The antibody-drug conjugate of claim 47, wherein the amino acid residues are selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(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).

49. The antibody-drug conjugate of any one of claims 1 to 47, 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.

50. The antibody-drug conjugate according to any one of claims 47 to 49, wherein E 1 or E 2 The peptide group indicated is an enzymatic cleavage element.

51. The antibody-drug conjugate according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2 The peptide group indicated is the hydrophilic portion.

52. The antibody-drug conjugate according to claim 50 or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2 is independently an enzymatic cleavage element selected from the group consisting of Among them E 1 or E 2 The ^ represents a direct attachment to V in formula (B) 1 or V 2 or the point of direct attachment to the -NH- group in formulas (C) and (D); and E 1 or E 2 The ^^ respectively indicate direct attachment to L 2 or L 3 point.

53. The antibody-drug conjugate according to claim 51 or a pharmaceutically acceptable salt thereof, wherein E 1 or E 2 is independently a hydrophilic moiety represented by where R E is a hydrophilic group R H .

54. The antibody-drug conjugate according to claim 53, or a pharmaceutically acceptable salt thereof, wherein 1 or E 2 Each hydrophilic group R H Independently wherein e is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

55. The antibody-drug conjugate of claim 54, wherein e is 24.

56. The antibody-drug conjugate according to any one of claims 28 to 55, or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 are independently a bond, -OC(=O)-* or Where * indicates attachment to D 1 or D 2 point.

57. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 28 to 55, wherein A 1 and A 2 independently a key or Where * indicates attachment to D 1 or D 2 point.

58. The antibody-drug conjugate according to any one of claims 28 to 55, or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 is independently a bond or -OC(=O)-*, where * represents attachment to D 1 or D 2 point.

59. The antibody-drug conjugate according to any one of claims 28 to 55, or a pharmaceutically acceptable salt thereof, wherein: (i)A 1 Japanese A 2 Corre-OC(=O)-*; (ii)A 1 and A 2 yes (iii)A 1 is -OC(=O)-* and A 2 It is a key; (iv)A 1 is -OC(=O)-* and A 2 yes (v)A 1 It is a key and A 2 yes or (vi)A 1 It is a key and A 2 is -OC(=O)-*, Where * indicates attachment to D 1 or D 2 point.

60. The antibody-drug conjugate of any one of claims 28 to 59, wherein A 1 and A 2 It is a key.

61. The antibody-drug conjugate of any one of claims 28 to 60, wherein i)L 4 and L 5 Each is independently a spacer moiety having the structure in: Z is -O-, -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is a bond, triazolyl or -CH2-triazolyl-, Where X is connected to R 2 or R 3 ;or (ii)L 4 and L 5 is independently a spacer moiety having the structure in: Z is -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is -CH2-triazolyl-C 1-4 Alkylene-OC(O)NHS(O)2NH-, -C 4-6 Cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -, -CH2-triazolyl-C 1-4 Alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4-6 Cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -, wherein each n is independently 1, 2 or 3, Where X is connected to R 2 or R 3 .

62. The antibody-drug conjugate according to claim 61, or a pharmaceutically acceptable salt thereof, wherein Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazolyl or -CH2-triazolyl-; and R L45 is independently H or C at each occurrence 1-3 alkyl.

63. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 28 to 62, wherein L 4 and L 5 Each is independently a spacer moiety selected from the following Among them L 4 or L 5 The @ indicates the point of direct attachment to the phenyl group, and L 4 or L 5 @@ indicates a direct attachment to R 2 or R 3 point.

64. The antibody-drug conjugate according to any one of claims 28 to 63, wherein R 2 and R 3 The hydrophilic groups represented by each independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 Substituted C2-C6 alkyl or C2-C6 alkyl substituted by 1 to 2 substituents independently selected from the following: -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1-4 Alkylene -P(O)(OCH2CH3)2 and -COOH groups.

65. The antibody-drug conjugate of any one of claims 28 to 64, wherein R 2 or R 3 Independently where n is an integer between 1 and 6, 66. The antibody-drug conjugate according to any one of claims 28 to 65, wherein R 2 or R 3 The hydrophilic groups represented by each independently comprise: (i) Polysarcosine having the following moieties: in f is an integer between 3 and 25; and R 23 is H, -CH3 or -CH2CH2C(=O)OH; or (ii) polyethylene glycol of the formula: in g and h are independently integers between 2 and 30.

67. The antibody-drug conjugate according to any one of claims 28 to 63, wherein R 2 or R 3 Said enzymatic cleavage elements are each independently comprised of:

68. The antibody-drug conjugate of any one of claims 28 to 63, wherein R 2 or R 3 Independently selected from the following: in g and h are independently integers between 20 and 30.

69. The antibody-drug conjugate of claim 66 or 68, wherein g is 23, 24, or 25; and h is 23, 24, or 25.

70. The antibody-drug conjugate of claim 28, wherein the dual linker is represented by the formula: in: A 1 and A 2 are each independently a bond, -OC(=O)-* or Among them A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., an integer between 2 and 5); n is an integer between 1 and 12 (e.g., an integer between 2 and 5); represents the point of attachment to Ab; and Indicates direct attachment to D 1 or D 2 point.

71. The antibody-drug conjugate of claim 70, wherein A 1 and A 2 are each independently a bond or -OC(=O)-*, wherein A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point.

72. The antibody-drug conjugate of claim 28, wherein the dual linker is represented by formula (D5): in: A 1 and A 2 are each independently a bond, -OC(=O)-* or Among them A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., an integer between 1 and 3); n is an integer between 1 and 12 (e.g., an integer between 5 and 10); represents the point of attachment to Ab; and Indicates direct attachment to D 1 or D 2 point.

73. The antibody-drug conjugate of claim 72, wherein A 1 and A 2 are each independently a bond or -OC(=O)-*, wherein A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point.

74. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein the dual linker is represented by the following formula: Each of A 1 or A 2 are independently a bond, -OC(=O)-* or Wherein * indicates the point of attachment to the anti-tumor payload; represents the point of attachment to the Ab; and represents a point of direct attachment to said anti-tumor payload, wherein at least one anti-tumor payload is a BH3 mimetic.

75. The antibody-drug conjugate of claim 74, wherein the anti-tumor payload is a drug conjugate of any one of claims 19-73. 1 or D 2 .

76. The antibody-drug conjugate of claim 75, wherein A 1 and A 2 are each independently a bond or -OC(=O)-*, wherein A 1 and A 2 * in the code indicates that the connection is to D 1 or D 2 point.

77. The antibody-drug conjugate of claim 75 or 76, wherein D 1 and D 2 Each is independently a BH3 mimetic.

78. The antibody-drug conjugate of any one of claims 19 to 77, wherein D 1 and D 2 One of the agents is a BH3 mimetic selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and the other is an anti-tumor non-BH3 mimetic selected from a topoisomerase 1 inhibitor or an antimitotic drug.

79. The antibody-drug conjugate of any one of claims 19 to 78, wherein D 1 and / or D 2 Each is independently selected from a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor.

80. The antibody-drug conjugate of any one of claims 19 to 79, wherein D 1 and D 2 Both are (i) Mcl-1 inhibitors; (ii) Bcl-2 inhibitors; or (iii) Bcl-xL inhibitors.

