MET BCL-XL INHIBITOR ANTIBODY-DRUG CONJUGATES AND MET METHODS OF USE THEREOF

Abstract

Disclosed is an anti-Met antibody-drug conjugate that binds to a human oncology target. The antibody-drug conjugate comprises a Bcl-xL inhibitor drug moiety and an anti-Met antibody or an antigen-binding fragment thereof that binds to an antigen target, such as an antigen expressed on tumor or other cancer cells. The disclosure further relates to methods and compositions for use in treating cancer by administering the antibody-drug conjugates provided herein. Also disclosed is a linker-drug conjugate that comprises a Bcl-xL inhibitor drug moiety and a method for making the same.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of the 35 U.S.C. §119(e) filing date of U.S. Provisional Application No. 63 / 344,460, filed May 20, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure relates to antibody-drug conjugates (ADCs) comprising Bcl-xL inhibitors and an antigen target, e.g., an anti-Met antibody or antigen-binding fragment thereof, that binds to an antigen expressed on a tumor or other cancer cell. The present disclosure further relates to methods and compositions useful for treating and / or diagnosing cancers that express a target antigen and / or are suitable for treatment by modulating Bcl-xL expression and / or activity, and methods of making these compositions. Linker-drug conjugates comprising a Bcl-xL inhibitor drug moiety and methods of making the same are also disclosed. [Background technology]

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

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

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

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

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

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

[0009] MET (also known as c-MET) is a receptor tyrosine kinase that contains a 50 kDa α-subunit and a 145 kDa β-subunit. The only known ligand for MET is hepatocyte growth factor (HGF), also known as scatter factor. Binding of HGF to MET leads to receptor dimerization and autophosphorylation of β-subunit residues Y1349 and Y1356, activation of downstream signaling pathways including the phosphoinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, the signal transducer and activator of transcription (STAT) pathway, the mitogen-activated protein kinase (MAPK) pathway, and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. This ultimately leads to increased mitogenesis, cell proliferation, cell survival, and cell motility. Dysregulation of MET or HGF activity can occur, for example, by overexpression, gene amplification, mutation, or alternative splicing of MET, or by HGF ligand-induced autocrine / paracrine loop signaling. Such dysregulation plays a role in many cancers by promoting cancer invasiveness, angiogenesis, metastasis, and tumor growth, thus resulting in a more aggressive cancer phenotype and poor prognosis.

[0010] It has been shown that MET can be overexpressed in a variety of tumor types, including gastric and esophageal cancer, cholangiocarcinoma, colon cancer, renal cancer, glioblastoma, and lung cancer (Recondo et al, 2020, Cancer Discovery Cancer Discov, 2020 Jul;10(7):922-934).

[0011] MET is also known to interact with signaling pathways involving other receptors such as EGFR, VEGFR, TGF-β, and HER3, and may play a role in resistance to treatments that target these receptors. MET inhibitors, such as anti-MET antibodies and antibody-drug conjugates, may therefore be effective in combination with other receptor inhibitors in overcoming the resistant phenotype.

[0012] The human MET receptor consists of an extracellular domain of 907 amino acids (residues 25-932). The extracellular domain can be subdivided into a SEMA domain (residues 27-515), a cysteine-rich plexin semaphorin integrin domain (PSI domain, residues 520-561) and four immunoglobulin-like domains defined by the following amino acid sequences: IPT1: AA 563-655; IPT2: AA 657-739; IPT3: AA 742-836; IPT4: AA 837-932. The domain definitions are described in Gherardi et al., Proc Natl Acad Sci US A. 100(21):12039-44 (2003) and in Uniprot entry P08581. The SEMA domain consists of seven beta sheets (blades) that fold into a seven-bladed propeller structure (Stamos J. et al., EMBO J. 23:2325-2335. (2004)). A furin cleavage site is present at positions 307-308, separating the SEMA domain into α and β chains. The SEMA-α domain is encoded by amino acid residues 27-307, including blades 1-4, and the SEMA-β domain is encoded by amino acid residues 308-515, including blades 5-7. The SEMA-α domain contains a binding site for the β chain of the HGF ligand, but the MET binding site of the HGF α chain is poorly understood (Merchant et al., Proc Natl Acad Sci US A. 110(32):E2987-96 (2013)). A single receptor requires both the IPT3 and IPT4 domains of the MET ECD to mediate high affinity HGF binding (Basilico et al., J Biol Chem. 283(30):21267-21277 (2008)).

[0013] Given its role in cancer biology and overexpression in several types of cancer, the MET receptor is an attractive target for active cancer treatment and for the development of anti-Met therapeutic antibodies and antibody-drug conjugates. Summary of the Invention

[0014] In some embodiments, the present disclosure provides, in part, novel antibody-drug conjugate (ADC) compounds that have biological activity against cancer cells. The compounds may slow, inhibit, and / or reverse tumor growth in mammals and / or may be useful for treating human cancer patients. The present disclosure more particularly relates to ADC compounds that, in some embodiments, can bind to and kill cancer cells. In some embodiments, the ADC compounds disclosed herein include a linker that attaches the Bcl-xL inhibitor to the full-length anti-Met antibody or antigen-binding fragment. In some embodiments, the ADC compounds can also be internalized into target cells after binding.

[0015] In some embodiments, the ADC compound has formula (1): Ab-(LD) p (1) where Ab is an anti-Met antibody or an antigen-binding fragment thereof; D is a Bcl-xL inhibitor; L is a linker covalently attaching Ab to D; p is an integer from 1 to 16. In some embodiments, the Ab is an antibody or antigen-binding fragment thereof that targets cancer cells.

[0016] In some embodiments, for ADC compounds of Formula (1), D is a Bcl-xL inhibitor compound of Formula (I') or Formula (II') covalently attached to a linker L:

[0017] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, R 1 and R 2 are, independently of each other, hydrogen; hydroxyl or C 1 ~C 6Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl; trifluoromethyl; and linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl (wherein the heterocycloalkyl group is a linear or branched C 1 ~C 6 or represents a group selected from the group consisting of: Or R 1 and R 2 are the carbon atoms that have them and C 3 ~C 6 Forming a cycloalkylene group, R 3 is hydrogen; C 3 ~C 6 Cycloalkyl; straight or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0018] [ka] represents a group selected from the group consisting of R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2-phenyl (wherein phenyl is a straight or branched C 1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N + R d R e R f ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 substituted by an alkoxy group); and the group:

[0019] [ka] or represents a group selected from the group consisting of Or R a and R b The nitrogen atom and ring B 1 Form or; Or R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e, R f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0020] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0021] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NORG1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , -C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - RG3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0022] [ka] R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl; R G5 is C optionally substituted with hydrogen or 1 to 3 halogen atoms 1 ~C 6 represents an alkyl group, R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, R 6 teeth, hydrogen; Linear or branched ~C 1 ~C 6 Alkylene-R 8 base; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0023] [ka] -X 2 -NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from the group consisting of R 7 is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0024] [ka] Cy represents a group selected from the group consisting of C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0025] [ka] represents a group selected from the group consisting of R 9 is a linear or branched C 1 ~C 6Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 represents a group selected from the group consisting of alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , and C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 and X 2 are each independently selected from trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6substituted by an alkoxy group); and the group:

[0026] [ka] or represents a group selected from the group consisting of or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8D forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5-, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2; B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; R 3 and R 8 one of the groups, if present, is covalently attached to the linker and the valency of the atom is not exceeded by one or more of the substituents attached to it; or

[0027] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, n=0, 1 or 2; ------ represents a single or double bond, A 4 and A 5 represent, independently of one another, a carbon or nitrogen atom, Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a linear or branched C 1~C 6 represents an alkyl group, R 1 is hydrogen; hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl; trifluoromethyl; and linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl (wherein the heterocycloalkyl group is a linear or branched C 1 ~C 6 Optionally substituted with an alkyl group; R 2 represents hydrogen or methyl; R 3 is hydrogen; linear or branched C 1 ~C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0028] [ka] represents a group selected from the group consisting of R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N + R d R e R f ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 substituted by an alkoxy group); and the group:

[0029] [ka] or represents a group selected from the group consisting of Or R a and R b The nitrogen atom and ring B 1 Form or; Or R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e , R fare each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0030] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0031] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NRG1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , -C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6アル Kinnill, C. 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0032] [ka] R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, hydroxyl substituted C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl; R G5 is C optionally substituted with hydrogen or 1 to 3 halogen atoms 1 ~C 6 represents an alkyl group, R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, R 6 teeth, hydrogen; Linear or branched -C 1 ~C 6 Alkylene-R 8 base; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0033] [ka] -X 2 -NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from the group consisting of R 7is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 ;

[0034] [ka] Cy represents a group selected from the group consisting of C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R'c;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0035] [ka] represents a group selected from the group consisting of R 9 is a linear or branched C 1 ~C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6represents a group selected from the group consisting of alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, halogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , and C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, and C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from the group consisting of alkoxy. 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 substituted by an alkoxy group); and the group:

[0036] [ka] or represents a group selected from the group consisting of or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2; B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; R 3 , R 8 and one of the G groups, if present, is covalently attached to the linker, and the valency of the atom is not exceeded by one or more substituents attached to it. Includes.

[0037] In some embodiments, for ADC compounds of Formula (I), D is a Bcl-xL inhibitor compound of Formula (I) or Formula (II) covalently attached to a linker L:

[0038] [ka] or any one of the foregoing enantiomers, diastereoisomers, and / or addition salts thereof with a pharma- ceutically acceptable acid or base (i.e., a pharma- ceutically acceptable salt), R1 and R 2 are, independently of each other, hydrogen; hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl;Trifluoromethyl;Linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl (wherein the heterocycloalkyl group is a linear or branched C 1 ~C 6 or represents a group selected from the group consisting of aryl, aryl, aryl and alkyl; Or R 1 and R 2 are the carbon atoms that have them and C 3 ~C 6 Forming a cycloalkylene group, R 3 is hydrogen; C 3 ~C 6 Cycloalkyl; straight or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0039] [ka] represents a group selected from R a and R bare each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N + R d R e R f ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 optionally substituted with an alkoxy group); Base:

[0040] [ka] or represents a group selected from Or R a and R b The nitrogen atom and ring B 1 Form or; Or R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e , R f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0041] [ka] represents a group selected from Het 2 teeth,

[0042] [ka] represents a group selected from A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0043] [ka] R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl; R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 alkynyl; halogen or -CN; R 6 teeth, hydrogen; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0044] [ka] -X 2 -NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from R 7 is a linear or branched C 1 ~C 6 Alkyl groups; (C 3 ~C 6 ) Cycloalkylene-R 8 ;or

[0045] [ka] Cy represents a group selected from C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a-CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0046] [ka] represents a group selected from R 9 is a linear or branched C 1 ~C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 represents a group selected from alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2-R 8 , C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from alkoxy 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 optionally substituted with an alkoxy group); Base:

[0047] [ka] or represents a group selected from or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R'd and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, -NH-SO 2 - represents m=0, 1 or 2; p=1, 2, 3 or 4 B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) may be fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2, oxo or piperidinyl, R 3 and R 8 one of the groups, if present, is covalently attached to the linker and the valency of the atom is not exceeded by one or more of the substituents attached to it; or

[0048] [ka] or the aforementioned enantiomers, diastereoisomers, and / or addition salts thereof with pharma- ceutically acceptable acids or bases (i.e., pharma- ceutically acceptable salts), n=0, 1 or 2; ------ represents a single or double bond, A 4 and A 5 represent, independently of one another, a carbon or nitrogen atom, Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, R 1 is hydrogen; hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 3 ~C 6 Cycloalkyl;Trifluoromethyl;Linear or branched C 1 ~C 6 Alkylene-heterocycloalkyl (wherein the heterocycloalkyl group is a linear or branched C 1 ~C 6 Optionally substituted by alkyl groups; R 2 represents hydrogen or methyl; R 3 is hydrogen; linear or branched C 1 ~C 4Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0049] [ka] represents a group selected from R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 substituted by alkyl); linear or branched C optionally substituted by 1 or 2 hydroxyl groups; 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR d R e ;C 1 ~C 6 Alkylene-N + R d R e Rf ;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is C 1 ~C 6 optionally substituted with an alkoxy group); Base:

[0050] [ka] or represents a group selected from Or R a and R b The nitrogen atom and ring B 1 Form or; Or R a , R b and R c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R c , R d , R e , R f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Or R d and R e The nitrogen atom and ring B 2 or Or R d , R e and R f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Het 1 teeth,

[0051] [ka] represents a group selected from Het 2 teeth,

[0052] [ka] represents a group selected from A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , C optionally substituted with a hydroxyl group 1 ~C6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 , each of which is combined with the atom to which it is attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0053] [ka] R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3~C 6 cycloalkyl; R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl;C 2 ~C 6 Alkenyl; C 2 ~C 6 alkynyl; halogen or -CN; R 6 teeth, hydrogen; -C 2 ~C 6 Alkenyl; -X 2 -OR 7 ;

[0054] [ka] -X 2 -NSO 2 -R 7 ; -C=C(R 9 )-Y 1 -OR 7 ; C 3 ~C 6 Cycloalkyl; C optionally substituted with a hydroxyl group 3 ~C 6 Heterocycloalkyl; C 3 ~C 6 Cycloalkylene-Y 2 -R 7 ; C 3 ~C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group7 base represents a group selected from: R 7 is a linear or branched C 1 ~C 6 Alkyl groups; (C 3 ~C 6 ) Cycloalkylene-R 8 ;or

[0055] [ka] Cy represents a group selected from C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R'c;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0056] [ka] represents a group selected from R 9 is a linear or branched C 1 ~C 6Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 represents a group selected from alkoxy, R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, halogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from alkoxy1 ~C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from alkoxy 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6 Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 optionally substituted with an alkoxy group); Base:

[0057] [ka] or represents a group selected from or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R' d , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, Y 1 is a linear or branched C 1 ~C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2-O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, -NH-SO 2 - represents m=0, 1 or 2; p=1, 2, 3 or 4 B 1 , B 2 , B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein the bicyclic group includes fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be any of fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo or piperidinyl, R 3 and R 8 One of the groups, if present, is covalently attached to the linker, and the valency of the atom is not exceeded by one or more of the substituents attached to it. Includes.

[0058] In some embodiments, for Formula (I) or Formula (II), G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 RG2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkyl, phenyl and -(CH 2 ) 1~4 -phenyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 form a heterocycloalkyl; or alternatively, G is

[0059] [ka] R G4 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl and C 3 ~C 6 cycloalkyl.

[0060] In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0061] In some embodiments, the linker (L) comprises an attachment group, at least one spacer group, and at least one cleavable group. In some cases, the cleavable group comprises a pyrophosphate group and / or a self-immolative group. In specific embodiments, L comprises an attachment group; at least one bridging spacer group; and at least one cleavable group comprising a pyrophosphate group and / or a self-immolative group.

[0062] In some embodiments, the antibody-drug conjugate has the formula (A):

[0063] [ka] (In the formula, R 1 is the attachment group, L 1 is a bridging spacer group, and E is a cleavable group. The linker-drug (or "linker-payload") moiety (LD) is

[0064] In some embodiments, the cleavable group comprises a pyrophosphate group. In some embodiments, the cleavable group comprises

[0065] [ka] Includes.

[0066] In some embodiments, the crosslinking spacer group comprises a polyoxyethylene (PEG) group. In some cases, the PEG group may be selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some embodiments, the crosslinking spacer group is -CO-CH 2 -CH 2 -PEG12-. In other embodiments, the bridging spacer group comprises a butanoyl, pentanoyl, hexanoyl, heptanoyl, or octanoyl group. In some embodiments, the bridging spacer group comprises a hexanoyl group.

[0067] In some embodiments, the attachment group is formed from at least one reactive group selected from a maleimide group, a thiol group, a cyclooctyne group, and an azide group. For example, a maleimide group has the structure:

[0068] [ka] may have:

[0069] An azide group has the structure: -N=N + =N - may have:

[0070] A cyclooctyne group has the structure:

[0071] [ka] (where:

[0072] [ka] is the binding to the antibody) may have:

[0073] In some instances, the cyclooctyne group has the structure:

[0074] [ka] (where:

[0075] [ka] is the binding to the antibody.

[0076] In some embodiments, the attachment group is

[0077] [ka] An expression containing

[0078] [ka] is the binding to the antibody.

[0079] In some embodiments, the antibody comprises:

[0080] [ka] (where:

[0081] [ka] is the binding to the antibody,

[0082] [ka] is a bond to a bridging spacer group). As used herein, the term "conjugated" refers to covalently attached or covalently linked.

[0083] In some embodiments, the bridging spacer group is conjugated or covalently linked to the cleavable group.

[0084] In some embodiments, the bridging spacer group is -CO-CH 2 -CH 2 -PEG12-.

[0085] In some embodiments, the cleavable group is -pyrophosphate-CH 2 -CH 2 -NH 2 -It is.

[0086] In some embodiments, the cleavable group is conjugated or covalently linked to the Bcl-xL inhibitor (D).

[0087] In some embodiments, the linker comprises an attachment group, at least one bridging spacer group, a peptide group, and at least one cleavable group.

[0088] In some embodiments, the antibody-drug conjugate has formula (B):

[0089] [ka] (In the formula, R 1 is the attachment group, L 1 is a bridging spacer, Lp is a peptide group containing 1 to 6 amino acid residues, E is a cleavable group, L 2 is a bridging spacer; m is 0 or 1; and D is a Bcl-xL inhibitor. In some instances, m is 1 and the bridging spacer is

[0090] [ka] Includes.

[0091] In some embodiments, at least one crosslink spacer comprises a PEG group. In some cases, the PEG group is selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15. In some cases, at least one crosslink spacer is * -C(O)-CH 2 -CH 2 -PEG1- ** , * -C(O)-CH 2 -PEG3- ** , * -C(O)-CH 2 -CH 2 -PEG12 ** , * -NH-CH 2 -CH 2 -PEG1- ** , polyhydroxyalkyl group, * -C(O)-N(CH 3 )-CH 2 -CH 2 -N(CH 3 )-C(O)- ** , * -C(O)-CH 2 -CH2 -PEG12-NH-C(O)CH 2 -CH 2 - ** where: ** indicates a direct or indirect point of attachment of at least one bridging spacer to the attachment group; * indicates the direct or indirect attachment point of at least one cross-linking spacer to the peptide group.

[0092] In some embodiments, L 1 teeth, * -C(O)-CH 2 -CH 2 -PEG1- ** , * -C(O)-CH 2 -PEG3- ** , * -C(O)-CH 2 -CH 2 -PEG12 ** , * -NH-CH 2 -CH 2 -PEG1- ** and polyhydroxyalkyl groups, wherein ** is R 1 L to 1 indicates the direct or indirect attachment point of * L to Lp 1 Indicates the direct or indirect attachment point of the

[0093] In some embodiments, m is 1 and L 2 is -C(O)-N(CH 3 )-CH 2 -CH 2 -N(CH 3 )-C(O)-.

[0094] In some embodiments, the peptide group comprises 1-12 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1-10 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1-8 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1-6 amino acid residues. In some embodiments, the peptide group comprises 1-4 amino acid residues. In some embodiments, the peptide group comprises 1-3 amino acid residues. In some embodiments, the peptide group comprises 1-2 amino acid residues. In some cases, the amino acid residues are selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). For example, the peptide group may include Val-Cit, Val-Ala, Val-Lys, sulfo-Ala-Val-Ala, Gly-Gly-Gly, and / or Gly-Gly-Phe-Gly (SEQ ID NO: 36). In some embodiments, the peptide group (Lp) is

[0095] [ka] In some embodiments, the peptide group (Lp) comprises one amino acid residue linked to the group:

[0096] [ka] Includes.

[0097] In some cases, the peptide group is

[0098] [ka] The present invention includes a group selected from the group consisting of

[0099] In some embodiments, the self-immolative group comprises para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0100] In some embodiments, m is 1 and the bridging spacer is

[0101] [ka] Includes.

[0102] In some embodiments, the linker-drug moiety-(LD) is

[0103] [ka]

[0104] [ka]

[0105] [ka]

[0106] [ka]

[0107] [ka] The compound is formed from a compound selected from:

[0108] In some embodiments, the antibody-drug conjugate comprises:

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka] (where:

[0115] [ka] is the bond to the antibody).

[0116] In some embodiments, the antibody-drug conjugate comprises a linker drug group-(LD), which has the formula (C):

[0117] [ka] (In the formula, R 1 is the attachment group, L 1 is a bridging spacer; L pis a peptide group containing 1 to 6 amino acids; D is a Bcl-xL inhibitor; G 1 -L 2 -A is a self-immolative spacer; L 2 is a bond, methylene, neopentylene or C 2 ~C 3アル Kenylene; A is a bond, -OC(=O)- * ,

[0118] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the attachment point to D);L 3 is the spacer moiety; R 2 is the hydrophilic portion) It is.

[0119] In some embodiments, the antibody-drug conjugate comprises a linker drug group-(LD), which has the formula (D):

[0120] [ka] (In the formula, R 1 is the attachment group; L 1 is a bridging spacer; Lp is a peptide group containing 1 to 6 amino acids; A is a bond, -OC(=O)- * ,

[0121] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the attachment point to D);L 3 is the spacer moiety; R 2 is the hydrophilic portion) It is.

[0122] In some embodiments, L 1 teeth,

[0123] [ka] ,or * -CH(OH)CH(OH)CH(OH)CH(OH)CH(OH)- ** where each n is an integer from 1 to 12; 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0124] In some embodiments, L 1 teeth,

[0125] [ka] where n is an integer from 1 to 12, and L 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0126] In some embodiments, L 1 teeth,

[0127] [ka] and n is 1, where L 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0128] In some embodiments, L 1 teeth,

[0129] [ka] and n is 12, where L 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0130] In some embodiments, L 1 teeth,

[0131] [ka] where n is an integer from 1 to 12, and L 1 of * indicates the direct or indirect attachment point to Lp, and L1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0132] In some embodiments, L 1 teeth,

[0133] [ka] where L 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 Indicates the direct or indirect point of attachment to.

[0134] In some embodiments, L 1 teeth, * -C(=O)(CH 2 ) m O(CH 2 ) m - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n - ** ; * -C(=O)(CH 2 ) m - ** ; * -C(=O)NH((CH 2 ) m O) t (CH 2 ) n - ** ; * -C(=O)O(CH 2 ) m SSC(R 3 ) 2 (CH 2 ) m C(=O)NR 3 (CH 2 ) m NR 3C(=O)(CH 2 ) m - ** ; * -C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)- ** ; * -C(=O)(CH 2 ) m X 1 (CH 2 ) m - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n - ** ; * -C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n - ** ; * -C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X1 (CH 2 ) n - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n - ** ; * -C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m - ** ; * -C(=O)(CH 2 ) m C(R 3 ) 2 - ** or * -C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m - ** where L is a bridging spacer comprising 1 of * indicates the direct or indirect attachment point to Lp, and L 1 of ** is R 1 indicates the direct or indirect point of attachment to X 1 teeth,

[0135] [ka] and; each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30.

[0136] In some embodiments, R 2 Polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1-3

[0137] [ka] C substituted with a group 2 ~C 6 Alkyl, or -OC(=O)NHS(O) 2 NHCH 2 CH 2 OCH 3 , -NHC(=O)C 1~4 Alkylene-P(O)(OCH 2 CH 3 ) 2 and C substituted with 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 In some embodiments, R 2 teeth,

[0138] [ka] (wherein n is an integer from 1 to 6);

[0139] [ka] It is.

[0140] In some embodiments, the hydrophilic moiety has the formula:

[0141] [ka] (where R is H, -CH3 CH 2 CH 2 NHC(=O)OR a , -CH 2 CH 2 NHC(=O)R a , or -CH 2 CH 2 C(=O)OR a and R' is OH, -OCH 3 , C.H. 2 CH 2 NHC(=O)OR a , -CH 2 CH 2 NHC(=O)R a , or -OCH 2 CH 2 C(=O)OR a and each of m and n is an integer of 2 to 25 (eg, 3 to 25), and

[0142] In some embodiments, the hydrophilic moiety is

[0143] [ka] Includes.

[0144] In some embodiments, the hydrophilic moiety is a polysarcosine, e.g., the moiety

[0145] [ka] (wherein n is an integer from 3 to 25; R is H, -CH 3 or -CH 2 CH 2 C(=O)OH).

[0146] In some embodiments, L 3 The structure

[0147] [ka] (where: W is -CH 2 -, -CH 2 O-, -CH 2 N(R b )C(=O)O-, -NHC(=O)C(R b ) 2 NHC(=O)O-, -NHC(=O)C(R b ) 2 NH-, -NHC(=O)C(R b ) 2 NHC(=O)-, -CH 2 N(XR 2 )C(=O)O-, -C(=O)N(XR 2 )-, -CH 2 N(XR 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR b C(=O)-, -CH 2 NR b C(=O)NH-, -CH 2 NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH-, where each R b are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl); X is a bond, triazolyl or -CH 2 -triazolyl-, X is R 2 is a spacer portion having a

[0148] In some embodiments, L 3 The structure

[0149] [ka] (where: W is -CH 2 -, -CH 2 O-, -CH 2 N(R b )C(=O)O-, -NHC(=O)C(R b ) 2 NHC(=O)O-, -NHC(=O)C(R b ) 2 NH-, -NHC(=O)C(R b ) 2 NHC(=O)-, -CH 2 N(XR 2 )C(=O)O-, -C(=O)N(XR 2 )-, -CH 2 N(XR 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR b C(=O)-, -CH 2 NR b C(=O)NH-, -CH 2 NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH-, where each R b are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl); X is -CH 2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4~6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -CH 2 -Triazolyl-C 1~4 Alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n - or -C 4~6 Cycloalkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n each n is independently 1, 2, or 3; and X is R 2 is a spacer portion having a

[0150] In some embodiments, the attachment group is formed by a reaction involving at least one reactive group, hi some cases, the attachment group is formed by reacting a first reactive group that is attached to a linker and a second reactive group that is attached to the antibody or is an amino acid residue of the antibody.

[0151] In some embodiments, at least one of the reactive groups is Thiol, Maleimide, Haloacetamides, Azide, Alkynes, Cyclooctene, Triarylphosphines, oxanobornadiene, Cyclooctyne, Diaryltetrazines, Monoaryltetrazines, Norbornene, aldehyde, Hydroxylamine, Hydrazine, NH 2 -NH-C(=O)-, ケトン, ビニルスルホン、 アジリジン、 Aminic acid residue,

[0152]

change

[0153]

change

[0154]

change

[0155]

change

[0156]

change

[0157]

change

[0158] In some embodiments, the first reactive group and the second reactive group are Thiols and maleimides, Thiols and haloacetamides, Thiols and vinyl sulfones, Thiols and aziridines, Azides and alkynes, Azide and cyclooctyne, Azide and cyclooctene, Azides and triarylphosphines, Azides and oxanobornadienes, diaryltetrazines and cyclooctenes, Monoaryltetrazines and norbornenes, Aldehydes and hydroxylamines, Aldehydes and hydrazines, Aldehydes and NH 2 -NH-C(=O)-, Ketones and hydroxylamines, Ketones and hydrazines, Ketones and NH2-NH-C(=O)-, Hydroxylamine and

[0159] [ka] , amines and

[0160] [ka] ,or CoA or CoA analog and serine residue Includes.

[0161] In some embodiments, the attachment group is

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka] and Where: R 32 , H, C 1~4alkyl, phenyl, pyrimidine or pyridine; R 35 , H, C 1~6 C substituted with alkyl, phenyl, or 1-3 -OH groups 1~4 is alkyl; Each R 7 are independently H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 Alkoxy and -C(=O)OH substituted C 1~4 alkyl; R 37 is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 8 is H or methyl; R 9 -H, -CH 3 Or phenyl.

[0166] In some embodiments, the peptide group (Lp) comprises 1-6 amino acid residues. In some embodiments, the peptide group (Lp) comprises 1-4 amino acid residues. In some embodiments, the peptide group comprises 1-3 amino acid residues. In some embodiments, the peptide group comprises 1-2 amino acid residues. In some embodiments, the amino acid residues are selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). In some embodiments, the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, sulfo-Ala-Val-Cit, sulfo-Ala-Val-Ala, Gly-Gly-Gly, and / or Gly-Gly-Phe-Gly (SEQ ID NO: 36).

[0167] In some embodiments, Lp is

[0168] [ka] is selected from the following.

[0169] In some embodiments, the linker-drug group-(LD) has the formula:

[0170] [ka] (In the formula, R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0171] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0172] [ka] (In the formula,

[0173] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0174] In some embodiments, the linker-drug group-(LD) has the formula:

[0175] [ka] (In the formula, R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0176] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0177] [ka] (In the formula,

[0178] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH2 C(=O)OH.

[0179] In some embodiments, the linker-drug group-(LD) has the formula:

[0180] [ka] (In the formula, R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0181] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0182] [ka] (In the formula,

[0183] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0184] In some embodiments, the linker-drug group-(LD) has the formula:

[0185] [ka] (In the formula, Each R is independently H, -CH 3 , and -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0186] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0187] [ka] (In the formula,

[0188] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0189] In some embodiments, the linker-drug group-(LD) has the formula:

[0190] [ka] (In the formula, Each R is independently H, -CH 3 , and -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0191] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0192] [ka] (In the formula,

[0193] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0194] In some embodiments, the linker-drug group-(LD) has the formula:

[0195] [ka] (In the formula, Xa is -CH 2 -, -OCH 2 -, -NHCH 2 -or- NRCH 2 -, and each R is independently H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- *,

[0196] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0197] [ka] (In the formula,

[0198] [ka] is the bond to the antibody; Xa, A, D and R are as defined above. In some embodiments, Xa is -CH 2 -or-NHCH 2 -; A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0199] In some embodiments, the linker-drug group-(LD) has the formula:

[0200] [ka] (In the formula, R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0201] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0202] [ka] (In the formula,

[0203] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0204] In some embodiments, the linker-drug group-(LD) has the formula:

[0205] [ka] (In the formula, Xb is -CH 2 -, -OCH 2 -, -NHCH 2 -or- NRCH 2 -, and each R is independently H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0206] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0207] [ka] (In the formula,

[0208] [ka] is the bond to the antibody; Xb, A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0209] In some embodiments, the linker-drug group-(LD) has the formula:

[0210] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0211] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R aare independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0212] [ka] (In the formula,

[0213] [ka] is a bond to an antibody; A is as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0214] In some embodiments, the linker-drug group-(LD) has the formula:

[0215] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0216] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- *(where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0217] [ka] (In the formula,

[0218] [ka] is a bond to an antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0219] In some embodiments, the linker-drug group-(LD) has the formula:

[0220] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0221] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0222] [ka] (In the formula,

[0223] [ka] is the binding to the antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0224] In some embodiments, the linker-drug group-(LD) has the formula:

[0225] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0226] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a )2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0227] [ka] (In the formula,

[0228] [ka] is the binding to the antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0229] In some embodiments, the linker-drug group-(LD) has the formula:

[0230] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0231] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- *or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0232] [ka] (In the formula,

[0233] [ka] is the binding to the antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0234] In some embodiments, the linker-drug group-(LD) has the formula:

[0235] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0236] [ka] , -OC(=O)N(CH 3 )CH 2 CH2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0237] [ka] (In the formula,

[0238] [ka] is the binding to the antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0239] In some embodiments, the linker-drug group-(LD) has the formula:

[0240] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0241] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * (where each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0242] [ka] (In the formula,

[0243] [ka] is the binding to the antibody; A and D are as defined above. In some embodiments, A is a bond or -OC(=O)- * It is.

[0244] In some embodiments, the linker-drug group-(LD) has the formula:

[0245] [ka] (In the formula, Each R is independently H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0246] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * and (Here, each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0247] [ka] (In the formula,

[0248] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0249] In some embodiments, the linker-drug group-(LD) has the formula:

[0250] [ka] (In the formula, Each R is independently H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)- * ,

[0251] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * and (Here, each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) In some embodiments, the linker-drug group-(LD) comprises or is formed from a compound of the formula:

[0252] [ka] (In the formula,

[0253] [ka] is the binding to the antibody; A, D and R are as defined above. In some embodiments, A is a bond or -OC(=O)- * and R is -CH 3 or -CH 2 CH 2 C(=O)OH.

[0254] In some embodiments, the linker-drug group-(LD) has the formula:

[0255] [ka] (In the formula, A is a bond, -OC(=O)- * ,

[0256] [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)- * or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)- * and (Here, each R a are independently H, C 1 ~C 6 Alkyl, and C 3 ~C 8 cycloalkyl; * indicates the point of attachment to D); D is a Bcl-xL inhibitor) The compound may include or be formed from the compound of formula (I).

[0257] In some embodiments, A is a bond.

[0258] In some embodiments, A is -OC(=O)- * It is.

[0259] In some embodiments, R is -CH 3 It is.

[0260] In some embodiments, R is -CH 2 CH 2 It is COOH.

[0261] In some embodiments, the antibody-drug conjugate comprises a linker-drug group-(LD), which is

[0262] [ka]

[0263] [ka]

[0264] [ka]

[0265] [ka]

[0266] [ka]

[0267] [ka]

[0268] [ka]

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka] The compound is formed from a compound selected from:

[0277] In some embodiments, the antibody-drug conjugate comprises a linker-drug group-(LD), which is

[0278] [ka]

[0279] [ka]

[0280]

change

[0281]

change

[0282]

change

[0283]

change

[0284]

change

[0285]

change

[0286]

change

[0287]

change

[0288]

change

[0289]

change

[0290]

change

[0291] [ka] comprising a formula selected from Where:

[0292] [ka] is the binding to the antibody.

[0293] In some embodiments, the Bcl-xL inhibitor (D) is a compound of formula (I):

[0294] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, where the variables are described above for formula (I). In some embodiments, R1 is a straight or branched C1-6 alkyl and R2 is H.

[0295] In some embodiments, the Bcl-xL inhibitor (D) is a compound of formula (II):

[0296] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, wherein the variables are as described above for formula (II). A1 and A5 both represent a nitrogen atom, R1 is a straight or branched C1-6 alkyl; R2 is H; n is 1; represents a single bond.

[0297] In some embodiments, the Bcl-xL inhibitor (D) is a compound of formula (IA) or (IIA):

[0298] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, Z 1 represents a bond or -O-; R 3 is hydrogen; C 3 ~C 6 Cycloalkyl; straight or branched C 1 ~C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ; and -X 1 -OR c represents a group selected from R a and R b are each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; 1 ~C 6 Alkyl; and C 1 ~C 6 Alkylene-SO 2 O - represents a group selected from R c is hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, Het 2 teeth,

[0299] [ka] represents a group selected from A 1 -NH-, -N(C 1 ~C 3 alkyl), O, S or Se; A 2 is N, CH, or C(R5 ) and G is -C(O)OH, -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , C optionally substituted with a hydroxyl group 1 ~C 6 Alkyl, halogen, -NO 2 -CN; - R in each occurrence G1 and R G2 each independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6selected from the group consisting of alkyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 is alkyl; or R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 Forming a heterocycloalkyl; R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R 5 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 represents a group selected from alkyl; halogen or -CN, R 6 teeth, -X 2 -OR 7 ; and Linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 base represents a group selected from R 7 is a linear or branched C 1 ~C 6 Alkyl groups; (C 3 ~C 6 ) Cycloalkylene-R 8 ;or

[0300] [ka] Cy represents a group selected from C 3 ~C 8 represents cycloalkyl, R 8 is hydrogen; linear or branched C 1 ~C 6 Alkyl, -NR' a R'b ; -NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b :-NR' c -X' 2 -N 3 and

[0301] [ka] represents a group selected from R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, R 11 is hydrogen, C 1 ~C 3 Alkylene-R 8 , -OC 1 ~C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 ~C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 ~C 8 Cycloalkylene -CH 2 -R 8 , C 3 ~C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen atom or a methyl group, or R 14 and R 15 forms a cyclohexyl with the carbon atom carrying it, R h and R i are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 ~C 6 A linear or branched C optionally substituted with one or two groups selected from alkoxy 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl (wherein phenyl is a straight or branched C 1 ~C 6 1 or 2 hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-SO 2 OH;C 1 ~C 6 Alkylene-SO 2 O - ;C 1 ~C 6Alkylene-COOH;C 1 ~C 6 Alkylene-PO(OH) 2 ;C 1 ~C 6 Alkylene-NR' d R' e ;C 1 ~C 6 Alkylene-N + R' d R' e R' f ;C 1 ~C 6 Alkylene-OC 1 ~C 6 Alkylene-OH;C 1 ~C 6 Alkylene-phenyl (wherein phenyl is hydroxyl or C 1 ~C 6 optionally substituted with an alkoxy group); Base:

[0302] [ka] or represents a group selected from or R' a and R' b The nitrogen atom and ring B 3 or or R' a , R' b and R' c are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, or R' d and R' e The nitrogen atom and ring B 4 or or R'd , R' e and R' f are nitrogen atoms with bridging C 3 ~C 8 forming a heterocycloalkyl, m=0, 1 or 2; p=1, 2, 3 or 4; B 3 and B. 4 are independent of each other, C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein the bicyclic group includes fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be any of fluorine, bromine, chlorine, linear or branched C 1 ~C 6 Alkyl, hydroxyl, -NH 2 , oxo or piperidinyl). Includes.

[0303] In some embodiments, for formula (IA) or (IIA), G is -C(O)OH, -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O)2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R in each occurrence G1 and R G2 each independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 ~C 6 selected from the group consisting of alkyl; - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 ~C 6 is alkyl; or - R G1 and R G2 are combined with the atoms to which they are attached to form C 3 ~C 8 Forms a heterocycloalkyl.

[0304] In some embodiments, for formula (I), (II), (IA) or (IIA), R 7 is a linear or branched C 1 ~C 6 Alkyl group; (C 3 ~C 6 ) Cycloalkylene-R 8 or

[0305] [ka] represents a group selected from where Cy is C 3 ~C 8 It represents cycloalkyl.