81. The antibody-drug conjugate of any one of claims 19 to 80, wherein D 1 and D 2 are the same.

82. The antibody-drug conjugate of any one of claims 19 to 80, wherein D 1 and D 2 are different.

83. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 19 to 80, wherein (i) D 1 and D 2 One of them is a Mcl-1 inhibitor and the other is a Bcl-2 inhibitor; (ii) D 1 and D 2 one of which is a Mcl-1 inhibitor and the other is a Bcl-xL inhibitor; or (iii) D 1 and D 2 One of them is a Bcl-2 inhibitor and the other is a Bcl-xL inhibitor.

84. The antibody-drug conjugate of any one of claims 19 to 80, wherein: (i)D 1 is a Mcl-1 inhibitor and D 2 It is a Mcl-1 inhibitor; (ii)D 1 is a Mcl-1 inhibitor and D 2 It is a Bcl-2 inhibitor; (iii)D 1 is a Bcl-xL inhibitor and D 2 It is a Bcl-xL inhibitor; (iv)D 1 is a Bcl-xL inhibitor and D 2 It is a Bcl-2 inhibitor; (v)D 1 is a Bcl-2 inhibitor and D 2 is a Mcl-1 inhibitor; or (vi)D 1 is a Mcl-1 inhibitor and D 2 It is a Bcl-xL inhibitor.

85. The antibody-drug conjugate according to any one of claims 19 to 74, or a pharmaceutically acceptable salt thereof, wherein D 1 is a BH3 mimetic and D 2 It is an anti-tumor non-BH3 mimetic.

86. The antibody-drug conjugate of claim 85 or a pharmaceutically acceptable salt thereof, wherein D 1 selected from the group consisting of a Mcl-1 inhibitor, a Bcl-2 inhibitor, and a Bcl-xL inhibitor, and D 2 It is a topoisomerase 1 inhibitor or antimitotic drug.

87. The antibody-drug conjugate according to claim 85 or 86, or a pharmaceutically acceptable salt thereof, wherein D 1 is a Bcl-xL inhibitor and D 2 It is a topoisomerase 1 inhibitor.

88. The antibody-drug conjugate according to claim 85 or 86, or a pharmaceutically acceptable salt thereof, wherein D 1 is a Bcl-xL inhibitor and D 2 It is an antimitotic drug.

89. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 75 to 84, wherein the Mcl-1 inhibitor is represented by formula (I): in: Ring D0 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Ring E0 is a furyl, thienyl or pyrrolyl ring, X 01 、X 03 、X 04 and X 05 are independently a carbon atom or a nitrogen atom, X 02 It's CR 026 group or nitrogen atom, means that the ring is aromatic, Y0 is a nitrogen atom or CR 03 Group, Z0 is a nitrogen atom or CR 04 Group, R 01 is a halogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, a straight chain or branched chain (C1-C6) haloalkyl group, a hydroxyl group, a hydroxyl (C1-C6) alkyl group, a straight chain or branched chain (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -C 08 、-(C0-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011’ or -SO2-(C1-C6)alkyl, R 02 、R 03 、R 04 and R 05 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a hydroxyl (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 031 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ' or -SO2-(C1-C6) alkyl, or (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, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, straight or branched (C1-C6)alkyl, (C0-C6)alkyl-NR 011 R 011 '、-NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 or oxo, R 06 and R 07 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ' or -SO2-(C1-C6) alkyl, or (R 06 ,R 07 ) pairs, when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a straight or branched (C1-C6)alkyl group, a -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 or oxo-substituted, W0 is a -CH2- group, a -NH- group or an oxygen atom, R 08 is a hydrogen atom, a straight-chain or branched (C1-C8) alkyl group, -CHR 0a R 0b group, an aryl group, a heteroaryl group, an aryl(C1-C6)alkyl group or a heteroaryl(C1-C6)alkyl group, R 09 is a hydrogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, -Cy 02 、-(C1-C6)alkyl-Cy 02 、-(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 、-Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 、-Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 03 , halogen atoms, cyano groups, -C(O)-R 014 or -C(O)-NR 014 R 014 ', R 010 is a hydrogen atom, a straight or branched (C1-C6) alkyl group, a straight or branched (C2-C6) alkenyl group, a straight or branched (C2-C6) alkynyl group, an aryl (C1-C6) alkyl group, a (C1-C6) cycloalkylalkyl group, a straight or branched (C1-C6) haloalkyl group or -(C1-C6) alkyl-O-C 04 , or (R 09 ,R 010 ) pair, when fused to 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, which optionally contains 1 to 3 heteroatoms selected from O, S and N, R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 , or (R 011 ,R 011 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted by 1 or 2 groups selected from linear or branched (C1-C6)alkyl groups, and wherein one or more carbon atoms of the linear or branched (C1-C6)alkyl group are optionally deuterated, R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 06 、-Cy 05 -(C0-C6)alkyl-Cy 06 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 06 、-Cy 05 -Cy 06 -O-(C0-C6)alkyl-Cy 07 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 09 、-Cy 05 -(C0-C6)alkyl-Cy 09 、-NH-C(O)-NH-R 011 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 09 、-C(O)-NR 011 R 011 '、-NR 011 R 011 '、-OR 011 、-NR 011 -C(O)-R 011 ', -O-(C1-C6)alkyl-OR 011 、-SO2-R 011 、-C(O)-OR 011 , R 013 、R 013 '、R 014 and R 014 ' are independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, R 0a is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 0b Yes-OC(O)-OR 0c Group, -OC(O)-NR 0c R 0c 'group or -OP(O)(OR 0c )2 group, R 0c and R 0c ' are independently a hydrogen atom, a linear or branched (C1-C8) alkyl group, a cycloalkyl group, a (C1-C6) alkoxy (C1-C6) alkyl group or a (C1-C6) alkoxycarbonyl (C1-C6) alkyl group, or (R 0c ,R 0c ') form, together with the nitrogen atom to which it is attached, a non-aromatic ring consisting of 5 to 7 ring members which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms chosen from oxygen and nitrogen, wherein the nitrogen is optionally substituted by a linear or branched (C1-C6)alkyl group, Cy 01 、Cy 02 、Cy 03 、Cy 04 、Cy 05 、Cy 06 、Cy 07 、Cy 08 and Cy 010 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted, Cy 09 yes or Cy 09 is a heteroaryl group substituted by a group selected from: -OP(O)(OR 020 )2;-OP(O)(O - M + )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ; Hydroxyl; Hydroxyl (C1-C6) alkyl; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; and -U0-(CH2) q0 -NR 021 R 021 ', R 015 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; Straight or branched (C1-C6) alkoxy (C1-C6) alkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or -(CH2) r0 -U0-(CH2) s0 - a heterocycloalkyl group, R 016 is a hydrogen atom; a hydroxyl group; a hydroxy(C1-C6)alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; (CH2) r0 -U0-V0-OP(O)(OR 020 )2 group; -OP(O)(O - M + )2 group; -OS(O)2OR 020 Group; -S(O)2OR 020 Group; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; -(CH2) p0 -OC(O)-NR 022 R 023 group; or -U0-(CH2) q0 -NR 021 R 021 'Group, R 017 is a hydrogen atom; -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 Group; -CH2-P(O)(OR 020 )2 group, -OP(O)(OR 020 )2 group; -OP(O)(O - M + )2 group; hydroxyl group; hydroxy(C1-C6)alkyl group; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl group; -U0-(CH2) q0 -NR 021 R 021 ' group; or aldonic acid, M + is a pharmaceutically acceptable monovalent cation, U0 is a bond or oxygen atom, V0 is -(CH2) s0 - group or -C(O)- group, R 018 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, R 019 is a hydrogen atom or a hydroxy(C1-C6)alkyl group, R 020 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 021 and R 021 ' are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a hydroxy (C1-C6) alkyl group, or (R 021 ,R 021 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom or a straight-chain or branched (C1-C6)alkyl group, R 022 is a (C1-C6)alkoxy(C1-C6)alkyl group, -(CH2) p0 -NR 024 R 024 ' group or -(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 20 Group, R 023 is a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group, or (R 022 ,R 023 ) form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 18 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 5 heteroatoms selected from O, S and N, wherein the resulting ring is optionally substituted with a hydrogen atom, a straight-chain or branched (C1-C6)alkyl group or a heterocycloalkyl group, R 024 and R 024 ' are independently a hydrogen atom or a linear or branched (C1-C6) alkyl group, or (R 024 ,R 024 ') form, together with the nitrogen atom to which they are attached, 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, and wherein the resulting ring is optionally substituted with a hydrogen atom or a linear or branched (C1-C6)alkyl group, R 025 is a hydrogen atom, a hydroxyl group or a hydroxy(C1-C6)alkyl group, R 026 is a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group or a cyano group, R 027 is a hydrogen atom or a linear or branched (C1-C6) alkyl group, R 028 Yes-OP(O)(O - )(O - ) group, -OP(O)(O - )(OR 030 ) group, -OP(O)(OR 030 )(OR 030 ') group, -(CH2) p0 -O-SO2-O - Group, -(CH2) p0 -SO2-O - Group, -(CH2) p0 -O-SO2-OR 030 Group, -Cy 010 、-(CH2) p0 -SO2-OR 030 Group, -OC(O)-R 029 Group, -OC(O)-OR 029 Group or -OC(O)-NR 029 R 029 'group; R 029 and R 029 'are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched amino (C1-C6) alkyl group, R 030 and R 030 'are independently a hydrogen atom, a linear or branched (C1-C6) alkyl group or an aryl (C1-C6) alkyl group, R 031 yes wherein the ammonium is optionally present in zwitterionic form or with a monovalent anionic counterion, n0 is an integer equal to 0 or 1, p0 is an integer equal to 0, 1, 2 or 3, q0 is an integer equal to 1, 2, 3 or 4, r0 and s0 are independently integers equal to 0 or 1; Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker, and wherein the valence of an atom is not exceeded by one or more substituents bonded thereto, or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