[0306] In some embodiments, for formula (I), (II), (IA) or (IIA), R 7 teeth,

[0307] [ka] represents a group selected from

[0308] In some embodiments, the Bcl-xL inhibitor (D) is a compound of formula (IB), (IC), (IIB) or (IIC):

[0309] [ka] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, For formula (IB) or (IC), R 3 is hydrogen; linear or branched C 1 ~C 6 Alkyl ; -X 1 -NR a R b ;-X 1 -N + R a R b R c ; and -X 1 -OR c represents a group selected from For formula (IIB) or (IIC), Z 1 represents a bond, R 3 represents hydrogen; or Z 1 represents -O-, R 3 -X 1 -NR a R b represents R a and R bare each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; 1 ~C 6 Alkyl; and C 1 ~C 6 Alkylene-SO 2 O - represents a group selected from R c is hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, R 6 -X 2 -OR 7 , or linear or branched C 1 ~C 6 Heteroarylene -R optionally substituted with an alkyl group 7 represents a group, R 7 teeth,

[0310] [ka] represents a group selected from R 8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from R 10 represents fluorine, R 12 and R 13 represent, independently of one another, a hydrogen atom or a methyl group, R 14 and R 15 are each independently a hydrogen or a methyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 ~C 6A linear or branched C optionally substituted with one or two groups selected from alkoxy 1 ~C 6 represents an alkylene group, X' 2 is a linear or branched C 1 ~C 6 represents alkylene, R' a and R' b are, independently of each other, hydrogen; one or two hydroxyl or C 1 ~C 6 Linear or branched C optionally substituted with alkoxy groups 1 ~C 6 Alkyl;C 1 ~C 6 Alkylene-NR' d R' e represents a group selected from; or R' a and R' b The nitrogen atom and ring B 3 Forming R' d , R' e are each independently hydrogen or a linear or branched C 1 ~C 6 represents an alkyl group, B 3 is C 3 ~C 8 represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein the bicyclic group includes fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, linear or branched C 1 ~C 6 may be substituted with one or two groups selected from alkyl, hydroxyl, and oxo. Includes.

[0311] In some embodiments, R 7 is the following group:

[0312] [ka] Represents.

[0313] In some embodiments, R 7 teeth,

[0314] [ka] represents a group selected from

[0315] In some embodiments, for formula (I), (IA), (IB), (IC), (II), (IIA), (IIB) or (IIC), R 8 teeth,

[0316] [ka] represents a group selected from Where:

[0317] [ka] represents a bond to the linker.

[0318] In some embodiments, B3 represents a C3-C8 heterocycloalkyl group selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 2,8-diasaspiro[4,5]decanyl group.

[0319] In some embodiments, D represents a Bcl-xL inhibitor covalently attached to a linker L, where the Bcl-xL inhibitor is a compound in Table A1:

[0320] [Table 1-1]

[0321] [Table 1-2]

[0322] [Table 1-3]

[0323] [Table 1-4]

[0324] [Table 1-5]

[0325] [Table 1-6]

[0326] [Table 1-7]

[0327] [Table 1-8]

[0328] [Table 1-9]

[0329] [Table 1-10]

[0330] [Table 1-11] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0331] In some embodiments, D comprises a formula selected from any one of the formulas in Table A2, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

[0332] [Table 2-1]

[0333] [Table 2-2]

[0334] [Table 2-3]

[0335] [Table 2-4]

[0336] [Table 2-5]

[0337] [Table 2-6]

[0338] [Table 2-7]

[0339] [Table 2-8]

[0340] [Table 2-9]

[0341] [Table 2-10]

[0342] [Table 2-11] Where:

[0343] [ka] represents a bond to the linker.

[0344] In some embodiments, -(LD) is formed from a compound selected from Table B, or an enantiomer, diastereoisomer, and / or a pharma- ceutically acceptable salt thereof. In some embodiments, the maleimide group in the compound of Table B is

[0345] [ka] forms a covalent bond with an antibody or an antigen-binding fragment (Ab) to

[0346] [ka] Part (where * indicates the point of attachment to Ab. For the compounds in Tables A1, A2, B and 1, depending on their electronic charge, these compounds may be coupled to one pharma- ceutically acceptable monovalent anionic counterion, M 1 - In some embodiments, the monovalent anionic counterion M 1 - can be selected from bromine, chlorine, iodine, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, etc. In some embodiments, the monovalent anionic counterion M 1 -is a trifluoroacetate or formate.

[0347] [Table 3-1]

[0348] [Table 3-2]

[0349] [Table 3-3]

[0350] [Table 3-4]

[0351] [Table 3-5]

[0352] [Table 3-6]

[0353] [Table 3-7]

[0354] [Table 3-8]

[0355] [Table 3-9]

[0356] [Table 3-10]

[0357]

Table 3-11

[0358]

Table 3-12

[0359]

Table 3-13

[0360]

Table 3-14

[0361]

Table 3-15

[0362]

Table 3-16

[0363]

Table 3-17

[0364]

Table 3-18

[0365]

Table 3-19

[0366]

Table 3-20

[0367]

Table 3-21

[0368]

Table 3-22

[0369]

Table 3-23

[0370]

Table 3-24

[0371]

Table 3-25

[0372]

Table 3-26

[0373]

Table 3-27

[0374]

Table 3-28

[0375]

Table 3-29

[0376]

Table 3-30

[0377]

Table 3-31

[0378]

Table 3-32

[0379]

Table 3-33

[0380]

Table 3-34

[0381]

Table 3-35

[0382]

Table 3-36

[0383]

Table 3-37

[0384]

Table 3-38

[0385]

Table 3-39

[0386]

Table 3-40

[0387]

Table 3-41

[0388]

Table 3-42

[0389]

Table 3-43

[0390]

Table 3-44

[0391]

Table 3-45

[0392]

Table 3-46

[0393]

Table 3-47

[0394]

Table 3-48

[0395]

Table 3-49

[0396]

Table 3-50

[0397]

Table 3-51

[0398] [Table 3-52]

[0399] [Table 3-53]

[0400] [Table 3-54]

[0401] In some embodiments, the antibody-drug conjugate has a formula describing any one of the structures shown in Table 1.

[0402] [Table 4-1]

[0403] [Table 4-2]

[0404] The ADC represented above has the following formula: Ab-(LD) p (1) (wherein Ab represents an anti-Met antibody or antigen fragment thereof covalently linked to a linker-payload (L / P) as depicted above; and p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0405] As used herein, "L / P" refers to a linker-payload, linker-drug, or linker-compound disclosed herein, and the terms "L#-P#" and "L#-C#" are used interchangeably to refer to a particular linker-drug disclosed herein, while the symbols "P#" and "C#" are used interchangeably to refer to a particular compound, unless otherwise specified. For example, "L1-C1" and "L1-P1" both refer to the same linker-payload structure disclosed herein, while "C1" and "P1" both refer to the same compound disclosed herein, including enantiomers, diastereoisomers, atropisomers, deuterated derivatives, and / or pharma- ceutically acceptable salts of any of the foregoing.

[0406] Also provided herein, in some embodiments, are compositions comprising multiple copies of an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein). In some embodiments, the average p of the antibody-drug conjugates in the composition is about 2 to about 4.

[0407] Also provided herein, in some embodiments, is a pharmaceutical composition comprising an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein) or composition (e.g., any of the exemplary compositions described herein) and a pharma- ceutically acceptable carrier.

[0408] Further provided herein in some embodiments are therapeutic uses for the described ADC compounds and compositions, for example, in the treatment of cancer. In some embodiments, the disclosure provides a method of treating cancer (e.g., a cancer that expresses the MET antigen targeted by an antibody or antigen-binding fragment of an ADC). In some embodiments, the disclosure provides a method of reducing a cancer cell population or slowing its expansion and growth in a subject. In some embodiments, the disclosure provides a method of determining whether a subject having or suspected of having cancer will respond to treatment with an ADC compound or composition disclosed herein.

[0409] Exemplary embodiments are methods of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses the target antigen MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0410] Another exemplary embodiment is a method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses the target antigen MET. In some embodiments, the tumor is melanoma, uveal melanoma, kidney cancer including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer including non-small cell lung cancer and small cell lung cancer, gastric cancer including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, or thymoma. In some embodiments, the tumor is lung cancer, pancreatic cancer, stomach cancer, kidney cancer, or liver 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%.

[0411] Another exemplary embodiment is a method of reducing or slowing the expansion and growth of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer cell population expresses the target antigen MET.

[0412] In some embodiments, the cancer cell population is from a tumor or a blood cancer. In some embodiments, the cancer cell population is from a tumor or a blood cancer. In some embodiments, the cancer cell population is from a tumor or a blood cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer cell population is from lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition slows the expansion and growth of the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0413] Another exemplary embodiment is an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject with cancer or a subject suspected of having cancer. In some embodiments, the cancer expresses the target antigen MET. In some embodiments, the cancer is a tumor or blood cancer. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer including non-small cell lung cancer and small cell lung cancer, gastric cancer including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, kidney cancer or liver cancer.

[0414] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in treating a subject having or suspected of having cancer. In some embodiments, the cancer expresses the target antigen MET. In some embodiments, the cancer is a tumor or hematological cancer ... cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0415] Another exemplary embodiment is the use of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) in a method of manufacturing a medicament for treating a subject having or suspected of having cancer. In some embodiments, the cancer expresses the target antigen MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer including non-small cell lung cancer and small cell lung cancer, gastric cancer including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0416] Another exemplary embodiment is a method of determining whether a subject having or suspected of having cancer will respond to treatment with an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample from a subject; contacting the sample with an antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample. In some embodiments, the cancer cells in the sample express the target antigen. In some embodiments, the cancer expresses the target antigen MET. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

[0417] Methods of producing the described ADC compounds and compositions are also disclosed. An exemplary embodiment is a method of producing an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a cleavable linker conjugated or covalently attached to a Bcl-xL inhibitor under conditions that allow conjugation. [Brief description of the drawings]

[0418] [Figure 1] FIG. 1 shows a scheme for site-specific cysteine ​​conjugation. [Diagram 2] FIG. 2 shows the in vitro activity of IgG2 anti-MET naked antibody and anti-Met-Bcl-xLi ADC in EBC-1, SNU-5 and LOUNH-91 (2D, CTG 120h) and H1650 (3D, CTG 120h) cell lines. [Diagram 3] FIG. 3 shows the viability curves and IC50 data of the ADC Ab Mc-L42C-P25 in HCC78 lung cancer cell lines as a single agent or in combination with paclitaxel. [Figure 4-1] FIG. 4a shows the inhibition, growth inhibition, and Loewe excess matrix obtained by naked anti-MetAb or anti-MET-Bcl-xLi ADC in combination with paclitaxel in the EBC-1 cell line. [Figure 4-2] FIG. 4b shows the matrix inhibition, growth inhibition, and Lowy excess obtained by naked anti-MetAb or anti-MET-Bcl-xLi ADC in combination with trametinib in the EBC-1 cell line. [Figure 5-1] FIG. 5a shows the matrix inhibition, growth inhibition, and Lowy excess obtained by naked anti-MetAb or anti-MET-Bcl-xLi ADC in combination with paclitaxel in the SNU-5 cell line. [Figure 5-2] FIG. 5b shows the matrix inhibition, growth inhibition, and Lowy excess obtained by naked anti-MetAb or anti-MET-Bcl-xLi ADC in combination with trametinib in the SNU-5 cell line. [Figure 6] FIG. 6 shows the matrix inhibition, growth inhibition, and Lowy excess obtained by anti-MET-Bcl-xLi ADCs in combination with paclitaxel or trametinib in HCC-78 cell lines. [Figure 7]FIG. 7 shows the matrix inhibition, growth inhibition, and Lowy excess obtained by anti-MET-Bcl-xLi ADCs in combination with paclitaxel or trametinib in the H1650 2D cell line. [Figure 8] FIG. 8 shows tumor volume (mm3) in EBC1-implanted female SCID mice treated with 30 mg / kg and / or 10 mg / kg of Ab F-L9C-P25, Ab Mc and Ab Mc-L9C-P25 administered once IV (n=6). [Figure 9] FIG. 9 shows the percentage of weight loss in EBC1-grafted female SCID mice treated with 30 mg / kg and / or 10 mg / kg Ab F-L9C-P25, Ab Mc and Ab Mc-L9C-P25 administered once IV (n=6). [Figure 10-1] FIG. 10A shows the in vitro activity of IgG1 and IgG2 anti-MET naked antibodies and anti-MET-Bcl-xL ADCs in the EBC-1 cell line (CTG 120h). [Figure 10-2] FIG. 10B shows the in vitro activity of IgG1 and IgG2 anti-MET naked antibodies and anti-MET-Bcl-xL ADCs in the SNU-5 cell line (CTG 120h). [Figure 10-3] FIG. 10C shows the in vitro activity of IgG1 and IgG2 anti-MET naked antibodies and anti-MET-Bcl-xL ADCs in the H1650(3D) cell line (CTG 120h). [Figure 11] FIG. 11 shows the in vitro activity of IgG1 and IgG2 anti-MET naked antibodies and anti-MET-Bcl-xL ADCs in combination with paclitaxel in HCC78 cell lines (CTG 120h). [Figure 12]FIG. 12 shows the mean tumor volume (mm3) + / - SEM in EBC1-grafted female SCID mice treated with Ab Mg, Ab Mc, Ab G-L42C-P25, Ab Mg-L42C-P25, Ab Mc-L42C-P25, Ab Mf-L42C-P25 and Ab Ma-L42C-P25 (3 or 6 mg / kg, IV, single dose, n=6). [Figure 13] FIG. 13 shows the mean + / - SEM % weight loss in EBC1-grafted female SCID mice upon treatment with Ab Mg, Ab Mc, Ab G-L42C-P25, Ab Mg-L42C-P25, Ab Mc-L42C-P25, Ab Mf-L42C-P25 and Ab Ma-L42C-P25 (3 or 6 mg / kg, single dose IV, n=6). [Figure 14] FIG. 14 shows tumor volume (mm3) in H1650-implanted female SCID mice treated IV with Ab Mc naked antibody (30 mg / kg), Ab F-L42C-P25 (30 mg / kg), Ab Mc-L42C-P25 (10 and 30 mg / kg) as single agents (two treatments on days 0 and 14) or in combination with 12.5 mg / kg paclitaxel injected IV three times on days 1, 8 and 15 (n=6; except for groups treated with Ab Mc-L42C-P25 at 30 mg / kg as single agents and in combination with 12.5 mg / kg paclitaxel, where n=4). [Figure 15] FIG. 15 shows the mean + / - SEM % weight loss in H1650-implanted female SCID mice treated IV with Ab Mc naked antibody (30 mg / kg), Ab F-L42C-P25 (30 mg / kg), Ab Mc-L42C-P25 (10 and 30 mg / kg) as single agents (two treatments on days 0 and 14) or in combination with 12.5 mg / kg paclitaxel injected IV three times on days 1, 8 and 15 (n=6; except for groups treated with Ab Mc-L42C-P25 at 30 mg / kg as single agents and in combination with 12.5 mg / kg paclitaxel, where n=4). [Figure 16]FIG. 16 shows tumor volume (mm3) in H1650 implanted female SCID mice treated IV with Ab Mg, Ab Mc, Ab Md naked antibody, Ab G-L42C-P25, Ab Mg-L42C-P25, Ab Mc-L42C-P25, Ab Md-L42C-P25, Ab Mf-L42C-P25, Ab Ma-L42C-P25 and Ab Mb-L42C-P25 in combination with osimertinib given orally at 15 mg / kg on days 1, 2, 3, 4, 7, 8, 9. [Figure 17] FIG. 17 shows the mean + / - SEM % of weight loss in H1650 implanted female SCID mice upon IV treatment with Ab Mg, Ab Mc, Ab Md naked antibody, Ab G-L42C-P25, Ab Mg-L42C-P25, Ab Mc-L42C-P25, Ab Md-L42C-P25, Ab Mf-L42C-P25, Ab Ma-L42C-P25 and Ab Mb-L42C-P25 at 30 mg / kg on day 1 in combination with osimertinib given orally at 15 mg / kg on days 1, 2, 3, 4, 7, 8, 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0419] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The disclosed compositions and methods may be more readily understood by reference to the following detailed description considered in connection with the accompanying drawings, which form a part of this disclosure.

[0420] Throughout this text, the description refers to compositions and methods of using the compositions. When this disclosure describes or claims features or embodiments related to compositions, such features or embodiments are equally applicable to methods of using the compositions. Similarly, when this disclosure describes or claims features or embodiments related to methods of using the compositions, such features or embodiments are equally applicable to the compositions.

[0421] When a range of values ​​is expressed, this includes embodiments using any specific value within that range. Moreover, reference to values ​​stated in a range includes each and every value within that range. All ranges are inclusive of their endpoints and are combinable. When values ​​are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of "or" means "and / or," unless the specific context of its use dictates otherwise. All references cited herein are incorporated by reference for any purpose. In the event of a conflict between the reference and the specification, the specification will control.

[0422] Unless the context of the description indicates otherwise, e.g., where a structure or fragment of a structure is depicted in the absence of a symbol indicating a particular point of attachment, it may be used by itself or attached to other components of the ADC, and it may do so in any orientation, e.g., an antibody may be attached at any suitable point of attachment to a chemical moiety such as a linker-drug. However, where indicated, the components of the ADC are attached in the orientation shown in the given formula. For example, if formula (1) is Ab-(LD) p and the group "-(LD)" is

[0423] [ka] When written as: the detailed structure of formula (1) is:

[0424] [ka] This is because

[0425] [ka] isn't it.

[0426] It should be understood that certain features of the disclosed compositions and methods that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0427] As used throughout this application, antibody drug conjugates can be identified using a naming convention in the general format of "target antigen / antibody-linker-payload". For example, simply, if an antibody drug conjugate is referred to as "target X-L0-P0", such a conjugate would include an antibody that binds to target X, a linker designated as L0, and a payload designated as P0. Alternatively, if an antibody drug conjugate is referred to as "anti-target X-L0-P0", such a conjugate would include an antibody that binds to target X, a linker designated as L0, and a payload designated as P0. In another alternative, if an antibody drug conjugate is referred to as "AbX-L0-P0", such a conjugate would include an antibody designated as AbX, a linker designated as L0, and a payload designated as P0. A control antibody drug conjugate that includes a non-specific isotype control antibody can be referred to as "isotype control IgG1-L0-P0" or "IgG1-L0-P0".

[0428] Any formula given herein is also intended to represent unlabeled forms of the compound, as well as isotopically labeled forms of the compound.Isotopically labeled compounds have the structure represented by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C. 14 C. 15 N,18 F, and 36 Thus, the present disclosure provides, for example, 3 H and 14 Compounds incorporating one or more of any of the preceding isotopes, including radioisotopes such as C; or 2 H and 13 It should be understood that this includes compounds in which non-radioactive isotopes such as C are present. Such isotope-labeled compounds may be used for metabolic studies ( 14 C), kinetic reaction studies (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0429] definition Various terms relating to the described embodiments are used throughout the specification and claims. Such terms should be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0430] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. The terms "being of," "including," and "containing," as in "comprising," "having," and "being of chemical formula," should be construed as open-ended terms (i.e., meaning "including but not limited to") unless otherwise stated. In addition, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment could be more narrowly claimed using the middle term "consisting essentially of" or the closed term "consisting of."

[0431] The terms "about" or "approximately," when used in the context of numerical values ​​and ranges, refer to a value or range that is close to or near the recited value or range, such that the implementation may be performed as intended, as would be apparent to one of ordinary skill in the art from the teachings contained herein. In some embodiments, about means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of the numerical amount. In one embodiment, the term "about" refers to a range of values ​​that is 10% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​that is 5% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​that is 1% greater or less than the stated value.