90. The antibody-drug conjugate of claim 89, wherein Cy 01 、Cy 02 、Cy 03 、Cy 04 、Cy 05 、Cy 06 、Cy 07 、Cy 08 and Cy 010 are independently a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted by one or more groups selected from the group consisting of: halogen; -(C1-C6)alkoxy; -(C1-C6)haloalkyl; -(C1-C6)haloalkoxy; -(CH2) p0 -O-SO2-OR 030 ; -(CH2) p0 -SO2-OR 030 ;-OP(O)(OR 020 )2;-OP(O)(O - M + )2;-CH2-P(O)(OR 020 )2;-(CH2) p0 -O-(CHR 018 -CHR 019 -O) q0 -R 020 ; Hydroxyl; Hydroxyl (C1-C6) alkyl; -(CH2) r0 -U0-(CH2) s0 -heterocycloalkyl; or -U0-(CH2) q0 -NR 021 R 021 '.

91. The antibody-drug conjugate of claim 89, wherein the Mcl-1 inhibitor is represented by formula (IA): in: Z0 is a nitrogen atom or CR 04 Group, R 01 is a halogen atom, a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, a straight chain or branched chain (C1-C6) haloalkyl group, a hydroxyl group, a straight chain or branched chain (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, -C 08 、-NR 011 R 011 ', R 02 、R 03 and R 04 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-NR 011 R 011 ', -O-(C1-C6)alkyl-R 031 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ' or -SO2-(C1-C6) alkyl, or (R 02 ,R 03 ) or (R 03 ,R 04 ) together with the carbon atom to which they are attached form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, wherein the ring is optionally substituted with a group selected from the group consisting of: straight or branched (C1-C6) alkyl, -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 and oxo, R 06 and R 07 are independently a hydrogen atom, a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C2-C6) alkenyl group, a straight-chain or branched (C2-C6) alkynyl group, a straight-chain or branched (C1-C6) haloalkyl group, a hydroxyl group, a straight-chain or branched (C1-C6) alkoxy group, -S-(C1-C6) alkyl group, a cyano group, a nitro group, -(C0-C6) alkyl-NR 011 R 011 ', -O-Cy 01 、-(C0-C6)alkyl-Cy 01 、-(C2-C6)alkenyl-Cy 01 , -(C2-C6)alkynyl-Cy 01 、-O-(C1-C6)alkyl-R 012 、-C(O)-OR 011 、-OC(O)-R 011 、-C(O)-NR 011 R 011 '、-NR 011 -C(O)-R 011 '、-NR 011 -C(O)-OR 011 ', -(C1-C6)alkyl-NR 011 -C(O)-R 011 ', -SO2-NR 011 R 011 ' or -SO2-(C1-C6) alkyl, or (R 06 ,R 07 ) pair, when fused with two adjacent carbon atoms, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains 1 to 3 heteroatoms selected from O, S and N, and wherein the resulting ring is optionally substituted with a group selected from the group consisting of a straight or branched (C1-C6) alkyl group, a -NR 013 R 013 ', -(C0-C6)alkyl-Cy 01 and oxo, R 08 is a hydrogen atom, a linear or branched (C1-C8)alkyl group, an aryl group, a heteroaryl group, an aryl-(C1-C6)alkyl group or a heteroaryl (C1-C6)alkyl group, R 09 is a straight chain or branched chain (C1-C6) alkyl group, a straight chain or branched chain (C2-C6) alkenyl group, a straight chain or branched chain (C2-C6) alkynyl group, -Cy 02 、-(C1-C6)alkyl-Cy 02 、-(C2-C6)alkenyl-Cy 02 , -(C2-C6)alkynyl-Cy 02 、-Cy 02 -Cy 03 , -(C2-C6)alkynyl-O-Cy 02 、-Cy 02 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 03 , halogen atoms, cyano groups, -C(O)-R 014 、-C(O)-NR 014 R 014 ', R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 , or (R 011 ,R 011 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom is optionally substituted with a linear or branched (C1-C6) alkyl group, and wherein one or more carbon atoms of the linear or branched (C1-C6) alkyl group are optionally deuterated, R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-Cy 06 、-Cy 05 -(C0-C6)alkyl-O-(C0-C6)alkyl-C 06 、-Cy 05 -(C0-C6)alkyl-NR 011 -(C0-C6)alkyl-Cy 06 、-Cy 05 -Cy 06 -O-(C0-C6)alkyl-Cy 07 、-Cy 05 -(C0-C6)alkyl-Cy 09 、-NH-C(O)-NH-R 011 、-C(O)-NR 011 R 011 '、-NR 011 R 011 '、-OR 011 、-NR 011 -C(O)-R 011 ', -O-(C1-C6)alkyl-OR 011 、-SO2-R 011 OR-C(O)-OR 011 , R 013 、R 013 '、R 014 and R 014 ' are independently a hydrogen atom or an optionally substituted linear or branched (C1-C6) alkyl group, Cy 01 、Cy 02 、Cy 03 、Cy 05 、Cy 06 、Cy 07 and Cy 08 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted, Cy 09 yes where R 015 、R 016 and R 017 As defined for formula (I), R 031 yes where R 027 and R 028 As defined for formula (I), Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker, or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

92. The antibody-drug conjugate of claim 89, wherein the Mcl-1 inhibitor is represented by formula (IB): in: R 01 is a linear or branched (C1-C6) alkyl group, R 03 is -O-(C1-C6)alkyl-NR 011 R 011 'or where R 011 and R 011 ' are independently a hydrogen atom, an optionally substituted linear or branched (C1-C6) alkyl group or -(C0-C6) alkyl-C 01 ; or (R 011 ,R 011 ') form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring containing 5 to 7 ring members, which optionally contains, in addition to the nitrogen atom, 1 to 3 heteroatoms selected from O, S and N, wherein the N atom may be substituted by 1 or 2 groups selected from the group consisting of a hydrogen atom or a linear or branched (C1-C6) alkyl group, And R 027 is a hydrogen atom and R 028 Yes - (CH2) p0 -O-SO2-O- group or -(CH2) p0 -SO2-OR 030 group; R 09 is a straight chain or branched (C2-C6) alkynyl group or -Cy 02 , R 012 Yes-Cy 05 、-Cy 05 -(C0-C6)alkyl-Cy 06 or -Cy 05 -(C0-C6)alkyl-Cy 09 , Cy 01 、Cy 02 、Cy 05 and Cy 06 are independently of one another a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, each of which is optionally substituted, Cy 09 yes R 015 、R 016 and R 017 is as defined for formula (I), Among them, if it exists, then R 03 、R 09 or R 012 At most one of the groups is covalently attached to the linker, or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

93. The antibody-drug conjugate of claim 92, wherein R 01 It is a methyl or ethyl group.

94. The antibody-drug conjugate of claim 92, wherein R 03 Yes -O-CH2-CH2-NR 011 R 011 ', where R 011 and R 011 Together with the nitrogen atom carrying it, it forms a piperazinyl group, which may be substituted by a hydrogen atom or a linear or branched (C1-C6) alkyl group.

95. The antibody-drug conjugate of claim 92, wherein R 03 Contains the following formula: where R 027 is a hydrogen atom and R 028 Yes - (CH2) p0 -SO2-OR 030 group.

96. The antibody-drug conjugate of claim 92, wherein R 03 Contains the following formula: wherein -* is a bond to the linker.

97. The antibody-drug conjugate of claim 92, wherein R 09 It's Cy 02 .

98. The antibody-drug conjugate of claim 97, wherein Cy 02 is an optionally substituted aryl group.

99. The antibody-drug conjugate of claim 92, wherein Cy 05 Contains a heteroaryl group selected from the group consisting of a pyrazolyl group and a pyrimidinyl group.

100. The antibody-drug conjugate of claim 92, wherein Cy05 is a pyrimidinyl group.

101. The antibody-drug conjugate of any one of claims 92 to 100, wherein the Mcl-1 inhibitor is covalently attached to R of Formula (I), (IA) or (IB). 03 ; or is covalently attached to R of formula (I), (IA) or (IB) 09 .

102. The antibody-drug conjugate of any one of claims 92 to 101, wherein the Mcl-1 inhibitor is represented by any one of the following formulae: or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or pharmaceutically acceptable salt of any of the foregoing.

103. The antibody-drug conjugate of any one of claims 75-84, wherein the Bcl-xL inhibitor is represented by Formula (II) or Formula (III): or any enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: R1 and R2 independently of one another represent a group selected from the group consisting of: hydrogen; a straight-chain or branched C1-C6 alkyl group, which is optionally substituted by a hydroxyl group or a C1-C6 alkoxy group; a C3-C6 cycloalkyl group; a trifluoromethyl group; and a straight-chain or branched C1-C6 alkylene-heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by a straight-chain or branched C1-C6 alkyl group; or R1 and R2 together with the carbon atoms carrying them form a C3-C6 cycloalkylene group, R3 represents a group selected from the following: hydrogen; C3-C6 cycloalkyl; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-COOR c ;-X1-PO(OH)2;-X1-SO2(OH);-X1-N3 and R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR d R e ; C1-C6 alkylene-N + R d R e R f ; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a C1-C6 alkoxy group; and the following groups: or R a and R b Together with the nitrogen atom carrying it, it forms ring B1; or R a 、R b and R c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, R c 、R d 、R e 、R f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, or R d and R e Together with the nitrogen atom carrying it, it forms ring B2, or R d 、R e and R f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, Het1 represents a group selected from the following: Het2 represents a group selected from the following: A1 is -NH-, -N(C1-C3 alkyl), O, S or Se, A2 is N, CH or C(R5), G is selected from: -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)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1 )NR G1 R G2 , -C1-C6 alkyl optionally substituted by hydroxyl groups, halogen, -NO2 and -CN, wherein: -R G1 and R G2 is independently selected at each occurrence from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; -R G3 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; or R G1 and R G2 and their respective atoms to which they are attached to form a C3-C8 heterocycloalkyl; or in the alternative, G is selected from: where R G4 is selected from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, and R G5 represents a hydrogen atom or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; halogen; and -CN, R6 represents a group selected from the following: hydrogen; a linear or branched-C1-C6 alkylene-R8 group; -C2-C6 alkenyl; -X2-O-R7; -X2-NSO2-R7; -C=C(R9)-Y1-O-R7; C3-C6 cycloalkyl; C3-C6 heterocycloalkyl optionally substituted by a hydroxy group; C3-C6 cycloalkylene-Y2-R7; C3-C6 heterocycloalkylene-Y2-R7 group, and a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group, R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8; wherein Cy represents a C3-C8 cycloalkyl group, R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and R9 represents a group selected from the group consisting of a linear or branched C1-C6 alkyl group, a trifluoromethyl group, a hydroxyl group, a halogen group, and a C1-C6 alkoxy group, R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl, R 11 represents a group selected from the group consisting of hydrogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8, R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group, R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group, R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy, X'2 represents a straight or branched C1-C6 alkylene group, R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' e R' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl or C1-C6 alkoxy group; and the following groups: or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3, or R' a , R' b and R' c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4, or R' d , R' e and R' f Together with the nitrogen atom carrying it, it forms a bridging C3-C 8D Heterocycloalkyl, Y1 represents a straight or branched C1-C4 alkylene group, Y2 represents bond, -O-, -O-CH2-, -O-CO-, -O-SO2-, -CH2-, -CH2-O, -CH2-CO-, -CH2-SO2-, -C2H5-, -CO-, -CO-O-, -CO-CH2-, -CO-NH-CH2-, -SO2-, -SO2-CH2-, -NH-CO- or -NH-SO2-, m=0, 1 or 2, B1, B2, B3 and B4 independently represent a C3-C8 heterocycloalkyl group which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, (iii) be substituted by one or two groups selected from the group consisting of fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl, wherein one of the R3 and R8 groups, if present, is covalently attached to the linker, and wherein the compound of atoms is not exceeded by one or more substituents bonded thereto; or or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: n=0, 1 or 2, ------ indicates a single bond or a double bond, A4 and A5 independently represent a carbon or nitrogen atom, Z1 represents a bond, -N(R)- or -O-, wherein R represents hydrogen or a linear or branched C1-C6 alkyl group, R1 represents a group selected from the following: hydrogen; a straight or branched C1-C6 alkyl group optionally substituted by a hydroxyl or C1-C6 alkoxy group; a C3-C6 cycloalkyl group; a trifluoromethyl group; and a straight or branched C1-C6 alkylene-heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by a straight or branched C1-C6 alkyl group; R2 represents hydrogen or methyl; R3 represents a group selected from the following: hydrogen; linear or branched C1-C4 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-COOR c ; -X1-PO(OH)2; -X1-SO2(OH); -X1-N3 and: R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR d R e ; C1-C6 alkylene-N + R d R e R f ; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a C1-C6 alkoxy group; and the group: or R a and R b Together with the nitrogen atom carrying it, it forms ring B1; or R a 、R b and R c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, R c 、R d 、R e 、R f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, or R d and R e Together with the nitrogen atom carrying it, it forms ring B2, or R d 、R e and R f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, Het1 represents a group selected from the following: Het2 represents a group selected from the following: A1 is -NH-, -N(C1-C3 alkyl), O, S or Se, A2 is N, CH or C(R5), G is selected from: -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)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1 )NR G1 R G2 , -C1-C6 alkyl optionally substituted by hydroxyl groups, halogen, -NO2 and -CN, wherein: -R G1 and R G2 is independently selected at each occurrence from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; -R G3 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl and -(CH2) 1-4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are each attached to form a C3-C8 heterocycloalkyl; or in the alternative, G is selected from: where R G4 is selected from hydrogen, C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, and R G5 represents a hydrogen atom or a C1-C6 alkyl group optionally substituted by 1 to 3 halogen atoms, R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; C2-C6 alkenyl; C2-C6 alkynyl; halogen; and -CN, R6 represents a group selected from the following: hydrogen; a linear or branched-C1-C6 alkylene-R8 group; -C2-C6 alkenyl; -X2-O-R7; -X2-NSO2-R7; -C=C(R9)-Y1-O-R7; C3-C6 cycloalkyl; C3-C6 heterocycloalkyl, which is optionally substituted with a hydroxy group; C3-C6 cycloalkylene-Y2-R7; C3-C6 heterocycloalkylene-Y2-R7 group, and a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group, R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8; wherein Cy represents a C3-C8 cycloalkyl group, R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and: R9 represents a group selected from the group consisting of a linear or branched C1-C6 alkyl group, a trifluoromethyl group, a hydroxyl group, a halogen group, and a C1-C6 alkoxy group, R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl, R 11 represents a group selected from the group consisting of hydrogen, halogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8, R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group, R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group, R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, X1 represents a linear or branched C1-C4 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy, X2 represents a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy, X'2 represents a straight or branched C1-C6 alkylene group, R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group, which is optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' e R' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl group or a C1-C6 alkoxy group; and the group: or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3, or R' a , R' b and R' c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4, or R' d , R' e and R' f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, Y1 represents a straight or branched C1-C4 alkylene group, Y2 represents bond, -O-, -O-CH2-, -O-CO-, -O-SO2-, -CH2-, -CH2-O, -CH2-CO-, -CH2-SO2-, -C2H5-, -CO-, -CO-O-, -CO-CH2-, -CO-NH-CH2-, -SO2-, -SO2-CH2-, -NH-CO- or -NH-SO2-, m=0, 1 or 2, B1, B2, B3 and B4 independently represent a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain one or two heteroatoms independently selected from oxygen, sulfur and nitrogen in addition to the nitrogen atom, (iii) be substituted by one or two groups selected from the group consisting of fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl, wherein one of the R3, R8 and G groups, if present, is covalently attached to the linker, and The compound in which an atom is not exceeded by one or more substituents bonded thereto.