[0432] The terms "antibody-drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to one or more therapeutic compounds (e.g., Bcl-xL inhibitors) linked to one or more antibodies or antigen-binding fragments. In some embodiments, an ADC has the general formula: Ab-(LD) p (Formula (1)) where Ab = antibody or antigen-binding fragment (e.g., an anti-Met antibody or antigen-binding fragment thereof), L = linker moiety, D = drug moiety (e.g., a Bcl-xL inhibitor drug moiety), and p = number of drug moieties per antibody or antigen-binding fragment. In ADCs that include Bcl-xL inhibitor drug moieties, "p" refers to the number of Bcl-xL inhibitor compounds linked to the antibody or antigen-binding fragment.

[0433] The term "antibody" is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the above, by at least one antigen recognition site in the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact immunoglobulins, and may be derived from natural or recombinant sources. An "intact" antibody is typically a glycoprotein that includes at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interrupted by more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The antibody can be a monoclonal antibody, a human antibody, a humanized antibody, a camelized antibody, or a chimeric antibody. The antibody can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass. The antibody can be an intact antibody or an antigen-binding fragment thereof.

[0434] In some embodiments, the antibody or antibody fragment disclosed herein comprises modified or engineered amino acid residues, e.g., one or more cysteine ​​residues, as sites for conjugation to a drug moiety (Junutula JR, et al., Nat Biotechnol 2008, 26:925-932). In one embodiment, the present disclosure provides modified antibodies or antibody fragments comprising substitutions of one or more amino acids with cysteines at the positions described herein. The sites for cysteine ​​substitutions are in the constant region of the antibody or antibody fragment, and thus are applicable to a variety of antibodies or antibody fragments, and the sites are selected to provide stable, homogenous conjugates. The modified antibody or fragment can have one, two, or more cysteine ​​substitutions, and these substitutions can be used in combination with other modification and conjugation methods described herein. Methods for inserting cysteines at specific locations in an antibody are known in the art, see, e.g., Lyons et al., (1990) Protein Eng., 3:703-708, WO 2011 / 005481, WO 2014 / 124316, WO 2015 / 138615. In certain embodiments, the modified antibody comprises a substitution of one or more amino acids with cysteines in its constant region selected from positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 191, 195, 197, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, ​​390, 392, 398, 400 and 422 of the antibody heavy chain, where the positions are numbered according to the EU system.In some embodiments, the modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine ​​in its constant region selected from positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of the light chain of the antibody or antibody fragment, where the positions are numbered according to the EU system, and the light chain is a human kappa light chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two or more amino acids with cysteine ​​in its constant region, where the combination includes a substitution at position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, or position 107 of the antibody light chain, where the positions are numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​in its constant region, the substitution being at position 375 of the antibody heavy chain, at position 152 of the antibody heavy chain, at position 360 of the antibody heavy chain, at position 107 of the antibody light chain, at position 165 of the antibody light chain, or at position 159 of the antibody light chain, where the positions are numbered according to the EU system, and the light chain is a kappa chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two amino acids with cysteine ​​in its constant region, the combination comprising substitutions at position 375 of the antibody heavy chain and at position 152 of the antibody heavy chain, where the positions are numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​at position 360 of the antibody heavy chain, where the positions are numbered according to the EU system. In other specific embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with a cysteine ​​at position 107 of the antibody light chain, where the positions are numbered according to the EU system, and where the light chain is a kappa chain.

[0435] The term "antibody fragment" or "antigen-binding fragment" or "functional antibody fragment", as used herein, refers to at least a portion of an antibody that retains the ability to specifically interact (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) with an epitope of an antigen (e.g., MET). Antigen-binding fragments may also retain the ability to be internalized into antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, and the like are intended to encompass the use of antibody-derived binding domains in the context of larger macromolecules, such as ADCs. It has been shown that fragments of full-length antibodies can perform the antigen-binding function of the full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies, e.g., sdAb (either VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bis-scFvs (see, e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):1126-36). Antigen-binding fragments can also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see US Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies).The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment comprising a variable region of a light chain and at least one antigen-binding fragment comprising a variable region of a heavy chain, where the light and heavy chain variable regions are contiguously linked, for example, via a synthetic linker, e.g., a short flexible polypeptide linker, and expressed as a single-chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, the scFv may have, for example, the VL and VH variable regions in either order relative to the N-terminus and C-terminus of the polypeptide, and the svFv may comprise VL-linker-VH or VH-linker-VL. Antigen-binding fragments are obtained using conventional techniques known to those skilled in the art, and the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. For example, antigen-binding fragments may be prepared by cleavage of the intact protein, for example, by protease or chemical cleavage.

[0436] The term "complementarity determining region" or "CDR" as used herein refers to the sequence of amino acids in an antibody variable region that confers antigen specificity and binding affinity. For example, there are generally three CDRs (e.g., HCDR1, HCDR2, and HCDR3) in each heavy chain variable region, and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable region. The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991) "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (the "Kabat" numbering scheme); Al-Lazikani et al. (1997) J Mol Biol. 273(4):927-48 (the "Chothia" numbering scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77) (the "IMGT" numbering scheme), or a combination thereof. In the combined Kabat and Chothia numbering scheme for a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, the CDRs correspond to the amino acid residues defined as part of the Kabat CDRs together with the amino acid residues defined as part of the Chothia CDRs. As used herein, CDRs defined according to the "Chothia" numbering scheme may also be referred to as "hypervariable loops."

[0437] In some embodiments, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered under Kabat as follows: 31 to 35 (HCDR1) (e.g., an insertion after position 35), 50 to 65 (HCDR2), and 95 to 102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered as follows: 24 to 34 (LCDR1) (e.g., an insertion after position 27), 50 to 56 (LCDR2), and 89 to 97 (LCDR3). In some embodiments, under Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1) (e.g., insertion after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, in some embodiments, the CDRs comprise or consist of, for example, amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH, and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. In some embodiments, under IMGT, the CDR amino acid residues in VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the CDR regions of an antibody may be determined using the program IMGT / DomainGap Align.

[0438] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies that make up the population are identical except for naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically contain a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-8, and Marks et al. (1991) J Mol Biol. 222:581-97. The term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope.

[0439] The monoclonal antibodies described herein can be non-human, human, or humanized. This term specifically includes "chimeric" antibodies in which a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0440] The term "human antibody" as used herein refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human. This term includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such a human sequence, e.g., a human germline sequence, or a mutated version of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik et al. ((2000) J Mol Biol. 296(1):57-86). The structure and location of immunoglobulin variable domains, e.g., CDRs, may be defined using well-known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and / or the ImMunoGenTics (IMGT) numbering. The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, or by somatic mutation in vivo, or by conservative substitutions that promote stability or manufacturing). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been grafted onto human framework sequences.

[0441] The term "recombinant human antibody," as used herein, refers to a human antibody that has been prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes, or hybridomas prepared therefrom, antibodies isolated from host cells transformed to express human antibodies, e.g., from transfectomas, antibodies isolated from recombinant combinatorial human antibody libraries, and antibodies prepared, expressed, created, or isolated by any other means including splicing all or a portion of a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In some embodiments, however, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from, and related to, human germline VH and VL sequences, sequences that may not naturally exist within the human antibody germline repertoire in vivo.

[0442] The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some instances, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species with the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize the immune response in the latter species.

[0443] As used herein, the term "humanized antibody" refers to forms of antibodies that contain sequences derived from human antibodies as well as non-human (e.g., murine) antibodies. Such antibodies are a type of chimeric antibody that contains minimal sequence derived from non-human immunoglobulin. In general, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. A humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. A humanized antibody can be further modified by substitution of residues in the Fv framework regions and / or within the replaced non-human residues to refine and / or optimize the specificity, affinity, and / or activity of the antibody.

[0444] The term "Fc region" as used herein refers to a polypeptide comprising at least a portion of the CH3, CH2, and hinge regions of the constant domain of an antibody. Optionally, the Fc region may comprise a CH4 domain present in some antibody classes. The Fc region may comprise the entire hinge region of the constant domain of an antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region and the CH1 region of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region CH3 region of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises the Fc region, the CH1 region, and the kappa / lambda region from the constant domain of the antibody. In some embodiments, the antibody or antigen-binding fragment comprises a constant region, e.g., a heavy chain constant region and / or a light chain constant region. In some embodiments, such constant regions are modified compared to the wild-type constant region. That is, the polypeptide may comprise changes or modifications to one or more of the three heavy chain constant domains (CH1, CH2, or CH3) and / or to the light chain constant region domain (CL). Examples of modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc.

[0445] "Internalizing" as used herein with respect to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that, upon binding to a cell, can be taken up (i.e., "internalized") through the lipid bilayer membrane of the cell into an internal compartment, preferably into a degradable compartment in the cell. For example, an internalizing anti-Met antibody can be taken up into the cell after binding to MET on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen (e.g., MET) and is an internalizing antibody or internalizing antigen-binding fragment (i.e., the ADC translocates through the cell membrane after antigen binding). In some embodiments, the internalizing antibody or antigen-binding fragment binds to a receptor on the cell surface. An internalizing antibody or internalizing antigen-binding fragment that targets a receptor on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is taken up into the cell via receptor-mediated endocytosis.

[0446] "Non-internalizing" as used herein with respect to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that remains on the cell surface upon binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen and is a non-internalizing antibody or non-internalizing antigen-binding fragment (i.e., the ADC remains on the cell surface and does not translocate through the cell membrane after antigen binding). In some embodiments, the non-internalizing antibody or antigen-binding fragment binds to a non-internalizing receptor or other cell surface antigen.

[0447] The term "MET", "MET proto-oncogene, receptor tyrosine kinase", "cMet" or "c-Met" as used herein refers to any native form of human MET protein. The term encompasses full-length human MET (e.g., NCBI Reference Sequence: NP_001120972.1; SEQ ID NO: 35) and any form of human MET that may result from cellular processing. The term also encompasses functional variants or fragments of human MET, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human MET (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to the wild-type protein). MET can be isolated from humans or produced recombinantly or by synthetic methods.

[0448] The term "anti-MET antibody" or "antibody that binds MET," as used herein, refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to MET. 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 MET. WO 2016 / 042412 provides exemplary MET-binding sequences, including exemplary anti-MET antibody sequences, and is incorporated herein by reference thereto. In some embodiments, the anti-MET antibodies used in the ADCs disclosed herein are internalizing antibodies or internalizing antigen-binding fragments.

[0449] The term "binding specificity" as used herein refers to the ability of an individual antibody or antigen-binding fragment to preferentially react with one antigenic determinant over a different antigenic determinant. Specificity indicates the degree to which an antibody or fragment preferentially binds to one antigenic determinant over a different antigenic determinant. Also as used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an anti-MET antibody) and a target antigen (e.g., MET) in a heterogeneous population of proteins and other biologics. An antibody can be tested for binding specificity by comparing binding to the appropriate antigen with binding to an unrelated antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to the appropriate antigen with at least 2, 5, 7, 10, or more times higher affinity than to an unrelated antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is one that binds only to a target antigen (e.g., MET) and does not bind (or shows minimal binding to) other antigens. In some embodiments, an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., MET) is at least 1×10 -6 Less than M, 1×10 -7 Less than M, 1×10 -8 Less than M, 1×10 -9 Less than M, 1×10 -10 Less than M, 1×10 -11 Less than M, 1×10 -12 Less than M or 1×10 -13 K less than M D In some embodiments, K D In some embodiments, K D is 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0450] The term "affinity" as used herein refers to the strength of interaction between an antibody and an antigen at a single antigenic site. Without being bound by theory, within each antigen-binding site, the variable region of an antibody "arm" interacts with the antigen at multiple sites through weak non-covalent forces, and the more interactions, the stronger the affinity typically is. The binding affinity of an antibody is the sum of the attractive and repulsive forces operating between an antigenic determinant and the binding site of the antibody.

[0451] "k on " or "k a The term "on-rate constant" refers to the on-rate constant for the association of an antibody to an antigen to form an antibody / antigen complex. The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0452] "k off " or "k d The term "off-rate constant" refers to the off-rate constant for dissociation of an antibody from the antibody / antigen complex. The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0453] "K D The term K" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. D is k a / k d The rate can be determined using standard assays such as surface plasmon resonance, biolayer interferometry, or ELISA assays.

[0454] The term "epitope" refers to a portion of an antigen that can be recognized and specifically bound by an antibody (or antigen-binding fragment). Epitope determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. When the antigen is a polypeptide, epitopes can be formed from adjacent amino acids, or non-adjacent amino acids juxtaposed by tertiary folding of the polypeptide. Epitopes can be "linear" or "conformational". Conformational and linear epitopes are distinguished in that binding to the former is lost in the presence of denaturing solvents, but not to the latter. The epitope bound by an antibody (or antigen-binding fragment) may be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of antigen-antibody complexes, as well as monitoring the binding of the antibody to fragments or mutated variants of the antigen, or monitoring the solvent accessibility of different portions of the antibody and antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) BioDrugs 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev Proteomics 2:745-56).

[0455] Competitive binding and epitope binning can also be used to determine antibodies that share the same or overlapping epitopes. Competitive binding can be performed as described in "Antibodies, A Laboratory Manual," Cold Spring Harbor Laboratory, Harlow and Lane (1 st edition 1988, 2 ndCompetitive binding can be assessed using a cross-blocking assay, such as the assay described in (E.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein (e.g., a binding protein comprising a CDR and / or variable domain selected from those identified in Tables C-D) to a target antigen, such as MET, by at least about 50% (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage therebetween) in a cross-blocking assay, and / or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance of antibodies or binding proteins binding at nearby epitopes (see, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66)). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes. For example, binding proteins that compete for binding can be "binned" into a group of binding proteins with overlapping or nearby epitopes, while those that do not compete are placed into another group of binding proteins that do not have overlapping or nearby epitopes.

[0456] As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues. The term encompasses amino acid polymers that contain two or more amino acids joined together by peptide bonds, amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as naturally occurring and non-naturally occurring amino acid polymers. The term includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, and the like. The term also includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0457] A "recombinant" protein refers to a protein (eg, an antibody) made using recombinant techniques, e.g., by the expression of a recombinant nucleic acid.

[0458] An "isolated" protein refers to a protein that is not associated with at least some of the materials with which it is normally associated in its natural state. For example, a naturally occurring polynucleotide or polypeptide present in a living organism is not isolated, but the same polynucleotide or polypeptide separated from some or all of the coexisting materials in a living organism is isolated. This definition includes the production of antibodies in a wide variety of organisms and / or host cells known in the art.

[0459] "Isolated antibody" as used herein is an antibody that has been identified and separated from one or more (e.g., most) of the components (by weight) of its original environment, for example, from the components of the hybridoma cell culture or different cell culture used for its production. In some embodiments, separation is performed to sufficiently remove components that may otherwise interfere with the suitability of the antibody for the desired application (e.g., for therapeutic use). Methods for preparing isolated antibodies are known in the art and include, but are not limited to, protein A chromatography, anion exchange chromatography, cation exchange chromatography, virus retention filtration, and ultrafiltration.

[0460] As used herein, the term "variant" refers to a nucleic acid sequence or amino acid sequence that differs from a reference nucleic acid sequence or amino acid sequence, respectively, but retains one or more biological properties of the reference sequence. A variant may contain one or more amino acid substitutions, deletions, and / or insertions (or corresponding substitutions, deletions, and / or insertions of codons) relative to the reference sequence. The changes in the nucleic acid variant may not change the amino acid sequence of the peptide encoded by the reference nucleic acid sequence, or may result in amino acid substitutions, additions, deletions, fusions, and / or truncations. In some embodiments, the nucleic acid variants disclosed herein encode the same amino acid sequence as that encoded by the unmodified nucleic acid, or encode modified amino acid sequences that retain one or more functional properties of the unmodified amino acid sequence. The changes in the sequence of the peptide variant are typically limited or conservative, such that the sequences of the unmodified peptide and the variant are overall very similar and, in many regions, identical. In some embodiments, the peptide variants retain one or more functional properties of the unmodified peptide sequence. Variants and unmodified peptides may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination.

[0461] Nucleic acid or peptide variants can be naturally occurring variants or variants that are not known to occur naturally. Nucleic acid and peptide variants can be made by mutagenesis techniques, by direct synthesis, or by other techniques known in the art. Variants do not necessarily require physical manipulation of a reference sequence. As long as a sequence contains different nucleic acids or amino acids compared to a reference sequence, it is considered a "variant" regardless of how it is synthesized. In some embodiments, variants have high sequence identity (i.e., 60% or more nucleic acid or amino acid sequence identity) compared to a reference sequence. In some embodiments, peptide variants encompass polypeptides with amino acid substitutions, deletions, and / or insertions, e.g., variants that also retain one or more functions of the reference sequence, so long as the polypeptide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% amino acid sequence identity with a reference sequence, or with a corresponding segment (e.g., a functional fragment) of a reference sequence. In some embodiments, nucleic acid variants include polynucleotides having amino acid substitutions, deletions, and / or insertions, so long as the polynucleotide has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% nucleic acid sequence identity with a reference sequence, or with a corresponding segment (e.g., a functional fragment) of a reference sequence.

[0462] The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. For nucleic acid sequences, conservatively modified variants refer to nucleic acids that code for identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids code for any given protein. For example, the codons GCA, GCC, GCG and GCU all code for the amino acid alanine. Thus, at any position where alanine is specified by a codon, the codon can be changed to any of the corresponding codons described without changing the encoded polypeptide. Such nucleic acid variations are "silent variations", which are one species of conservatively modified variations. Every nucleic acid sequence herein that codes for a polypeptide also describes every possible silent variation of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be modified to give a functionally identical molecule. Thus, each silent variation of a nucleic acid that codes for a polypeptide is implicit in each described sequence. For polypeptide sequences, conservatively modified variants include individual substitutions, deletions, or additions to the polypeptide sequence that result in the replacement of an amino acid with a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art.

[0463] The term "conservative sequence modification" as used herein refers to an amino acid modification that does not significantly affect or change the binding characteristics of, for example, an antibody or antigen-binding fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into an antibody or antigen-binding fragment by standard techniques known in the art, such as, for example, site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue that has a similar side chain. Families of amino acid residues that have similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, in some embodiments, one or more amino acid residues within an antibody can be replaced with other amino acid residues from the same side chain family, and the altered antibodies can be tested using the functional assays described herein.

[0464] The term "homologous" or "identity" as used herein refers to the subunit sequence identity between two polymer molecules, e.g., between two nucleic acid molecules, such as between two DNA molecules or between two RNA molecules, or between two polypeptide molecules. If a subunit position in both of the two molecules is occupied by the same monomeric subunit, e.g., if a position in each of the two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a linear function of the number of matching or homologous positions. For example, if half of the positions in the two sequences (e.g., 5 positions in a polymer 10 subunits in length) are matched or homologous, the two sequences are 50% homologous, and if 90% of the positions (e.g., 9 out of 10) are matched or homologous, the two sequences are 90% homologous.

[0465] The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where the amino acid sequence fragment in the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to the reference sequence (without additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions where identical amino acid residues are present in both sequences to obtain the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity. The output is the percent identity of the subject sequence to the query sequence. The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Generally, amino acid identity or homology between the proteins disclosed herein and variants thereof, including variants of target antigens (such as MET) and variants of antibody variable domains (including individual variant CDRs), is at least 80% to the sequences represented herein, e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, nearly 100%, or 100% identity or homology.