104. The antibody-drug conjugate of claim 103, wherein the Bcl-xL inhibitor is represented by formula (IIA) or (IIIA): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: Z1 represents a bond or -O-, R3 represents a group selected from the following: hydrogen; C3-C6 cycloalkyl; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ;-X1-OR c ;-X1-N3 and R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; and a C1-C6 alkylene group -SO2O - , R c represents hydrogen or a linear or branched C1-C6 alkyl group, Het2 represents a group selected from the following: A1 is -NH-, -N(C1-C3 alkyl), O, S or Se, A2 is N, CH or C(R5), G is selected from: -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 G1 C(O)OR G3 、-C(=NOR G1 )NR G1 R G2 、-NR G1 C(=NCN)NR G1 R G2 、-NR G1 S(O)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、-C(=NR G1 )NR G1 R G2 , -C1-C6 alkyl optionally substituted by a hydroxyl group, -C(O)NR G5 S(O)2R G4 , halogen, -NO2 and -CN, among which: -R G1 、R G2 、R G4 and R G5 is independently selected at each occurrence from hydrogen and C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms; -R G3 is a C1-C6 alkyl group which is optionally substituted by 1 to 3 halogen atoms; or R G1 and R G2 are combined with the atoms to which they are each attached to form a C3-C8 heterocycloalkyl; R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R5 represents a group selected from the group consisting of: C1-C6 alkyl optionally substituted by 1 to 3 halogen atoms; halogen and -CN, R6 represents a group selected from the following: a linear or branched-C1-C6 alkylene-R8 group; -X2-O-R7; and a heteroarylene-R7 group, which is optionally substituted with a straight-chain or branched C1-C6 alkyl group, R7 represents a group selected from the following: a linear or branched C1-C6 alkyl group; (C3-C6) cycloalkylene-R8; wherein Cy represents a C3-C8 cycloalkyl group, R8 represents a group selected from the following: hydrogen; linear or branched C1-C6 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-N3 and: R 10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CF3 and methyl, R 11 represents a group selected from the group consisting of hydrogen, C1-C3 alkylene-R8, -O-C1-C3 alkylene-R8, -CO-NR h R i and -CH=CH-C1-C4 alkylene-NR h R i , -CH=CH-CHO, C3-C8 cycloalkylene-CH2-R8 and C3-C8 heterocycloalkylene-CH2-R8, R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group, R 14 and R 15 independently of one another represent hydrogen or a methyl group, or R 14 and R 15 Together with the carbon atom carrying it, it forms a cyclohexyl group, R h and R i independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen and C1-C6 alkoxy, X'2 represents a straight or branched C1-C6 alkylene group, R' a and R' b represents, independently of one another, a group selected from the group consisting of: hydrogen; heterocycloalkyl; -SO2-phenyl, wherein the phenyl group may be substituted by a linear or branched C1-C6 alkyl group; a linear or branched C1-C6 alkyl group, which is optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-SO2OH; C1-C6 alkylene-SO2O - ; C1-C6 alkylene-COOH; C1-C6 alkylene-PO(OH)2; C1-C6 alkylene-NR' d R' e ; C1-C6 alkylene-N + R' d R' e R' f ; C1-C6 alkylene-O-C1-C6 alkylene-OH; C1-C6 alkylene-phenyl, wherein the phenyl group may be substituted by a hydroxyl group or a C1-C6 alkoxy group; and the group: or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3, or R' a , R' b and R' c Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, R' c , R' d , R' e , R' f independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, or R' d and R' e Together with the nitrogen atom carrying it, it forms ring B4, or R' d , R' e and R' f Together with the nitrogen atom carrying it, it forms a bridged C3-C8 heterocycloalkyl group, m=0, 1 or 2, p = 1, 2, 3 or 4, B3 and B4 independently represent a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) in addition to the nitrogen atom, may contain one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, (iii) be substituted by one or two groups selected from the following: fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl, -NH2, oxo and piperidinyl.

105. The antibody-drug conjugate of claim 104, wherein G is selected from: -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 G1 C(O)OR G3 、-C(=NOR G1 )NR G1 R G2 、-NR G1 C(=NCN)NR G1 R G2 、-NR G1 S(O)2NR G1 R G2 、-S(O)2R G3 、-S(O)2NR G1 R G2 、-NR G1 S(O)2R G2 、-NR G1 C(=NR G2 )NR G1 R G2 、-C(=S)NR G1 R G2 、C(=NR G1 )NR G1 R G2 , halogen, -NO2 and -CN.

106. The antibody-drug conjugate according to any one of claims 103 to 105, wherein R7 represents a group selected from the group consisting of: a linear or branched C1-C6 alkyl group; a (C3-C6)cycloalkylene-R8; wherein Cy represents a C3-C8 cycloalkyl group.

107. The antibody-drug conjugate according to any one of claims 103 to 105, wherein R7 represents a group selected from:

108. The antibody-drug conjugate of claim 103, wherein the Bcl-xL inhibitor is represented by Formula (IIB), (IIC), (IIIB), or (IIIC): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: For formula (IIB) or (IIC), R3 represents a group selected from the following: hydrogen; linear or branched C1-C6 alkyl; -X1-NR a R b ;-X1-N + R a R b R c ; and-X1-OR c ; For formula (IIIB) or (IIIC), Z1 represents a bond, and R3 represents hydrogen; or Z1 represents -O-, and R3 represents -X1-NR a R b , R a and R b represents, independently of one another, a group selected from the group consisting of: hydrogen; a linear or branched C1-C6 alkyl group optionally substituted by one or two hydroxyl groups; and a C1-C6 alkylene group -SO2O - , R c represents hydrogen or a linear or branched C1-C6 alkyl group R6 represents -X2-O-R7 or a heteroarylene-R7 group optionally substituted by a linear or branched C1-C6 alkyl group, R7 represents a group selected from the following: R8 represents a group selected from the following: -NR' a R' b ;-O-X'2-NR' a R' b ; and -X'2-NR' a R' b , R 10 represents fluorine, R 12 and R 13 independently of one another represent a hydrogen atom or a methyl group, R 14 and R 15 independently of one another represent hydrogen or a methyl group, X1 and X2 independently of one another represent a linear or branched C1-C6 alkylene group, which is optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxy, halogen, C1-C6 alkoxy, X'2 represents a straight or branched C1-C6 alkylene group, R' a and R' b independently of one another represent a group selected from the following: hydrogen; linear or branched C1-C6 alkyl optionally substituted by one or two hydroxyl or C1-C6 alkoxy groups; C1-C6 alkylene-NR' d R' e ; or R' a and R' b Together with the nitrogen atom carrying it, it forms ring B3, R' d , R' e independently of one another represent hydrogen or a linear or branched C1-C6 alkyl group, B3 represents a C3-C8 heterocycloalkyl group, which may: (i) be a monocyclic or bicyclic group, wherein the bicyclic group includes a fused, bridged or spiro ring system, (ii) contain one or two heteroatoms independently selected from oxygen and nitrogen in addition to the nitrogen atom, (iii) be substituted by one or two groups selected from the following: fluorine, bromine, chlorine, straight or branched C1-C6 alkyl, hydroxyl and oxo.

109. The antibody-drug conjugate according to any one of claims 103 to 108, wherein R7 represents the following group:

110. The antibody-drug conjugate according to any one of claims 103 to 108, wherein R7 represents a group selected from:

111. The antibody-drug conjugate according to any one of claims 103 to 110, wherein R8 represents a group selected from: in represents a bond to the linker.

112. The antibody-drug conjugate according to any one of claims 103 to 111, wherein B3 represents a C3-C8 heterocycloalkyl group selected from the group consisting of a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group and a 4,4-difluoropiperidin-1-yl group.

113. The antibody-drug conjugate of any one of claims 103 to 112, wherein the Bcl-xL inhibitor is represented by any one of: or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

114. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 75 to 84, wherein the Bcl-2 inhibitor is represented by Formula (IV) or Formula (V): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: A1 represents a hydrogen or halogen atom, a linear or branched (C1-C6) polyhalogenated alkyl group, a linear or branched (C1-C6) alkyl group or a cycloalkyl group, A2 represents a linear or branched (C1-C6) alkyl group, which is optionally substituted by a group selected from the group consisting of halogen, hydroxy, linear or branched (C1-C6) alkoxy, NR'R" and morpholine, or A2 represents a linear or branched (C1-C6) polyhalogenated alkyl group or a cyclopropyl group, It is understood that R' and R" independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a (C1-C4)alkyl-NR1R2 group or a (C1-C4)alkyl-OR6 group, R1 and R2 independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, or R1 and R2 form a heterocycloalkyl group with the nitrogen atom carrying it, R3 represents an aryl or heteroaryl group, it being understood that one or more carbon atoms of the aforementioned groups or their possible substituents may be deuterated, R4 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 aforementioned groups or their possible substituents may be deuterated, R5 represents a hydrogen or halogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched (C1-C6) alkoxy group, R6 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, R a and R d Each represents a hydrogen atom and (R b ,R c ) together with the carbon atom carrying it forms 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, R b represents a hydrogen or halogen atom and R c represents a hydroxyl or methoxy group, or: R a and R d Each represents a hydrogen atom, R b represents a hydroxyl or methoxy group and R c represents a halogen atom, or or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing, wherein: Z1 and Z2 both represent methyl groups, or they form together with the atoms carrying them a fused piperidine group, T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a (C1-C4)alkylene-NR1R2 group, a (C1-C4)alkylene-OR i Group, R1 and R2 independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, or R1 and R2 together with the nitrogen atom carrying them form a heterocycloalkyl group, which is optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups and halogen atoms, R3 represents a group selected from the following: R4 represents a group selected from the following: R5 represents a hydrogen atom, a halogen atom or a hydroxyl group, R6 represents hydrogen, a linear or branched (C1-C6) alkyl group or a halogen atom, Alk represents a linear or branched (C1-C6) alkyl group, A1 represents C-Y4 or a nitrogen atom, A2 represents CH or a nitrogen atom, Cy1 represents a phenyl group, a heteroaryl group, a cycloalkyl group or a heterocycloalkyl group, wherein the phenyl group, the heteroaryl group, the cycloalkyl group and the heterocycloalkyl group are optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxyl group, a cycloalkyl group and a halogen atom, and the heterocycloalkyl group is optionally further substituted by an oxo group, Cy2 represents a phenyl or heteroaryl group, wherein the phenyl and heteroaryl groups are optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxyl group and a halogen atom, X represents a bond, -O-, -S- or NR k , Y1 and Y5 independently represent a group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a linear or branched (C1-C6) alkyl group and a linear or branched (C1-C6) alkoxy group, Y2 and Y4 independently represent a group selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group and a heterocycloalkyl group optionally substituted by a linear or branched (C1-C6) alkyl group, Y3 represents a group selected from the following: a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkynyl group, -(C1-C4) alkylene group, l , linear or branched (C1-C6) alkoxy group, -O-phenyl, -S-phenyl, -O-(C1-C4) alkylene-Cy3, -O-(C1-C4) alkylene-Cy4, -O-Cy3, -O-(C1-C4) alkylene-NR g R h , -(C1-C4)alkylene-Cy3, -(C1-C4)alkylene-Cy4, Cy3, Cy4, and: The alkylene portion of the aforementioned group may be straight chain or branched, Cy3 represents a heterocycloalkyl group optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group, a hydroxyl group, a cycloalkyl group, a heterocycloalkyl group and a halogen atom optionally substituted by 1 to 3 halogen atoms, Cy4 represents a cycloalkyl group optionally substituted by one to three groups selected from the group consisting of a linear or branched (C1-C6) alkyl group, a hydroxyl group, a cycloalkyl group, a heterocycloalkyl group and a halogen atom optionally substituted by 1 to 3 halogen atoms, R a and R b independently of one another represent a hydrogen atom or a halogen atom, R c represents a group selected from the group consisting of hydrogen, linear or branched (C1-C6)alkyl optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NR d R e 、(C1-C6)alkylene-OR j , cycloalkyl, heterocycloalkyl and (C1-C6)alkylene-heterocycloalkyl groups, R' c and R” c independently of one another represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, R d and R e independently of one another represent a hydrogen atom, a linear or branched (C1-C6) 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 independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by one to three halogen atoms, a cycloalkyl group, a heterocycloalkyl group or a -(C1-C6)alkylene-heterocycloalkyl group, R i 、R j and R k independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or a -(C1-C6)alkylene-cycloalkyl group, R l represents a hydrogen atom, a linear or branched (C1-C6) alkyl group or a linear or branched (C1-C6) alkylene-heterocycloalkyl group, R m represents hydrogen or a linear or branched (C1-C6) alkyl group.