[0466] The comparison of sequences and the determination of percent identity between two sequences can be accomplished using mathematical algorithms. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J Mol Biol. 48:444-53) algorithm implemented in the GAP program in the GCG software package, using either a Blossum62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna.CMP matrix, and a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. An exemplary set of parameters is the Blossum62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences may also be determined using the algorithm of Meyers and Miller ((1989) CABIOS 4:11-17) as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0467] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination of two or more thereof. The term "therapeutic agent" or "drug" refers to an agent that can modulate a biological process and / or has biological activity. The Bcl-xL inhibitors described herein and ADCs containing them are exemplary therapeutic agents.

[0468] The term "chemotherapeutic agent" or "anti-cancer agent" is used herein to refer to any agent that is effective in the treatment of cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Chemotherapeutic agents include antibodies, biomolecules, and small molecules, including the Bcl-xL inhibitors described herein and ADCs containing them. A chemotherapeutic agent may be a cytotoxic agent or a cytostatic agent. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or proliferation of cells. The term "cytotoxic agent" refers to a substance that primarily causes cell death by interfering with the expression activity and / or function of a cell.

[0469] The term "B-cell lymphoma-extra-large" or "Bcl-xL" as used herein refers to any native form of human Bcl-xL, an anti-apoptotic member of the Bcl-2 protein family. The term encompasses full-length human Bcl-xL (e.g., UniProt reference sequence: Q07817-1), as well as any form of human Bcl-xL that may result from cellular processing. The term also encompasses functional variants or fragments of human Bcl-xL, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human Bcl-xL (i.e., variants and fragments are included unless the context indicates that the term is used to refer only to wild-type protein). Bcl-xL can be isolated from humans or produced recombinantly or by synthetic methods.

[0470] The terms "inhibit" or "inhibition" or "inhibiting" as used herein means reducing a measurable amount, biological activity or biological process, which may include, but does not require, complete prevention or inhibition. In some embodiments, "inhibition" means reducing the expression and / or activity of Bcl-xL and / or one or more upstream modulators or downstream targets thereof.

[0471] The term "Bcl-xL inhibitor," as used herein, refers to an agent capable of reducing the expression and / or activity of Bcl-xL and / or one or more of its upstream modulators or downstream targets. Exemplary Bcl-xL modulators (including exemplary inhibitors of Bcl-xL) are described in WO 2021 / 018858, WO 2021 / 018857, WO 2010 / 080503, WO 2010 / 080478, WO 2013 / 055897, WO 2013 / 055895, WO 2016 / 094509, WO 2016 / 094517, WO 2016 / 094505, Tao et al., ACS Medicinal Chemistry Letters (2014), 5(10), 1088-109, and Wang et al., ACS Medicinal Chemistry Letters (2020), 11(10), 1829-1836, WO 2021 / 018858 and WO 2021 / 018857, each of which is incorporated by reference herein as exemplary Bcl-xL modulators, including exemplary Bcl-xL inhibitors that may be included as drug moieties in the disclosed ADCs.

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

[0473] The term "cancer" as used herein refers to the presence of cells with characteristics characteristic of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological features. Often, cancer cells may be in the form of a tumor or mass, but such cells may exist alone in a subject or circulate in the bloodstream as independent cells, such as leukemia or lymphoma cells. The term "cancer" includes all types of cancer and cancer metastasis, including blood cancer, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Blood cancers may include B-cell malignancies, cancers of the blood (leukemia), cancers of plasma cells (myeloma, e.g., multiple myeloma), or cancers of the lymph nodes (lymphoma). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias may include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), and the like. The terms "acute lymphoblastic leukemia" and "acute lymphocytic leukemia" may be used interchangeably to describe ALL. Lymphomas may include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and the like. Other hematological cancers may include myelodysplastic syndromes (MDS). Solid tumors may include carcinomas, such as adenocarcinomas, such as breast cancer, pancreatic cancer, prostate cancer, colon or colorectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, and the like.In some embodiments, the cancer is selected from the group consisting of melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0474] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, either benign or malignant, including precancerous lesions.In some embodiments, the tumor is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer, including oral cancer, cervical cancer and endocervical cancer, bladder cancer and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, or thymoma.In some embodiments, the tumor is lung cancer, pancreatic cancer, gastric cancer, kidney cancer, or liver cancer.

[0475] The terms "tumor cell" and "cancer cell" may be used interchangeably herein and refer to an individual cell or the total population of cells derived from a tumor or cancer, including both non-tumorigenic cells and cancer stem cells. When referring only to cells that lack the ability to reproduce and differentiate, the terms "tumor cell" and "cancer cell" are modified by the term "non-tumorigenic" to distinguish the cells from cancer stem cells.

[0476] The terms "target negative", "target antigen negative", or "antigen negative" as used herein refer to the absence of target antigen expression by a cell or tissue. The terms "target positive", "target antigen positive", or "antigen positive" refer to the presence of target antigen expression. For example, a cell or cell line that does not express a target antigen may be described as target negative, while a cell or cell line that expresses a target antigen may be described as target positive.

[0477] The terms "subject" and "patient" are used interchangeably herein to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[0478] The term "subject in need of treatment," as used herein, refers to a subject who would benefit biologically, medically, or in quality of life from treatment (e.g., treatment with any one or more of the exemplary ADC compounds described herein).

[0479] As used herein, the terms "treat," "treating," or "treatment" refer to any improvement in any outcome of a disease, disorder, or condition, e.g., extended survival, lower mortality, and / or reduced side effects, resulting from an alternative therapeutic modality. In some embodiments, treatment includes delaying or ameliorating the disease, disorder, or condition (i.e., delaying, halting, or reducing the onset of the disease, or at least one of its clinical symptoms). In some embodiments, treatment includes delaying, alleviating, or ameliorating at least one physical parameter of the disease, disorder, or condition, including those that may be unrecognizable by the patient. In some embodiments, treatment includes modulating the disease, disorder, or condition physically (e.g., stabilization of a recognizable symptom), physiologically (e.g., stabilization of a physical parameter), or both. In some embodiments, treatment includes administration of a described ADC compound or composition to a subject, e.g., a patient, to obtain the treatment benefits enumerated herein. Treatment may be to cure, heal, relieve, delay, prevent, alleviate, alter, correct, ameliorate, ameliorate, improve, or affect a disease, disorder, or condition (e.g., cancer), a symptom of a disease, disorder, or condition (e.g., cancer), or a predisposition to a disease, disorder, or condition (e.g., cancer). In some embodiments, in addition to treating a subject having a disease, disorder, or condition, the compositions disclosed herein may also be provided prophylactically to prevent or reduce the likelihood of the occurrence of the disease, disorder, or condition.

[0480] As used herein, the terms "prevent," "preventing," or "prevention" of a disease, disorder, or condition refers to prophylactic treatment of a disease, disorder, or condition, or delaying the onset or progression of a disease, disorder, or condition.

[0481] As used herein, a "pharmaceutical composition" refers to a composition, e.g., a preparation of an ADC compound or composition, in addition to at least one other (and optionally two or more other) components suitable for administration to a subject, e.g., a pharma- ceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The pharmaceutical compositions provided herein are in a form that allows for administration and thereafter provides the intended biological activity of the active ingredient and / or achieves a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain additional components that are unacceptably toxic to the subject to whom the formulation will be administered.

[0482] As used herein, the terms "pharmaceutical acceptable carrier" and "physiologically acceptable carrier", which may be used interchangeably, refer to a carrier or diluent that does not cause significant irritation to a subject and does not neutralize the biological activity and properties of the administered ADC compound or composition, and / or any additional therapeutic agent in the composition. Pharmaceutically acceptable carriers may enhance or stabilize the composition, or can be used to facilitate the preparation of the composition. Pharmaceutically acceptable carriers may include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption retardants, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.Carrier may be selected to minimize adverse side effects in the subject and / or to minimize the degradation of the active ingredient.Adjuvants may also be included in any of these formulations.

[0483] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Formulations for parenteral administration can contain excipients such as, for example, sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalenes. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants, including, for example, polysorbate 20.

[0484] The term " pharmaceutically acceptable salt " as used herein refers to salt that does not nullify the biological activity and properties of the compound of the present invention and does not cause significant irritation to the subject to which it is administered. Examples of such salts include, but are not limited to, (a) the acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and the salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.; and (b) the salts formed with elemental anions, such as chlorine, bromine, and iodine. See, e.g., Haynes et al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database," J. Pharmaceutical Sciences, vol. 94, no. 10 (2005), and Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, vol. 66, no. 1 (1977), which are incorporated herein by reference.

[0485] In some embodiments, depending on their electronic charge, the antibody-drug conjugates (ADCs), linkers, payloads, and linker-payloads described herein are coupled to a monovalent anionic counterion M 1 - Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharma- ceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M 1 - may be selected from bromine, chlorine, iodine, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, and the like. In some embodiments, the monovalent anionic counterion M 1 - is a trifluoroacetate or formate.

[0486] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound described herein, e.g., an ADC compound or composition described herein, that produces a desired therapeutic result (i.e., reduction or inhibition of enzyme or protein activity, relief of symptoms, alleviation of symptoms or conditions, delay of disease progression, reduction of tumor size, inhibition of tumor growth, prevention of metastasis). In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount induces or causes side effects, but only as tolerated by the treating clinician, given the patient's condition. In some embodiments, a therapeutically effective amount is effective in detectably killing, reducing, and / or inhibiting the growth or spread of cancer cells, the size or number of tumors, and / or other measures of the level, stage, progression, and / or severity of cancer. The term also applies to a dose that induces a specific response in a target cell, e.g., reduction, delay, or inhibition of cell growth. A therapeutically effective amount can be determined by initially administering a low dose and then gradually increasing the dose until the desired effect is achieved. The therapeutically effective amount may also vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be easily determined by those skilled in the art. The specific amount may vary depending, for example, on the specific pharmaceutical composition, the subject and its age, and existing health conditions or risk of health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered. In the case of cancer, a therapeutically effective amount of the ADC may reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0487] As used herein, the term "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a compound disclosed herein, e.g., an ADC compound or composition described herein, that is effective at dosages and for periods of time necessary to achieve the desired prophylactic result. Typically, a prophylactically effective amount is lower than a therapeutically effective amount, since a prophylactic dose is used in subjects at a pre- or early stage of disease. In some embodiments, a prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with cancer.

[0488] The term "p" or "drug loading" or "drug:antibody ratio" or "drug to antibody ratio" or "DAR" refers to the number of drug moieties per antibody or antigen-binding fragment, i.e., drug loading, or the number of -LD moieties per antibody or antigen-binding fragment (Ab) in an ADC of formula (1). In an ADC that includes a Bcl-xL inhibitor drug moiety, "p" refers to the number of Bcl-xL inhibitor compounds linked to an antibody or antigen-binding fragment. For example, if two Bcl-xL inhibitor compounds are linked to an antibody or antigen-binding fragment, then p=2. In a composition that includes multiple copies of an ADC of formula (1), "average p" refers to the average number of -LD moieties per antibody or antigen-binding fragment, also referred to as "average drug loading".

[0489] Antibody-drug conjugates Antibody-drug conjugate (ADC) compounds of the present disclosure include those with anti-cancer activity. In particular, ADC compounds include antibodies or antigen-binding fragments conjugated (i.e., covalently attached by a linker) to a drug moiety (e.g., a Bcl-xL inhibitor), where the drug moiety when not conjugated to an antibody or antigen-binding fragment has a cytotoxic or cytostatic effect. In some embodiments, the drug moiety when not conjugated to an antibody or antigen-binding fragment can reduce the expression and / or activity of Bcl-xL and / or its one or more upstream modulators or downstream targets. Without being bound by theory, by targeting Bcl-xL expression and / or activity, in some embodiments, the ADCs disclosed herein may provide potent anti-cancer agents. Also, without being bound by theory, by conjugating a drug moiety to an antibody that binds to an antigen associated with expression in tumor cells or cancer, the ADCs may provide improved activity, better cytotoxic specificity, and / or reduced off-target killing compared to the drug moiety when administered alone.

[0490] In some embodiments, the components of the ADC are thus selected so that: (i) in isolation, they retain one or more therapeutic properties exhibited by the antibody and drug moieties; (ii) they maintain the specific binding properties of the antibody or antigen-binding fragment; (iii) they optimize drug loading and drug-to-antibody ratio; (iv) they enable delivery of the drug moiety, e.g., intracellular delivery, via stable attachment to the antibody or antigen-binding fragment; (v) they maintain ADC stability as an intact conjugate until transport or delivery to the target site; (vi) they minimize aggregation of the ADC before or after administration; (vii) they enable a therapeutic effect, e.g., a cytotoxic effect, of the drug moiety after cleavage or other release mechanisms in the cellular environment; (viii) they exhibit in vivo anti-cancer treatment efficacy in isolation that is comparable to or superior to that of the antibody and drug moiety; (ix) they minimize off-target killing by the drug moiety; and / or (x) they exhibit desirable pharmacokinetic and pharmacodynamic properties, formulatability, and toxicological / immunological profiles. Each of these properties may provide improved ADCs for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0491] The disclosed ADC compounds may selectively deliver an effective dose of a cytotoxic or cytostatic agent to cancer cells or tumor tissues. In some embodiments, the cytotoxic and / or cytostatic activity of the ADC depends on the target antigen expression in the cells. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells that express the target antigen while minimizing off-target killing. In some embodiments, the disclosed ADCs do not exhibit cytotoxic and / or cytostatic effects on cancer cells that do not express the target antigen.

[0492] In certain aspects, provided herein are ADC compounds comprising an anti-Met antibody or antigen-binding fragment thereof (Ab), a Bcl-xL inhibitor drug moiety (D), and a linker moiety (L) that covalently attaches the Ab to D. In some embodiments, provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab) that targets a cancer cell, a Bcl-xL inhibitor drug moiety (D), and a linker moiety (L) that covalently attaches the Ab to D. In some embodiments, the antibody or antigen-binding fragment can bind to a tumor-associated antigen (e.g., MET), for example, with high specificity and high affinity. In some embodiments, the antibody or antigen-binding fragment is internalized into the target cell upon binding, for example, into a degradable compartment in the cell. In some embodiments, the ADC is internalized upon binding to the target cell, undergoes degradation, releases the Bcl-xL inhibitor drug moiety, and kills the cancer cell. The Bcl-xL inhibitor drug moiety may be released from the antibody and / or linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0493] An exemplary ADC has formula (1): Ab-(LD) p (1) where Ab=anti-Met antibody or antigen-binding fragment, L=linker moiety, D=Bcl-xL inhibitor drug moiety, and p=number of Bcl-xL inhibitor drug moieties per antibody or antigen-binding fragment. has.

[0494] A.Antibodies The antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cell. In some embodiments, the antibody or antigen-binding fragment (Ab) of formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. In some embodiments, the cell or the cancer cell expresses MET. In some embodiments, the target antigen MET has the following amino acid sequence: <NCBI Reference Sequence: NP_001120972.1>

[0495] [Chem.]

[0496] An antibody or antigen-binding fragment can bind to a target antigen with a dissociation constant (K D ) of ≤1 mM, ≤100 nM, or ≤10 nM, or any amount in between, as measured, for example, by BIAcore® analysis. In some embodiments, K D is from 1 pM to 500 pM. In some embodiments, K D is between 500 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM.

[0497] In some embodiments, the antibody or antigen-binding fragment is a four-chain antibody (also referred to 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 the ability to provide at least one function of an immunoglobulin.

[0498] In some embodiments, the antibody or antigen-binding fragment is an internalizing antibody or an internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody or an internalizing antigen-binding fragment thereof binds to a target cancer antigen expressed on the surface of a cell and enters the cell upon binding. In some embodiments, the Bcl-xL inhibitor drug moiety 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, after the ADC has entered and is present in a cell expressing the target cancer antigen (i.e., after the ADC has been internalized).

[0499] In some embodiments, the antibody comprises a mutation that mediates reduced or absent antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, these mutations are known as Fc-silencing, Fc-silent, or Fc-silence mutations. In some embodiments, amino acid residues L234 and L235 of the IgG1 constant region are replaced with A234 and A235 (also known as "LALA"). In some embodiments, amino acid residue N297 of the IgG1 constant region is replaced with A297 (also known as "N297A"). In some embodiments, amino acid residues D265 and P329 of the IgG1 constant region are replaced with A265 and A329 (also known as "DAPA"). Other antibody Fc-silencing mutations may be used. In some embodiments, Fc-silencing mutations are used in combination with, for example, D265A, N297A, and P329A (also known as "DANAPA").

[0500] As shown herein, when modifications are made to antibodies, they are further designated with the modification.For example, if selected amino acids in the antibody are changed to cysteine ​​(e.g., E152C, S375C according to EU numbering of antibody heavy chain to facilitate conjugation to linker-drug moiety), they are designated as "CysMab", or if the antibody is modified with Fc silencing mutations D265A, N297A and P329A according to EU numbering of IgG1 constant region, "DANAPA" is added to the name of the antibody.When antibodies are used in antibody drug conjugates, they are named using the following format: antibody designation-linker-payload.

[0501] In some embodiments, the anti-Met antibody in the antibody drug conjugate of the present disclosure is the anti-Met antibody 9006 and 9338 described in patent application WO 2016 / 042412, which is incorporated herein by reference (see Tables 2-5 below).

[0502] In some embodiments, the anti-Met antibody in the antibody drug conjugate of the present disclosure is anti-Met antibody 8902 (see Tables 2-5 below). The variable domain heavy and light chain (VH and VL) amino acid sequences of this antibody are provided in SEQ ID NOs: 37 and 38, respectively, and the corresponding nucleotide sequences are provided in SEQ ID NOs: 49 and 50, respectively (see Table 2a). The full length heavy and light chain amino acid sequences (HC and LC) are available in SEQ ID NOs: 45 and 46 (IgG1 chain) and SEQ ID NOs: 47 and 48 (IgG2 chain), respectively. The amino acid sequences of the heavy chain CDRs (H-CDR1, H-CDR2 and H-CDR3) and light chain CDRs (L-CDR1, L-CDR-2 and L-CDR3) of the 8902 antibody are shown in SEQ ID NOs: 39, 40 and 41, and SEQ ID NOs: 42, 43 and 44, respectively. The CDR sequences are assigned according to the IMGT® definition.

[0503] [Table 5]

[0504] [Table 6]

[0505] [Table 7]

[0506] [Table 8-1]

[0507] [Table 8-2]

[0508] [Table 9]

[0509] In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein may comprise any set of heavy and light chain variable domains listed in the table above, or a set of six CDRs from any set of heavy and light chain variable domains listed in the table above. In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein may comprise any set of heavy and light chain variable domains listed in the table above, or a set of six CDRs from any set of heavy and light chain variable domains listed in the table above. In some embodiments, the antibody or antigen-binding fragment of the ADC disclosed herein may comprise any set of heavy and light chain variable domains listed in the table above, or a set of six CDRs from any set of heavy and light chain variable domains listed in the table above. -8 K less than M D In particular, the ADCs may comprise amino acid sequences that are conservatively modified and / or homologous to the sequences listed in the table above, so long as they retain the sequence described above (e.g., in the Table 1) and retain one or more functional properties of the ADCs disclosed herein (e.g., ability to be internalized, ability to bind to an antigen target, e.g., an antigen expressed on a tumor or other cancer cell, etc.).