115. The antibody-drug conjugate of claim 114, or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is represented by formula (IV), or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

116. The antibody-drug conjugate of claim 114 or 115, wherein in formula (IV), (i) A1 represents a hydrogen atom or a methyl group; or (ii) A1 and A2 both represent methyl groups.

117. The antibody-drug conjugate of any one of claims 114 to 116, wherein in formula (IV), T represents a 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 trifluoromethyl group.

118. The antibody-drug conjugate of any one of claims 114 to 117, wherein in formula (IV), R3 represents a group selected from the group consisting of 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-pyrrolidinone, Pyrrolidine, thiophene, pyrazine, 1H-pyrazolo[3,4-b]pyridine, 1,2-oxazole and pyrazolo[1,5-a]pyrimidine, these groups optionally have one or more substituents selected from the following: halogen, linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkoxy, cyano, cyclopropyl, oxetane, tetrahydrofuran, -CO-O-CH3, trideuteromethyl, 2-(morpholin-4-yl)ethyl and 2-(morpholin-4-yl)ethoxy.

119. The antibody-drug conjugate of claim 114, wherein the Bcl-2 inhibitor is represented by formula (V), or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

120. The antibody-drug conjugate of claim 114, wherein the Bcl-2 inhibitor is represented by formula (Va): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

121. The antibody-drug conjugate of claim 119 or 120, wherein R3 in formula (V) or (Va) represents the following group: and R c represents a group selected from the group consisting of hydrogen, linear or branched (C1-C6)alkyl optionally substituted by 1 to 3 halogen atoms, (C1-C6)alkylene-NR d R e 、(C1-C6)alkylene-OR j , cycloalkyl, heterocycloalkyl and (C1-C6)alkylene-heterocycloalkyl groups.

122. The antibody-drug conjugate of claim 121, wherein R c Represents a methyl group.

123. The antibody-drug conjugate according to any one of claims 119 to 121, wherein R4 in formula (V) or (Va) represents the following group:

124. The antibody-drug conjugate of claim 119, wherein the Bcl-2 inhibitor is represented by formula (Vb): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

125. The antibody-drug conjugate of claim 124, wherein R in formula (Vb) c Represents a methyl group.

126. The antibody-drug conjugate of claim 119, wherein the Bcl-2 inhibitor is represented by formula (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj): or an enantiomer, diastereomer and / or pharmaceutically acceptable salt of any of the foregoing.

127. The antibody-drug conjugate of any one of claims 119 to 126, wherein in Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj): (i) X represents a bond; (ii) A1 represents C-Y4; (iii)R a and R b All represent hydrogen atoms; (iv) R5 represents a hydrogen atom, a hydroxyl group or a fluorine atom, preferably a hydroxyl group; (v) R6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom; (vi) A1 represents CH and Y2 represents a hydrogen atom; (vii) Y1 and Y5 both represent a hydrogen atom, or: Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively; (viii) Y3 represents an -O-(C1-C6)alkylene-heterocycloalkyl group or an -O-(C1-C4)alkylene-Cy3 group; (ix) Y3 represents a group selected from the group consisting of 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]hept-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]dec-9-yl}ethoxy ethoxy, 2-{4-oxa-7-azaspiro[2.5]oct-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)prop-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: express (xi) T represents a linear or branched (C1-C6)alkyl group or a (C1-C4)alkylene-NR1R2 group; and / or (xii) T represents a group selected from the group consisting of a methyl group, a (piperidin-1-yl)methyl group, a (morpholin-4-yl)methyl group, a (piperidin-1-yl)ethyl group, a [(3R)-3-fluoropyrrolidin-1-yl]methyl group, a (4-fluoropiperidin-1-yl)methyl group, a [methyl(propan-2-yl)amino]methyl group, a (azepan-1-yl)methyl group, a (pyrrolidin-1-yl)methyl group, a [(3S)-3-methylpiperidin-1-yl]methyl group, a [(3R)-3-methylpiperidin-1-yl]methyl group, a [(1RS,5SR)-3-azabicyclo[3.1.0]hexan-3-yl]methyl group, a [(2S)-2-methylpiperidin-1-yl]methyl group, a {6-azaspiro[2.5] ]hept-5-ylmethyl, 2-azaspiro[3.3]hept-2-ylmethyl}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]hept-5-ylmethyl, 2-azaspiro[3.3]hept-2-ylmethyl and aminomethyl.

128. The antibody-drug conjugate of any one of claims 119 to 126, wherein in Formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), or (Vj): (i) X represents a bond; (ii) A1 represents C-Y4; (iii)R a and R b All represent hydrogen atoms; (iv) R5 represents a hydrogen atom, a hydroxyl group or a fluorine atom, preferably a hydroxyl group; (v) R6 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom; (vi) A1 represents CH and Y2 represents a hydrogen atom; (vii) Y1 and Y5 both represent a hydrogen atom, or: Y1 and Y5 represent a fluorine atom and a hydrogen atom, respectively; (viii) Y3 represents an -O-(C1-C6)alkylene-heterocycloalkyl group; (ix) Y3 represents a group selected from the group consisting of 2-(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]dec-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, 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)prop-2-yl]oxy, 2-(3,3-dimethylmorpholin-4-yl)ethoxy and [(oxan-4-yl)methoxy]methyl; (x) Group: express (xi) T represents a linear or branched (C1-C6)alkyl group or a (C1-C4)alkylene-NR1R2 group; and / or (xii) T represents a group selected from the group consisting of 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]hexan-3-yl]methyl, [(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.

129. The antibody-drug conjugate of claim 127 or 128, wherein in formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj), R5 represents a hydroxyl group and R6 represents a hydrogen atom.

130. The antibody-drug conjugate of claim 127 or 128, wherein in formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi) or (Vj), Y3 represents an -O-(C1-C4)alkylene-Cy3 group.

131. The antibody-drug conjugate of any one of claims 114-130, wherein the Bcl-2 inhibitor is represented by any one of:

132. The antibody-drug conjugate of claim 86 or 87, wherein the topoisomerase 1 inhibitor is 133. The antibody-drug conjugate of claim 86 or 88, wherein the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane.

134. The antibody-drug conjugate of claim 133, wherein the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

135. The antibody-drug conjugate of any one of claims 1 to 134, wherein the antibody or antigen-binding fragment thereof binds to a target antigen on a cancer cell.

136. The antibody-drug conjugate of claim 135, wherein: (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 selected from CD48, CD74, EphA2, PCAD, TROP2, B7-H3, or 5T4 or HER2.