[0510] In some embodiments, the antibodies or antigen-binding fragments of the ADCs disclosed herein further comprise human heavy and light chain constant domains or fragments thereof. For example, the antibodies or antigen-binding fragments of the described ADCs may comprise a human IgG heavy chain constant domain (e.g., IgG1 or IgG2) and a human kappa or lambda light chain constant domain. In some embodiments, the antibodies or antigen-binding fragments of the described ADCs comprise a human immunoglobulin G subtype 1 (IgG1) heavy chain constant domain with a human Ig kappa light chain constant domain. In some embodiments, the antibodies or antigen-binding fragments of the described ADCs comprise a human immunoglobulin G subtype 2 (IgG2) heavy chain constant domain with a human Ig kappa light chain constant domain.

[0511] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof has the following amino acid sequence: HCDR1 of SEQ ID NO:5 or SEQ ID NO:11 or SEQ ID NO:39; HCDR2 of SEQ ID NO:6 or SEQ ID NO:12 or SEQ ID NO:40; HCDR3 of SEQ ID NO:7 or SEQ ID NO:13 or SEQ ID NO:41; a VH chain comprising at least one of and / or the amino acid sequence: LCDR1 of SEQ ID NO:8 or SEQ ID NO:14 or SEQ ID NO:42; LCDR2 of SEQ ID NO:9 or SEQ ID NO:15 or SEQ ID NO:43; LCDR3 of SEQ ID NO: 10 or SEQ ID NO: 16 or SEQ ID NO: 44 A VL chain comprising at least one of Includes.

[0512] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof has the following amino acid sequence: HCDR1 of SEQ ID NO:5 or SEQ ID NO:11; HCDR2 of SEQ ID NO:6 or SEQ ID NO:12; HCDR3 of SEQ ID NO:7 or SEQ ID NO:13; a VH chain comprising at least one of and / or the amino acid sequence: LCDR1 of SEQ ID NO:8 or SEQ ID NO:14; LCDR2 of SEQ ID NO:9 or SEQ ID NO:15; LCDR3 of SEQ ID NO: 10 or SEQ ID NO: 16 A VL chain comprising at least one of Includes.

[0513] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises at least two, three, four or five CDR sequences selected from the group consisting of HCDR1 of SEQ ID NO:5 or SEQ ID NO:11, HCDR2 of SEQ ID NO:6 or SEQ ID NO:12, HCDR3 of SEQ ID NO:7 or SEQ ID NO:13, LCDR1 of SEQ ID NO:8 or SEQ ID NO:14, LCDR2 of SEQ ID NO:9 or SEQ ID NO:15, and LCDR3 of SEQ ID NO:10 or SEQ ID NO:16.

[0514] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises at least two, three, four or five CDR sequences selected from the group consisting of HCDR1 of SEQ ID NO:5 or SEQ ID NO:11 or SEQ ID NO:39, HCDR2 of SEQ ID NO:6 or SEQ ID NO:12 or SEQ ID NO:40, HCDR3 of SEQ ID NO:7 or SEQ ID NO:13 or SEQ ID NO:41, LCDR1 of SEQ ID NO:8 or SEQ ID NO:14 or SEQ ID NO:42, LCDR2 of SEQ ID NO:9 or SEQ ID NO:15 or SEQ ID NO:43, and LCDR3 of SEQ ID NO:10 or SEQ ID NO:16 or SEQ ID NO:44.

[0515] In some embodiments, the anti-Met 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:5, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:6, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:7; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:8, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:9, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:10.

[0516] In some embodiments, the anti-Met 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:11, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:12, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:13; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:14, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:15, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:16.

[0517] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 39, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 41; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 42, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44.

[0518] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 1 and a light chain variable region amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 1 and a light chain variable region amino acid sequence of SEQ ID NO: 2, or a sequence that is at least 95% identical to a disclosed sequence. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 1, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2.

[0519] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 3 and a light chain variable region amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 3 and a light chain variable region amino acid sequence of SEQ ID NO: 4, or a sequence that is at least 95% identical to a disclosed sequence. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 3, and / or a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 4.

[0520] In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 37 and a light chain variable region amino acid sequence of SEQ ID NO: 38. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 37 and a light chain variable region amino acid sequence of SEQ ID NO: 38, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 37, 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: 38.

[0521] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 17, or a sequence that is at least 95% identical to SEQ ID NO: 17, and a light chain amino acid sequence of SEQ ID NO: 18, or a sequence that is at least 95% identical to SEQ ID NO: 18. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 17 and a light chain amino acid sequence of SEQ ID NO: 18, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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: 17, 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: 18.

[0522] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 19, or a sequence that is at least 95% identical to SEQ ID NO: 19, and a light chain amino acid sequence of SEQ ID NO: 20, or a sequence that is at least 95% identical to SEQ ID NO: 20. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO: 20, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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: 19, 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: 20.

[0523] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45, or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to SEQ ID NO: 46. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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: 45, 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: 46.

[0524] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:21, or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22, or a sequence that is at least 95% identical to SEQ ID NO:22. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:21 and a light chain amino acid sequence of SEQ ID NO:22, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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:21, 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:22.

[0525] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:23, or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24, or a sequence that is at least 95% identical to SEQ ID NO:24. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:23 and a light chain amino acid sequence of SEQ ID NO:24, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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:23, 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:24.

[0526] In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47, or a sequence that is at least 95% identical to SEQ ID NO: 47, and a light chain amino acid sequence of SEQ ID NO: 48, or a sequence that is at least 95% identical to SEQ ID NO: 48. In some embodiments, the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 48, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the anti-Met 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: 47, 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: 48.

[0527] In some embodiments, the anti-Met antibody or antigen-binding fragment of the ADC disclosed herein is an anti-Met bispecific binding molecule.

[0528] As used herein, a bispecific binding molecule may be a dual variable domain antibody, i.e., the two arms of the antibody contain two different variable domains, or may be in the form of an antibody fragment, such as a bispecific Fab fragment or a bispecific scFv. This is useful when one wishes to create a bivalent or multivalent antibody on a single polypeptide chain, or when one wishes to create a bispecific antibody. For example, a bispecific or multivalent antibody may be created that specifically binds to human MET and to another molecule.

[0529] In some embodiments, the anti-Met bispecific binding molecule is a bispecific antibody described in Table 6.

[0530] [Table 10]

[0531] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 9006 and a second anti-Met antibody 9338, or an antigen-binding portion thereof.

[0532] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 9006 and a second anti-Met antibody 8902, or antigen-binding portions thereof.

[0533] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 9338 and a second anti-Met antibody 8902, or antigen-binding portions thereof.

[0534] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 9006 and a second antibody, or antigen-binding portion thereof.

[0535] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 9338 and a second antibody, or antigen-binding portion thereof.

[0536] In some embodiments, the bispecific binding molecule has the binding specificity of a first anti-Met antibody 8902 and a second antibody, or antigen-binding portion thereof.

[0537] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively.

[0538] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 39, 40, 41, 42, 43, and 44, respectively.

[0539] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 39, 40, 41, 42, 43, and 44, respectively.

[0540] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:2, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:4.

[0541] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:2, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:37 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:38.

[0542] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 4, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 38.

[0543] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:25 or a sequence that is at least 95% identical to SEQ ID NO:25, and a light chain amino acid sequence of SEQ ID NO:26 or a sequence that is at least 95% identical to SEQ ID NO:26, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO:27 or a sequence that is at least 95% identical to SEQ ID NO:27, and a light chain amino acid sequence of SEQ ID NO:28 or a sequence that is at least 95% identical to SEQ ID NO:28. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:25 and a light chain amino acid sequence of SEQ ID NO:26, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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:25, 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:26. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:27 and a light chain amino acid sequence of SEQ ID NO:28, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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:27, 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:28.

[0544] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO: 17 or a sequence that is at least 95% identical to SEQ ID NO: 17, and a light chain amino acid sequence of SEQ ID NO: 18 or a sequence that is at least 95% identical to SEQ ID NO: 18, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO: 45 or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46 or a sequence that is at least 95% identical to SEQ ID NO: 46. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 17 and a light chain amino acid sequence of SEQ ID NO: 18, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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: 17, 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: 18. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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: 45, 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: 46.

[0545] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO: 19 or a sequence that is at least 95% identical to SEQ ID NO: 19, and a light chain amino acid sequence of SEQ ID NO: 20 or a sequence that is at least 95% identical to SEQ ID NO: 20, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO: 45 or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46 or a sequence that is at least 95% identical to SEQ ID NO: 46. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 19 and a light chain amino acid sequence of SEQ ID NO: 20, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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: 19, 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: 18. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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: 45, 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: 46.

[0546] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:21 or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22 or a sequence that is at least 95% identical to SEQ ID NO:22, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO:23 or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24 or a sequence that is at least 95% identical to SEQ ID NO:24. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:21 and a light chain amino acid sequence of SEQ ID NO:22, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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:21, 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:22. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:23 and a light chain amino acid sequence of SEQ ID NO:24, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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:23, 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:24.

[0547] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:21 or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22 or a sequence that is at least 95% identical to SEQ ID NO:22, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO:47 or a sequence that is at least 95% identical to SEQ ID NO:47, and a light chain amino acid sequence of SEQ ID NO:48 or a sequence that is at least 95% identical to SEQ ID NO:48. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:21 and a light chain amino acid sequence of SEQ ID NO:22, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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:21, 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:22. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 48, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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: 47, 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: 48.

[0548] In some embodiments, the bispecific binding molecule comprises an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:23 or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24 or a sequence that is at least 95% identical to SEQ ID NO:24, and an antigen-binding portion of a second antibody having a heavy chain amino acid sequence of SEQ ID NO:47 or a sequence that is at least 95% identical to SEQ ID NO:47, and a light chain amino acid sequence of SEQ ID NO:48 or a sequence that is at least 95% identical to SEQ ID NO:48. In some embodiments, the first antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO:23 and a light chain amino acid sequence of SEQ ID NO:24, or a sequence that is at least 95% identical to the disclosed sequences. In some embodiments, the first antibody of the bispecific binding molecule 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:23, 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:24. In some embodiments, the second antibody of the bispecific binding molecule comprises a heavy chain amino acid sequence of SEQ ID NO: 47 and a light chain amino acid sequence of SEQ ID NO: 48, or sequences that are at least 95% identical to the disclosed sequences. In some embodiments, the second antibody of the bispecific binding molecule 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: 47, 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: 48.

[0549] Residues in two or more polypeptides are said to "correspond" if they occupy similar positions in the polypeptide structures. Similar positions in two or more polypeptides can be determined by aligning the polypeptide sequences based on amino acid sequence or structural similarity. Those skilled in the art will understand that it may be necessary to introduce gaps into either sequence to produce a satisfactory alignment.

[0550] In some embodiments, the amino acid substitutions are of a single residue. Insertions are usually in the order of about 1 to about 20 amino acid residues, although much larger insertions can be tolerated as long as biological function is retained (e.g., binding to the target antigen). Deletions usually range from about 1 to about 20 amino acid residues, although in some cases deletions can be much larger. Substitutions, deletions, insertions, or any combination thereof can be used to arrive at the final derivative or variant. Generally, these changes are made to a few amino acids so as to minimize alteration of the molecule, particularly the immunogenicity and specificity of the antigen-binding protein. However, larger changes can be tolerated in certain circumstances. Conservative substitutions can be made according to the following chart, presented as Table 7.

[0551] Table 7 Original residue Exemplary substitution Ala Ser Arg-Lys Asn Gln, His Asp Glu Cys Ser Gln Asn Glu Asp GlyPro His Asn, Gln Ile Leu, Val Leu Ile, Val Lys, Arg, Gln, Glu Met Leu, Ile Phe, Met, Leu, Tyr Ser Thr Thr Ser Trp Tyr Tyr, Trp, Phe Val Ile, Leu

[0552] In some embodiments where variant antibody sequences are used in ADCs, the variants typically exhibit the same qualitative biological activity and induce the same immune response, but the variants may also be selected to modify the characteristics of the antigen-binding protein, if necessary. Alternatively, the variants may be designed to alter the biological activity of the antigen-binding protein. For example, glycosylation sites may be altered or removed.

[0553] A variety of antibodies may be used with the ADCs used to target cancer cells herein. As shown below, the linker-payload in the ADCs disclosed herein is surprisingly effective with different tumor antigen targeting antibodies. Suitable antigens that are expressed on cancer cells and not on healthy cells, or expressed on cancer cells at a higher level than on healthy cells, are known in the art, as are antibodies thereto. Additional antibodies against the antigen targets may be prepared by those skilled in the art. These antibodies may be used with the linkers and Bcl-xL inhibitor payloads disclosed herein. In some embodiments, the antibodies or antigen-binding fragments target MET and have provided, among other things, improved drug:antibody ratios, aggregation levels, stability (i.e., in vitro and in vivo stability), tumor targeting (i.e., cytotoxicity, efficacy), minimized off-target killing, and / or treatment efficacy. Improved treatment efficacy may be measured in vitro or in vivo and may include reduced tumor growth rate and / or reduced tumor volume.

[0554] In some embodiments, surrogate antibodies against the same target, or antibodies against different antigen targets, are used and provide at least some of the favorable functional properties described above (e.g., improved stability, improved tumor targeting, improved treatment efficacy, etc.).

[0555] Linker In some embodiments, the linker in the ADC is stable outside the cell in a manner sufficient to be therapeutically effective. In some embodiments, the linker is stable outside the cell, such that the ADC remains intact when present in extracellular conditions (e.g., before transport or delivery to the cell). The term "intact" as used in the context of the ADC means that the antibody or antigen-binding fragment remains attached to the drug moiety (e.g., Bcl-xL inhibitor).

[0556] As used herein, "stable" in the context of a linker or an ADC comprising a linker means that no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 3%, or no more than about 1% (or any percentage in between) of the linkers in a sample of the ADC are cleaved (or otherwise not intact in the case of the entire ADC) when the ADC is present in extracellular conditions. In some embodiments, the linkers and / or ADCs disclosed herein are stable compared to alternative linkers and / or ADCs with alternative linkers and / or Bcl-xL inhibitor payloads. In some embodiments, the ADCs disclosed herein may remain intact for more than about 48 hours, more than about 60 hours, more than about 72 hours, more than about 84 hours, or more than about 96 hours.

[0557] Whether a linker is stable outside a cell can be determined, for example, by including the ADC in plasma for a period of time (e.g., 2, 4, 6, 8, 16, 24, 48, or 72 hours) and then quantifying the amount of free drug moiety present in the plasma. Stability can allow time for the ADC to localize to the target cancer cells and prevent premature release of the drug moiety, which can reduce the therapeutic index of the ADC by indiscriminately damaging both normal and cancer tissues. In some embodiments, the linker is stable outside the target cell and releases the drug moiety from the ADC once inside the cell, so that the drug can bind to its target. As such, an effective linker (i) maintains the specific binding properties of the antibody or antigen-binding fragment; (ii) allows for delivery, e.g., intracellular delivery, of the drug moiety via stable attachment to the antibody or antigen-binding fragment; (iii) remains stable and intact until the ADC is transported or delivered to its target site; and (iv) allows for the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage or alternative release mechanisms.

[0558] Linkers can affect the physicochemical properties of ADCs. Many cytotoxic agents are hydrophobic in nature, so linking them to antibodies with additional hydrophobic moieties can lead to aggregation. ADC aggregates are insoluble and often limit the achievable drug loading on antibodies, which can negatively impact the efficacy of ADCs. Protein aggregates of biologics are also generally associated with increased immunogenicity. As shown below, the linkers disclosed herein result in ADCs with low aggregation levels and desirable levels of drug loading.

[0559] Linkers can be "cleavable" or "non-cleavable" (Ducry and Stump (2010) Bioconjugate Chem. 21:5-13). Cleavable linkers are designed to release the drug moiety (e.g., a Bcl-xL inhibitor) when subjected to certain environmental factors, e.g., when internalized into a target cell, while non-cleavable linkers generally rely on degradation of the antibody or antigen-binding fragment itself.

[0560] The term "alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. 1 ~C 6 The term "alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. 1 ~C 6 Non-limiting examples of "alkyl" groups include methyl (C 1 Alkyl), Ethyl (C 2 alkyl), 1-methylethyl (C 3 Alkyl), n-propyl (C 3 Alkyl), isopropyl (C 3 Alkyl), n-Butyl (C 4 Alkyl), Isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 Alkyl), n-pentyl (C 5 Alkyl), isopentyl (C 5 Alkyl), neopentyl (C 5 Alkyl) and Hexyl (C 6 alkyl).

[0561] The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and containing at least one double bond. 2 ~C 6The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. 2 ~C 6 Non-limiting examples of "alkenyl" groups include ethenyl (C 2 alkenyl), prop-1-enyl (C 3 alkenyl), but-1-enyl (C 4 alkenyl), pent-1-enyl (C 5 alkenyl), pent-4-enyl (C 5 alkenyl), penta-1,4-dienyl (C 5 alkenyl), hex-1-enyl (C 6 alkenyl), hex-2-enyl (C 6 alkenyl), hex-3-enyl (C 6 alkenyl), hexa-1-,4-dienyl (C 6 alkenyl), hexa-1-,5-dienyl (C 6 alkenyl) and hexa-2-,4-dienyl (C 6 alkenyl). 2 ~C 3 The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having 2 to 3 carbon atoms, and attached to the remainder of the molecule by a single bond. 2 ~C 3 Non-limiting examples of "alkenyl" groups include ethenyl (C 2 alkenyl) and prop-1-enyl (C 3 alkenyl).

[0562] The term "alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. 1 ~C 6The term "alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 6 carbon atoms. 1 ~C 6 Non-limiting examples of alkylene groups include methylene (C 1 Alkylene, Ethylene (C 2 Alkylene), 1-methylethylene (C 3 Alkylene), n-propylene (C 3 Alkylene), isopropylene (C 3 Alkylene), n-butylene (C 4 Alkylene), Isobutylene (C 4 Alkylene), sec-butylene (C 4 alkylene), tert-butylene (C 4 Alkylene), n-pentylene (C 5 Alkylene), isopentylene (C 5 alkylene), neopentylene (C 5 alkylene), and hexylene (C 6 alkylene).

[0563] The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond. 2 ~C 6 The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 6 carbon atoms. 2 ~C 6 Non-limiting examples of "alkenylene" groups include ethenylene (C 2 alkenylene), prop-1-enylene (C 3 alkenylene), buta-1-enylene (C 4 alkenylene), pent-1-enylene (C 5 alkenylene), pent-4-enylene (C 5alkenylene), penta-1,4-dienylene (C 5 alkenylene), hex-1-enylene (C 6 alkenylene), hex-2-enylene (C 6 alkenylene), hex-3-enylene (C 6 alkenylene), hexa-1-,4-dienylene (C 6 alkenylene), hexa-1-,5-dienylene (C 6 alkenylene) and hexa-2-,4-dienylene (C 6 Alkenylene). 2 ~C 6 The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 3 carbon atoms. 2 ~C 3 Non-limiting examples of "alkenylene" groups include ethenylene (C 2 alkenylene) and prop-1-enylene (C 3 alkenylene).

[0564] "Cycloalkyl", or "C 3 ~C 8 The term "cycloalkyl" as used herein refers to a saturated, monocyclic, fused bicyclic, fused tricyclic, or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and adamantanyl. Monocyclic C 3 ~C 8 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0565] The term "aryl," as used herein, refers to a phenyl, naphthyl, biphenyl, or indenyl group.

[0566] The term "heteroaryl," as used herein, refers to any monocyclic or bicyclic group 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).

[0567] The term "cycloalkyl" as used herein refers to any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members, which may include fused, bridged, or spiro ring systems. Non-limiting examples of fused bicyclic or bridged ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Monocyclic C 3 ~C 8 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0568] The term "heterocycloalkyl" refers to a group consisting of 3 to 10 ring members, including oxygen, sulfur, SO, SO 2 C means any monocyclic or bicyclic non-aromatic carbocyclic group containing 1 to 3 heteroatoms selected from , and nitrogen, it being understood that bicyclic groups may be fused or spiro. 3 ~C 8 Heterocycloalkyl refers to a heterocycloalkyl having 3 to 8 ring carbon atoms. Heterocycloalkyl can have 4 to 10 ring members.

[0569] The terms heteroarylene, cycloalkylene, and heterocycloalkylene refer to divalent heteroaryl, cycloalkyl, and heterocycloalkyl.

[0570] The term "haloalkyl" as used herein refers to a straight or branched alkyl chain that is substituted with one or more halogen groups in place of hydrogen along the hydrocarbon chain. Examples of halogen groups suitable for substitution in haloalkyl groups include fluorine, bromine, chlorine, and iodine. A haloalkyl group may contain multiple halogen groups in place of hydrogen in the alkyl chain, where the halogen groups may be attached to the same carbon or to different carbons in the alkyl chain.

[0571] As used herein, alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups include optionally substituted linear or branched (C 1 ~C 6 ) alkyl, optionally substituted linear or branched (C 2 ~C 6 ) alkenyl groups, optionally substituted linear or branched (C 2 ~C 6 ) alkynyl groups, optionally substituted linear or branched (C 1 ~C 6 )alkoxy, optionally substituted (C 1 ~C 6 ) alkyl-S-, hydroxy, oxo (or N-oxide, where appropriate), nitro, cyano, -C(O)-OR 0 ', -OC(O)-R 0 ', -C(O)-NR 0 'R 0 '', -NR 0 'R 0 '', -(C=NR 0 ')-OR 0 '', linear or branched (C 1 ~C 6 ) optionally substituted with 1 to 4 groups selected from haloalkyl, trifluoromethoxy, or halogen, where R 0 ' and R 0 '' are each independently a hydrogen atom or an optionally substituted linear or branched (C1 ~C 6 ) alkyl group, linear or branched (C 1 ~C 6 ) One or more of the carbon atoms of an alkyl group are optionally deuterated.

[0572] The term "polyoxyethylene," "polyethylene glycol," or "PEG," as used herein, refers to 2 CH 2 In certain embodiments, the polyethylene or PEG group refers to a linear, branched, or star-shaped configuration composed of -(OCH 2 CH 2 ) t * -, where t is 1 to 40 or 4 to 40, and "-" indicates the end toward the self-immolative spacer, * -" indicates the point of attachment to the end group R', where R' is OH, OCH 3 or OCH 2 CH 2 In other embodiments, the polyethylene or PEG group is -(CH 2 CH 2 O) t * -, where t is 1 to 40 or 4 to 40, and "-" indicates the end toward the self-immolative spacer, * -" indicates the point of attachment to the end group R'', where R'' is H, CH 3 or CH 2 CH 2 For example, the term "PEG12" as used herein means that t is 12.

[0573] The term "polyalkylene glycol" as used herein means (O(CH 2 ) m ) n In certain embodiments, the polyethylene or PEG group refers to a linear, branched, or star-shaped configuration composed of -(O(CH 2 ) m )t * -, where m is 1 to 10, t is 1 to 40 or 4 to 40, and "-" indicates the end toward the self-immolative spacer, * -" indicates the point of attachment to the end group R', where R' is OH, OCH 3 or OCH 2 CH 2 C(=O)OH. In other embodiments, the polyethylene or PEG group is -((CH 2 ) m O) t * -, where m is 1 to 10, t is 1 to 40 or 4 to 40, and "-" indicates the end toward the self-immolative spacer, * -" indicates the point of attachment to the end group R'', where R'' is H, CH 3 or CH 2 CH 2 C(=O)OH.

[0574] The term "reactive group," as used herein, is a functional group that can form a covalent bond with a functional group on an antibody, antibody fragment, or another reactive group attached to an antibody or antibody fragment. Non-limiting examples of such functional groups include the reactive groups in Table 8 provided herein.

[0575] The term "attachment group" or "coupling group" as used herein refers to a bivalent moiety that links a bridging spacer to an antibody or fragment thereof. An attachment group or coupling group is a bivalent moiety formed by the reaction between a reactive group and a functional group on an antibody or fragment thereof. Non-limiting examples of such bivalent moieties include the bivalent chemical moieties provided in Tables 8 and 9 provided herein.

[0576] The term "bridge spacer", as used herein, refers to one or more linker components that link a bivalent peptide spacer to a reactive group, link a bivalent peptide spacer to a coupling group, or link an attachment group to at least one cleavable group, and are covalently attached together to form a bivalent moiety. In certain embodiments, the "bridge spacer" comprises a carboxyl group attached to the N-terminus of the bivalent peptide spacer via an amide bond.

[0577] The term "spacer moiety," as used herein, refers to one or more linker components that are covalently attached together to form a moiety that links a self-immolative spacer to a hydrophilic moiety.

[0578] The term "bivalent peptide spacer," as used herein, refers to a bivalent linker that includes one or more amino acid residues covalently attached together to form a moiety that links a bridging spacer to a self-immolative spacer. The one or more amino acid residues may be a residue of an amino acid selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine.

[0579] In certain embodiments, a "bivalent peptide spacer" is a peptide spacer, each of whose residues is selected from the group consisting of alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg ... a combination of 2 to 4 amino acid residues independently selected from amino acid residues selected from the group consisting of Arg, serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine, for example, -ValCit * ;-CitVal * ;-AlaAla * ;-AlaCit * ;-CitAla * ;-AsnCit * ;-CitAsn * ;-CitCit * ;-ValGlu * ;-GluVal * ;-SerCit * ;-CitSer * ;-LysCit * ;-CitLys * ;-AspCit * ;-CitAsp * ;-AlaVal * ;-ValAla * ;-PheAla * ;-AlaPhe * ;-PheLys * ;-LysPhe * ;-ValLys * ;-LysVal * ;-AlaLys * ;-LysAla * ;-PheCit * ;-CitPhe * ;-LeuCit *;-CitLeu * ;-IleCit * ;-CitIle * ;-PheArg * ;-ArgPhe * ;-CitTrp * ;-TrpCit * ;-PhePheLys * ;-LysPhePhe * ;-DPhePheLys * ;-DLysPhePhe * ;-GlyPheLys * ;-LysPheGly * -GlyPheLeuGly-[SEQ ID NO:29]; -GlyLeuPheGly-[SEQ ID NO:30]; -AlaLeuAlaLeu-[SEQ ID NO:31], -GlyGlyGly * -GlyGlyGlyGly- [SEQ ID NO: 32]; -GlyPheValGly- [SEQ ID NO: 33]; and -GlyValPheGly- [SEQ ID NO: 34], where "-" indicates the point of attachment to the bridging spacer, * " indicates the point of attachment to the self-immolative spacer.

[0580] The term "linker component" as used herein refers to a chemical moiety that is part of a linker. Examples of linker components include alkylene groups: -(CH 2 ) n - (where in this example n is 1 to 18); alkenylene group; alkynylene group; alkenyl group; alkynyl group; ethylene glycol unit: -OCH 2 CH 2 -or-CH 2 CH 2 O-; Polyethylene glycol unit: (-CH 2 CH 2 O-) x(wherein x in this example is 2-20); -O-; -S-; carbonyl: -C(=O); ester: (=O)-O or OC(=O); carbonate: -OC(=O)O-; amine: -NH-; tertiary amine; amide: -C(=O)-NH-, -NH-C(=O)- or -C(=O)N(C 1~6 Alkyl; Carbamate: -OC(=O)NH- or -NHC(=O)O; Urea: -NHC(=O)NH; Sulfonamide: -S(O) 2 NH- or -NHS(O) 2 ;Ether: -CH 2 O- or -OCH 2 alkylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphate and phosphonate; alkenylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphate and phosphonate; alkynylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxyl, amine, amino acid, saccharide, phosphate and phosphonate; C 1 ~C 10 alkylene (wherein one or more methylene groups are replaced by one or more -S-, -NH-, or -O- moieties); ring systems having two available attachment points, such as phenyl (including 1,2-, 1,3-, and 1,4-di-substituted phenyl), C 5 ~C 6 Heteroaryl, C 3 ~C 8 Cycloalkyl (including 1,1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and 1,4-disubstituted cyclohexyl), and C 4 ~C 8alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Ci), a residue of an amino acid selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Me), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine; and the residue is selected from the residues of amino acids selected from the group consisting of Val-Cit, Cit-Val, Ala-Ala, Ala-Met, Asparagine (Asn), Proline (Pro), Glutamine (Gln), Arginine (Arg), Serine (Ser), Threonine (Thr), Valine (Val), Tryptophan (Trp), Tyrosine (Tyr), Citrulline (Cit), Norvaline (Nva), Norleucine (Nle), Selenocysteine ​​(Sec), Pyrrolysine (Pyl), Homoserine, Homocysteine, and Desmethylpyrrolysine, e.g., Val-Cit; Cit-Val; Ala-Ala; Ala- Cit;Cit-Ala;Asn-Cit;Cit-Asn;Cit-Cit;Val-Glu;Glu-Val;Ser-Cit;Cit-Ser;Lys-Cit;Cit-Lys;Asp-Cit;Cit-Asp;Ala-Val;Val-Ala;Phe-Lys ;Lys-Phe;Val-Lys;Lys-Val;Ala-Lys;Lys-Ala;Phe-Cit;Cit-Phe;Leu-Cit;Cit-Leu;Ile-Cit;Cit-Ile;Phe-Arg;Arg-Phe;Cit-Trp;and Trp-Cit;and self-immolative spacers, where the self-immolative spacer comprises one or more protecting (trigger) groups that are susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage;

[0581] Non-limiting examples of such self-immolative spacers include:

[0582] [ka] (where: PG is a protecting (trigger) group; X a is O, NH or S; X b are O, NH, and NCH. 3 or S; X c is O or NH; Y a is CH 2 , C.H. 2 O or CH 2 NH; Y b is CH 2 , O or NH; Y c is a bond, CH 2 , O or NH; LG is a leaving group, e.g., the drug moiety (D) of the linker-drug group of the invention. Examples include:

[0583] Additional non-limiting examples of such self-immolative spacers are described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0584] In addition, a linker component can be a chemical moiety that is readily formed by a reaction between two reactive groups. Non-limiting examples of such chemical moieties are provided in Table 8.

[0585] [Table 11-1]

[0586] [Table 11-2]

[0587] [Table 11-3]

[0588] [Table 11-4]

[0589] [Table 11-5]

[0590] [Table 11-6]

[0591] Here, R in Table 8 32 , H, C 1~4 R in Table 8 is alkyl, phenyl, pyrimidine or pyridine. 35 , H, C 1~6 C substituted with alkyl, phenyl, or 1-3 -OH groups 1~4 Each R in Table 8 is alkyl. 7 are independently H, C 1~6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1~4 Alkoxy and -C(=O)OH substituted C 1~4 alkyl; R in Table 8 37is independently selected from H, phenyl and pyridine; q in Table 8 is 0, 1, 2 or 3; R in Table 8 8 and R 13 is H or methyl; R in Table 8 9 and R 14 -H, -CH 3 or phenyl; R in Table 8 is H or any suitable substituent; R in Table 8 is 50 is H.

[0592] In addition, the linker component can be a group listed in Table 9 below.

[0593] [Table 12-1]

[0594] [Table 12-2]

[0595] [Table 12-3]

[0596] [Table 12-4]

[0597] As used herein, when a substructure of a compound is shown, it is represented by a wavy line (

[0598] [ka] ) indicates the point of attachment of the substructure to the rest of the molecule.

[0599] The terms "self-immolative spacer" and "self-immolative group", as used herein, refer to a moiety that contains one or more trigger groups (TGs) that are activated by acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage, whereupon the protecting groups are removed, which results in a cascade of decomposition reactions that result in the temporally sequential release of leaving groups. Such a cascade of reactions can be, but is not limited to, 1,4-, 1,6-, or 1,8-elimination reactions.

[0600] Non-limiting examples of self-immolative spacers or groups include:

[0601] [ka] (wherein such groups may be optionally substituted, TG is a trigger group; X a is O, NH or S; X b are O, NH, and NCH. 3 or S; X c is O or NH; Y a is CH 2 , C.H. 2 O or CH 2 NH; Y b is CH 2 , O or NH; Y c is a bond, CH 2 , O or NH; LG is a leaving group, e.g., the drug moiety (D) of the linker-drug group of the invention. Examples include:

[0602] Additional non-limiting examples of self-immolative spacers are described in Angew. Chem. Int. Ed. 2015, 54, 7492-7509.

[0603] In certain embodiments, the self-immolative spacer has the structure

[0604] [ka] (wherein Lp is an enzymatically cleavable bivalent peptide spacer, A, D, L 3 and R 2 are as defined herein) It is a part having the following structure.

[0605] In a preferred embodiment, the self-immolative spacer has the structure

[0606] [ka] (wherein Lp is an enzymatically cleavable bivalent peptide spacer, and D, L 3 and R 2 are as defined herein) In some embodiments, D is a moiety having the formula: In some embodiments, D is a quaternized tertiary amine-containing Bcl-xL inhibitor.

[0607] In another preferred embodiment, the self-immolative spacer has the structure

[0608] [ka] (wherein Lp is an enzymatically cleavable bivalent peptide spacer, and D, L 3 and R 2 are as defined herein) It is a part having the following structure.

[0609] The term "hydrophilic moiety," as used herein, refers to a moiety that has hydrophilic properties that increase the aqueous solubility of the drug moiety (D) when the drug moiety (D) is attached to a linker group of the invention. Examples of such hydrophilic groups include, but are not limited to, polyethylene glycol, polyalkylene glycol, sugars, oligosaccharides, polypeptides, 1-3 amino acids,

[0610] [ka] C substituted with a group 2 ~C 6 Examples of such alkyl groups include alkyl.

[0611] Drug portion In some embodiments, an intermediate that is a precursor of a linker moiety is reacted with a drug moiety (e.g., a Bcl-xL inhibitor) under appropriate conditions. In some embodiments, a reactive group is used on the drug and / or intermediate or linker. The product of the reaction between the drug and intermediate, or the derivatized drug (drug and linker), is then reacted with an antibody or antigen-binding fragment under conditions that promote conjugation of the drug and intermediate, or the derivatized drug and the antibody or antigen-binding fragment. Alternatively, the intermediate or linker may be first reacted with an antibody or antigen-binding fragment, or a derivatized antibody or antigen-binding fragment, and then reacted with the drug or derivatized drug.

[0612] Several different reactions are available for the covalent attachment of drug moieties and / or linker moieties to antibodies or antigen-binding fragments. This is often accomplished by reaction of one or more amino acid residues of the antibody or antigen-binding fragment, including the amine groups of lysine, the free carboxylic acid groups of glutamic acid and aspartic acid, the sulfhydryl groups of cysteine, and various moieties of aromatic amino acids. For example, non-specific covalent attachment may be performed using a carbodiimide reaction to link a carboxy (or amino) group on the drug moiety to an amino (or carboxy) group on the antibody or antigen-binding fragment. In addition, bifunctional agents such as dialdehydes or imidoesters may also be used to link an amino group on the drug moiety to an amino group on the antibody or antigen-binding fragment. The Schiff base reaction is also available for the attachment of drugs (e.g., Bcl-xL inhibitors) to binders. This method involves periodate oxidation of drugs containing glycol or hydroxy groups, thus forming an aldehyde, which is then reacted with the binder. Attachment occurs via the formation of a Schiff base with the amino group of the binding agent. Isothiocyanates may also be used as coupling agents to covalently attach drugs to binding agents. Other techniques are known to those skilled in the art and are within the scope of this disclosure. Examples of drug moieties that can be made and linked to antibodies or antigen-binding fragments using a variety of chemistries known in the art include Bcl-xL inhibitors, such as those described and exemplified herein.

[0613] Suitable drug moieties may include compounds of formula (I), (IA), (IB), (IC), (II), (IIA), (IIB) or (IIC), or enantiomers, diastereoisomers, and / or pharma- ceutically acceptable acid or base addition salts thereof. In addition, the drug moiety may include any of the compounds of Bcl-xL inhibitors (D) described herein.

[0614] In some embodiments, the drug moiety (D) comprises a formula selected from Table A2.

[0615] In some embodiments, the drug moiety (D) comprises a Bcl-xL inhibitor known in the art, such as ABT-737 and ABT-263.

[0616] In some embodiments, the drug moiety (D) is

[0617] [ka] The Bcl-xL inhibitors include those selected from the group consisting of

[0618] In some embodiments, the linker-drug (or "linker-payload") moiety-(LD) may comprise a compound in Table B, or an enantiomer, diastereoisomer, deuterated derivative, and / or pharma- ceutically acceptable salt of any of the foregoing.

[0619] Drug Loading Drug loading is represented by p, also referred to herein as the drug-to-antibody ratio (DAR). Drug loading may range from 1 to 16 drug moieties per antibody or antigen-binding fragment. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p is an integer from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 2. In some embodiments, p is 4.

[0620] Drug loading may be limited by the number of attachment sites on the antibody or antigen-binding fragment. In some embodiments, the linker moiety (L) of the ADC is attached to the antibody or antigen-binding fragment through a chemically active group on one or more amino acid residues on the antibody or antigen-binding fragment. For example, the linker may be attached to the antibody or antigen-binding fragment through a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., to the N- or C-terminus, to the epsilon amino group of one or more lysine residues, to the free carboxylic acid group of one or more glutamic or aspartic acid residues, or to the sulfhydryl group of one or more cysteine ​​residues). The site to which the linker is attached may be a native residue in the amino acid sequence of the antibody or antigen-binding fragment, or it may be introduced into the antibody or antigen-binding fragment, for example, by recombinant DNA techniques (e.g., by introducing a cysteine ​​residue into the amino acid sequence) or by protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis).

[0621] In some embodiments, the number of drug moieties that can be conjugated to an antibody or antigen-binding fragment is limited by the number of free cysteine ​​residues. For example, if the attachment is a cysteine ​​thiol group, the antibody may have only one or a few cysteine ​​thiol groups, or may have only one or a few sufficiently reactive thiol groups through which a linker can be attached. Generally, antibodies do not contain many free and reactive cysteine ​​thiol groups that can be linked to drug moieties. In fact, most cysteine ​​thiol residues in antibodies are involved in either inter- or intra-chain disulfide bonds. Thus, conjugation to cysteines may require at least partial reduction of the antibody in some embodiments. Over-attachment of linker-toxins to an antibody may destabilize the antibody by reducing available cysteine ​​residues to form disulfide bonds. Thus, an optimal drug:antibody ratio should increase the potency of the ADC (by increasing the number of drug moieties attached per antibody) without destabilizing the antibody or antigen-binding fragment. In some embodiments, the optimal ratio may be 2, 4, 6, or 8. In some embodiments, the optimal ratio may be 2 or 4.