137. The antibody-drug conjugate of claim 135 or 136, wherein the antibody or antigen-binding fragment thereof is selected from Table D1.

138. The antibody-drug conjugate of any one of claims 135 to 137, wherein the antibody or antigen-binding fragment thereof comprises i) three heavy chain CDR sequences and three light chain CDR sequences selected from an antibody in Tables D3 and D8, ii) a heavy chain variable region sequence and a light chain variable region sequence selected from an antibody in Tables D2 and D8, or iii) a heavy chain sequence and a light chain sequence selected from an antibody in Tables D4, D5, and D7.

139. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, and 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, and 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, and 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, and 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, and 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) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 7) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 215, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and 8) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

174.

140. The antibody-drug conjugate of claim 135, 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.

141. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-CD74 antibody comprising: (a) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; (b) the heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence at least 95% identical to SEQ ID NO: 236, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; or (c) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 239, or a sequence at least 95% identical to SEQ ID NO:

239.

142. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 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, and 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, and 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) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:51, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:52, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:53; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:54, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:55, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

56.

143. The antibody-drug conjugate of claim 135, 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.

144. The antibody-drug conjugate of claim 135, 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 at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 243, or a sequence 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 at least 95% identical to SEQ ID NO: 242, and a light chain amino acid sequence of SEQ ID NO: 243, or a sequence at least 95% identical to SEQ ID NO: 243; (c) a heavy chain amino acid sequence of SEQ ID NO: 240, or a sequence at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 69, or a sequence at least 95% identical to SEQ ID NO:

70.

145. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, and 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, and 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, and 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) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:39, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:40, and 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.

146. The antibody-drug conjugate of claim 135, 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.

147. The antibody-drug conjugate of claim 135, 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 at least 95% identical to SEQ ID NO: 245, and a light chain amino acid sequence of SEQ ID NO: 66 or a sequence at least 95% identical to SEQ ID NO:

66.

148. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, and 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, and 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, and 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) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 310, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, and 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.

149. The antibody-drug conjugate of claim 135, 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.

150. The antibody-drug conjugate of claim 135, 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 at least 95% identical to SEQ ID NO: 248, and a light chain amino acid sequence of SEQ ID NO: 250, or a sequence at least 95% identical to SEQ ID NO:

250.

151. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 319, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 320, and 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, and 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, and 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) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; 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.

152. The antibody-drug conjugate of claim 135, 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.

153. The antibody-drug conjugate of claim 135, 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 at least 95% identical to SEQ ID NO: 252, and a light chain amino acid sequence of SEQ ID NO: 254 or a sequence at least 95% identical to SEQ ID NO:

254.

154. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising three heavy chain CDRs and three light chain CDRs selected from: 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 349, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 350, and 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; 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 355, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 356, and 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 6) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 361, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 362, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 363; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 364, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 365, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

366.

155. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising a heavy chain variable region and a light chain variable region selected from: 4) 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; 5) 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 6) 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.

156. The antibody-drug conjugate of claim 135, wherein the antibody or antigen-binding fragment thereof is an anti-MET antibody comprising a heavy chain and a light chain selected from: 7) the heavy chain amino acid sequence of SEQ ID NO: 367, or a sequence at least 95% identical to SEQ ID NO: 367, and the light chain amino acid sequence of SEQ ID NO: 368, or a sequence at least 95% identical to SEQ ID NO: 368; 8) the heavy chain amino acid sequence of SEQ ID NO: 369, or a sequence at least 95% identical to SEQ ID NO: 369, and the light chain amino acid sequence of SEQ ID NO: 370, or a sequence at least 95% identical to SEQ ID NO: 370; 9) the heavy chain amino acid sequence of SEQ ID NO: 371, or a sequence at least 95% identical to SEQ ID NO: 371, and the light chain amino acid sequence of SEQ ID NO: 372, or a sequence at least 95% identical to SEQ ID NO: 372; 10) the heavy chain amino acid sequence of SEQ ID NO: 373, or a sequence at least 95% identical to SEQ ID NO: 373, and the light chain amino acid sequence of SEQ ID NO: 374, or a sequence at least 95% identical to SEQ ID NO: 374; 11) the heavy chain amino acid sequence of SEQ ID NO: 375, or a sequence at least 95% identical to SEQ ID NO: 375, and the light chain amino acid sequence of SEQ ID NO: 370, or a sequence at least 95% identical to SEQ ID NO: 370; and 12) the heavy chain amino acid sequence of SEQ ID NO: 376, or a sequence at least 95% identical to SEQ ID NO: 376, and the light chain amino acid sequence of SEQ ID NO: 372, or a sequence at least 95% identical to SEQ ID NO:

372.

157. The antibody-drug conjugate of any one of claims 154-156, wherein the two anti-tumor payloads are Bcl-xL inhibitors.

158. The antibody-drug conjugate of any one of claims 139-156, wherein the antibody or antigen-binding fragment thereof comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or antigen-binding fragment thereof, wherein positions are numbered according to the EU system.

159. The antibody-drug conjugate of any one of claims 139-156, wherein the antibody or antigen-binding fragment thereof comprises one or more Fc silent mutations.

160. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 1 to 159, wherein the average a of the antibody-drug conjugates in the composition is from about 1 to about 8, e.g., about 1 to about 6, about 1 to about 4, or about 1 to about 2.

161. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 159 or the composition of claim 160, and a pharmaceutically acceptable carrier.

162. A method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161.

163. The method of claim 162, wherein the cancer expresses a target antigen.

164. The method of claim 162 or 163, wherein the cancer is a tumor or a hematological cancer, optionally 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, gastric cancer, colon cancer, or head and neck cancer.

165. A method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161.

166. The method of claim 165, wherein the tumor expresses a target antigen.

167. The method of claim 165 or 166, wherein the tumor is breast cancer, stomach cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

168. A method of reducing or inhibiting a hematological cancer in a subject, comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161.

169. The method of claim 168, wherein the hematological cancer expresses a target antigen.

170. The method of claim 168 or 169, wherein the hematological cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

171. The method of any one of claims 165 to 170, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of a tumor or hematologic cancer by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

172. A method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161.

173. The method of claim 172, wherein the cancer cell population expresses a target antigen.

174. The method of claim 172 or 173, wherein the cancer cell population is from a tumor or hematologic cancer, optionally wherein the cancer cell population is from 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, gastric cancer, colon cancer, or head and neck cancer.

175. The method of any one of claims 172 to 173, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or slows the expansion of the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

176. The method of any one of claims 162 to 175, wherein the antibody-drug conjugate is administered as a monotherapy.

177. The method of any one of claims 162 to 175, wherein the antibody-drug conjugate is administered adjunctively with another therapeutic agent or radiation therapy.

178. The method of claim 177, wherein the antibody-drug conjugate is administered in an amount effective to sensitize the tumor cells to one or more additional therapeutic agents and / or radiation therapy.

179. The method of any one of claims 162 to 175, further comprising administering at least one additional therapeutic agent to the subject in need thereof.

180. The method of claim 179, wherein the one additional therapeutic agent is a taxane, a vinca alkaloid, a MEK inhibitor, an ERK inhibitor, a topoisomerase inhibitor, or a RAF inhibitor.

181. Use of the antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161 in the preparation of a medicament for (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting tumor growth in a subject, (iii) reducing or inhibiting hematologic cancers in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

182. The antibody-drug conjugate of any one of claims 1 to 159, the composition of claim 160, or the pharmaceutical composition of claim 161, for use in (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting tumor growth in a subject, (iii) reducing or inhibiting a hematologic cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

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