[0622] In some embodiments, the antibody or antigen-binding fragment is exposed to reducing conditions before conjugation to generate one or more free cysteine ​​residues. In some embodiments, the antibody can be reduced with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) under partial or total reducing conditions to generate reactive cysteine ​​thiol groups. Unpaired cysteines can be generated by partial reduction with a limited molar equivalent of TCEP, which can reduce the interchain disulfide bonds that connect the light and heavy chains (one pair per HL pairing) and the two heavy chains in the hinge region (two pairs per HH pairing in the case of human IgG1) while leaving the intrachain disulfide bonds intact (Stefano et al. (2013) Methods Mol Biol. 1045:145-71). In embodiments, disulfide bonds in antibodies are electrochemically reduced, for example, by using a working electrode that applies alternating reduction and oxidation voltages. This approach can allow for the online coupling of disulfide bond reduction to an analytical device (e.g., an electrochemical detection device, an NMR spectrometer, or a mass spectrometer) or a chemical separation device (e.g., a liquid chromatograph (e.g., HPLC) or an electrophoretic device (see, for example, US Patent Publication No. 2014 / 0069822). In some embodiments, antibodies are subjected to denaturing conditions to expose reactive nucleophilic groups on amino acid residues such as cysteine.

[0623] Drug loading of ADCs may be controlled in different ways, for example, (i) by limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody; (ii) by limiting the time or temperature of the conjugation reaction; (iii) partial or limited reducing conditions for cysteine ​​thiol modification; and / or (iv) by recombinantly manipulating the amino acid sequence of the antibody such that the number and position of cysteine ​​residues are modified to control the number and / or position of linker-drug attachments.

[0624] In some embodiments, a free cysteine ​​residue is introduced into the amino acid sequence of the antibody or antigen-binding fragment. For example, a cysteine ​​engineered antibody can be prepared in which one or more amino acids of a parent antibody are replaced with a cysteine ​​amino acid. Any form of antibody can be so engineered, i.e., mutated. For example, a parent Fab antibody fragment can be engineered to form a cysteine ​​engineered Fab, called a "ThioFab". Similarly, a parent monoclonal antibody can be engineered to form a "ThioMab". Single-site mutations provide a single engineered cysteine ​​residue in a ThioFab, while single-site mutations provide two engineered cysteine ​​residues in a ThioMab due to the dimeric nature of IgG antibodies. DNA encoding amino acid sequence variants of a parent polypeptide can be prepared by various methods known in the art (see, for example, the methods described in WO 2006 / 034488). These methods include, but are not limited to, preparation by site-directed (or oligonucleotide-mediated) mutagenesis, PCR mutagenesis, and cassette mutagenesis of earlier prepared DNA encoding the polypeptide. Recombinant antibody variants may also be constructed by restriction fragment steering or by overlap extension PCR using synthetic oligonucleotides. ADCs of formula (1) include, but are not limited to, antibodies with one, two, three, or four engineered cysteine ​​amino acids (Lyon et al. (2012) Methods Enzymol. 502:123-38). In some embodiments, one or more free cysteine ​​residues are already present in the antibody or antigen-binding fragment without the use of engineering, in which case the existing free cysteine ​​residues may be used to conjugate the antibody or antigen-binding fragment to a drug moiety.

[0625] When two or more nucleophilic groups react with a drug-linker intermediate or linker moiety reagent, followed by a drug moiety reagent, in a reaction mixture containing multiple copies of an antibody or antigen-binding fragment and a linker moiety, the resulting product can be a mixture of ADC compounds having a distribution of one or more drug moieties attached to each copy of the antibody or antigen-binding fragment in the mixture. In some embodiments, the drug loading in the mixture of ADCs resulting from the conjugation reaction ranges from 1 to 16 attached drug moieties per antibody or antigen-binding fragment. The average number of drug moieties per antibody or antigen-binding fragment (i.e., average drug loading, or average p) can be calculated by any conventional method known in the art, for example, by mass spectrometry (e.g., liquid chromatography-mass spectrometry (LC-MS)) and / or high performance liquid chromatography (e.g., HIC-HPLC). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is determined by liquid chromatography-mass spectrometry (LC-MS). In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 1.5 to about 3.5, about 2.5 to about 4.5, about 3.5 to about 5.5, about 4.5 to about 6.5, about 5.5 to about 7.5, about 6.5 to about 8.5, or about 7.5 to about 9.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 2 to about 4, about 3 to about 5, about 4 to about 6, about 5 to about 7, about 6 to about 8, about 7 to about 9, about 2 to about 8, or about 4 to about 8.

[0626] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 2. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 2.

[0627] In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 4. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5. In some embodiments, the average number of drug moieties per antibody or antigen-binding fragment is 4.

[0628] In some embodiments, the term "about" when used in reference to the average number of drug moieties per antibody or antigen-binding fragment means plus or minus 20%, 15%, 10%, 5%, or 1%. In one embodiment, the term "about" refers to a range of values ​​10% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​5% greater or less than the stated value. In another embodiment, the term "about" refers to a range of values ​​1% greater or less than the stated value.

[0629] Individual ADC compounds, or "species," can be identified in the mixture by mass spectrometry and separated, for example, by UPLC or HPLC, such as hydrophobic interaction chromatography (HIC-HPLC). In some embodiments, a homogeneous or near-homogeneous ADC product having a single loading value can be isolated from the conjugation mixture, for example, by electrophoresis or chromatography.

[0630] In some embodiments, higher drug loading (e.g., p>16) may cause aggregation, insolubility, toxicity, or loss of cell permeability of certain antibody-drug conjugates. Higher drug loading may also negatively affect the pharmacokinetics (e.g., clearance) of certain ADCs. In some embodiments, lower drug loading (e.g., p<2) may reduce the potency of certain ADCs against target-expressing cells. In some embodiments, drug loading for ADCs of the present disclosure ranges from about 2 to about 16, about 2 to about 10, about 2 to about 8; about 2 to about 6; about 2 to about 5; about 3 to about 5; about 2 to about 4; or about 4 to about 8.

[0631] In some embodiments, a drug loading and / or average drug loading of about 2 is achieved, for example, using partial reduction of intrachain disulfides on the antibody or antigen-binding fragment, providing beneficial properties. In some embodiments, a drug loading and / or average drug loading of about 4 or about 6 or about 8 is achieved, for example, using partial reduction of intrachain disulfides on the antibody or antigen-binding fragment, providing beneficial properties. In some embodiments, a drug loading and / or average drug loading of less than about 2 may result in unacceptably high levels of unconjugated antibody species, which may compete with the ADC for binding to the target antigen and / or may provide reduced treatment efficacy. In some embodiments, a drug loading and / or average drug loading of greater than about 16 may result in unacceptably high levels of product heterogeneity and / or ADC aggregation. A drug loading and / or average drug loading of greater than about 16 may also affect the stability of the ADC due to loss of one or more chemical bonds required to stabilize the antibody or antigen-binding fragment.

[0632] The present disclosure includes a method for producing the described ADC. Briefly, the ADC includes an antibody or antigen-binding fragment as an antibody or antigen-binding fragment, a drug moiety (e.g., a Bcl-xL inhibitor), and a linker that joins the drug moiety and the antibody or antigen-binding fragment. In some embodiments, the ADC can be prepared using a linker with a reactive functionality to covalently attach to the drug moiety and to the antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment is functionalized to prepare a functional group that is reactive with a linker or drug-linker intermediate. For example, in some embodiments, a cysteine ​​thiol of the antibody or antigen-binding fragment can form a bond with a reactive functional group of a linker or drug-linker intermediate to produce an ADC. In some embodiments, antibodies or antigen-binding fragments are prepared using reactive glutamines specifically functionalized with bacterial transglutaminase (BTG)-amine-containing cyclooctyne BCN (N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethyloxycarbonyl]-1,8-diamino-3,6-dioxaoctane) moieties. In some embodiments, site-specific conjugation of a linker or drug-linker intermediate to the BCN moiety of the antibody or antigen-binding fragment is performed, for example, as described and exemplified herein. Generation of ADCs can be accomplished by techniques known to those of skill in the art.

[0633] In some embodiments, ADCs are produced by contacting an antibody or antigen-binding fragment with a linker and a drug moiety (e.g., a Bcl-xL inhibitor) in a sequential manner, such that the antibody or antigen-binding fragment is first covalently linked to the linker and then the preformed antibody-linker intermediate is reacted with the drug moiety. The antibody-linker intermediate may or may not be subjected to a purification step before contacting with the drug moiety. In other embodiments, ADCs are produced by contacting an antibody or antigen-binding fragment with a linker-drug compound that is preformed by reacting the linker with the drug moiety. The preformed linker-drug compound may or may not be subjected to a purification step before contacting with the antibody or antigen-binding fragment. In other embodiments, the antibody or antigen-binding fragment is contacted with the linker and drug moiety in one reaction mixture, allowing for simultaneous formation of covalent bonds between the antibody or antigen-binding fragment and the linker, and between the linker and the drug moiety. This method of producing an ADC may involve a reaction in which an antibody or antigen-binding fragment is contacted with an antibody or antigen-binding fragment prior to the addition of the linker to the reaction mixture, or vice versa. In some embodiments, the ADC is produced by reacting an antibody or antigen-binding fragment with a linker conjugated to a drug moiety, such as a Bcl-xL inhibitor, under conditions that allow conjugation.

[0634] The ADC prepared according to the above-described method may be subjected to a purification step.The purification step may include any biochemical method known in the art for purifying protein, or any combination of the methods.These include, but are not limited to, tangential flow filtration (TFF), affinity chromatography, ion exchange chromatography, any charge or isoelectric point-based chromatography, mixed mode chromatography, such as CHT (ceramic hydroxyapatite), hydrophobic interaction chromatography, size exclusion chromatography, dialysis, filtration, selective precipitation, or any combination thereof.

[0635] Therapeutic Uses and Compositions Disclosed herein is a method of using the compositions described herein, for example, the disclosed ADC compounds or compositions, in treating a subject for a disorder, for example, cancer.The compositions, for example, ADCs, may be administered alone or in combination with at least one additional inactive and / or active agent, for example, at least one additional therapeutic agent, and may be administered in any pharma-ceutically acceptable formulation, dosage, and dosing regimen.Treatment efficacy may be assessed for toxicity as well as efficacy indicators and adjusted accordingly.Efficacy measures include, but are not limited to, cytostatic and / or cytotoxic effects observed in vitro or in vivo, reduction in tumor volume, tumor growth inhibition, and / or prolonged survival.

[0636] Methods for determining whether an ADC exhibits a cytostatic and / or cytotoxic effect on cells are known. For example, the cytotoxic or cytostatic activity of an ADC can be measured, for example, by exposing mammalian cells expressing the target antigen of the ADC in cell culture medium; culturing the cells for a period of about 6 hours to about 6 days; and measuring cell viability (e.g., using CellTiter-Glo® (CTG) or MTT cell viability assays). Cell-based in vitro assays may also be used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) of the ADC.

[0637] To determine cytotoxicity, necrosis or apoptosis (programmed cell death) may be measured. Necrosis is typically accompanied by increased cell membrane permeability, cell swelling, and cell membrane rupture. Apoptosis can be quantified, for example, by measuring DNA fragmentation. Commercial photometric methods for quantitative in vitro determination of DNA fragmentation are available. Examples of such assays, including TUNEL (detects incorporation of labeled nucleotides in fragmented DNA) and ELISA-based assays, are described in Biochemica (1999) 2:34-7 (Roche Molecular Biochemicals).

[0638] Apoptosis may also be determined by measuring morphological changes in cells. For example, loss of cell membrane integrity, as by necrosis, can be determined by measuring the uptake of certain dyes (e.g., fluorescent dyes such as acridine orange or ethidium bromide). Methods for measuring the number of apoptotic cells are described in Duke and Cohen, Current Protocols in Immunology (Coligan et al., eds. (1992) pp. 3.17.1-3.17.16). Cells can also be labeled with DNA dyes (e.g., acridine orange, ethidium bromide, or propidium iodide), and the cells can be observed for chromatin condensation and margination along the inner nuclear membrane. Apoptosis may also be determined in some embodiments by screening for caspase activity. In some embodiments, the Caspase-Glo® assay can be used to measure the activity of caspase-3 and caspase-7. In some embodiments, the assay provides a luminescent caspase-3 / 7 substrate in a reagent optimized for caspase activity, luciferase activity, and cell lysis. In some embodiments, addition of Caspase-Glo® 3 / 7 Reagent in an "add-mix-measure" format can result in cell lysis followed by caspase cleavage of the substrate and generation of a "glow-type" luminescent signal generated by luciferase. In some embodiments, luminescence can be proportional to the amount of caspase activity present and can serve as an indicator of apoptosis. Other morphological changes that can be measured to determine apoptosis include, for example, cytoplasmic condensation, increased membrane blebbing, and cell shrinkage. Determination of any of these effects on cancer cells indicates that the ADC is useful in treating cancer.

[0639] Cell viability may be measured by determining the uptake of a dye, such as, for example, neutral red, trypan blue, crystal violet, or ALAMAR™ blue, in the cells (see, e.g., Page et al. (1993) Intl J Oncology 3:473-6). In such assays, cells are incubated in medium containing the dye, the cells are washed, and the remaining dye, which reflects the cellular uptake of the dye, is measured spectrophotometrically.

[0640] Cell viability may also be measured, for example, by quantifying ATP, an indicator of metabolically active cells. In some embodiments, the in vitro potency and / or cell viability of the prepared ADC or Bcl-xL inhibitor compound may be evaluated using the CellTiter-Glo® (CTG) cell viability assay, as described in the Examples provided herein. In this assay, in some embodiments, a single reagent (CellTiter-Glo® Reagent) is added directly to cells cultured in serum-supplemented medium. Addition of the reagent results in cell lysis and the generation of a luminescent signal that is proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture.

[0641] Cell viability may also be measured, for example, by measuring the reduction of tetrazolium salts. In some embodiments, the in vitro potency and / or cell viability of the prepared ADC or Bcl-xL inhibitor compound may be evaluated using the MTT cell viability assay, as described in the Examples provided herein. In this assay, in some embodiments, the yellow tetrazolium MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) is reduced by metabolically active cells, in part, by the action of dehydrogenase enzymes, to generate reducing equivalents such as NADH and NADPH. The resulting intracellular purple formazan can then be solubilized and quantified by spectrophotometric means.

[0642] In certain aspects, the disclosure features a method of killing, inhibiting or modulating the growth of cancer cells or tissues by disrupting the expression and / or activity of Bcl-xL and / or one or more upstream modulators or downstream targets thereof. The method may be used with any subject in which disruption of Bcl-xL expression and / or activity provides a therapeutic benefit. Subjects who may benefit from disrupting Bcl-xL expression and / or activity include, but are not limited to, subjects having or at risk of having cancer, such as tumors or blood cancers. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0643] In some embodiments, the disclosed ADCs may be administered in any cell or tissue that expresses MET, e.g., a MET-expressing cancer cell or tissue. Exemplary embodiments include a method of killing a MET-expressing cancer cell or tissue. The method may be used with any cell or tissue that expresses MET, e.g., a cancerous cell or metastatic lesion. Non-limiting examples of MET-expressing cancers include melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow carcinoma, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. Non-limiting examples of MET expressing cells include melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma, and a cell containing a recombinant nucleic acid encoding MET or a portion thereof.

[0644] An exemplary method includes contacting a cell with an effective amount, i.e., an amount sufficient to kill the cell, of an ADC described herein. The method can be used on cells in culture, e.g., in vitro, in vivo, ex vivo, or in situ. For example, cells expressing MET (e.g., cells collected by biopsy of a tumor or metastatic lesion; cells from an established cancer cell line; or recombinant cells) can be cultured in vitro in culture medium, and the contacting step can be affected by adding an ADC to the culture medium. The method specifically results in the death of cells expressing MET, including cancer cells expressing MET. Alternatively, the ADC can be administered to a subject by any suitable route of administration (e.g., intravenously, subcutaneously, or by direct contact with tumor tissue) to have an effect in vivo.

[0645] The in vivo efficacy of the disclosed ADC therapeutic composition can be assessed in suitable animal models.For example, xenogeneic cancer models can be used, in which cancer explants or passaged xenograft tissues are introduced into immunocompromised animals such as nude mice or SCID mice (Klein et al. (1997) Nature Med. 3:402-8).Efficacy can be predicted using assays that measure inhibition of tumor formation, tumor regression, or metastasis, etc.

[0646] In vivo assays that assess the promotion of tumor death by mechanisms such as apoptosis may also be used. In some embodiments, mice bearing tumor-derived xenografts treated with the therapeutic composition can be examined for the presence of apoptotic foci and compared to mice bearing untreated control xenografts. The extent to which apoptotic foci are found in the tumors of the treated mice provides an indication of the therapeutic efficacy of the composition.

[0647] Further provided herein is a method for treating a disorder, e.g., cancer. The compositions described herein, e.g., the ADCs disclosed herein, can be administered to a non-human mammal or human subject for therapeutic purposes. The therapeutic method includes administering a therapeutically effective amount of a Bcl-xL inhibitor to a subject having or suspected of having cancer, a composition comprising such an inhibitor, e.g., an ADC in which the inhibitor is linked to a targeting antibody that binds to an antigen that is (1) expressed on cancer cells, (2) accessible for binding, and / or (3) localized or preferentially expressed on the surface of cancer cells compared to non-cancer cells.

[0648] An exemplary embodiment is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a composition, e.g., an ADC, composition, or pharmaceutical composition disclosed herein (e.g., any of the exemplary ADC, composition, or pharmaceutical composition disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the cancer is a tumor or hematological cancer. In some embodiments, the cancer is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer is lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer.

[0649] Another exemplary embodiment is a method of delivering a Bcl-xL inhibitor to a cell expressing MET, comprising conjugating the Bcl-xL inhibitor to an antibody that immunospecifically binds to a MET epitope and exposing the cell to an ADC. Exemplary cancer cells expressing MET that are in need of treatment by an ADC of the disclosure include melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer, and ovarian cancer. cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or cells derived from myeloma.

[0650] In certain aspects, the disclosure further provides methods of reducing or inhibiting tumor growth (e.g., a MET-expressing tumor), comprising administering a therapeutically effective amount of an ADC or a composition comprising an ADC. In some embodiments, the treatment is sufficient to reduce or inhibit tumor growth, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, extend survival time, and / or maintain or improve quality of life in a patient. In some embodiments, the tumor is resistant or refractory to treatment with an antibody or antigen-binding fragment of the ADC (e.g., an anti-MET antibody) when administered alone, and / or the tumor is resistant or refractory to treatment with a Bcl-xL inhibitor drug moiety when administered alone.

[0651] An exemplary embodiment is a method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the tumor is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer, including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, or thymoma. In some embodiments, the tumor is lung cancer, pancreatic cancer, gastric cancer, kidney cancer, or liver cancer. In some embodiments, administration of the ADC, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% compared to growth in the absence of treatment.

[0652] Another exemplary embodiment is a method of delaying or slowing the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor expresses a target antigen. In some embodiments, the tumor is melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer, including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, or thymoma. In some embodiments, the tumor is lung cancer, pancreatic cancer, gastric cancer, kidney cancer, or liver cancer. In some embodiments, administration of the ADC, composition, or pharmaceutical composition slows or retards tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% compared to growth in the absence of treatment.

[0653] In certain aspects, the disclosure further provides a method of reducing or slowing the expansion of a cancer cell population (e.g., a MET-expressing cancer cell population), comprising administering a therapeutically effective amount of an ADC or a composition comprising an ADC.

[0654] Exemplary embodiments are methods of reducing or slowing the expansion and growth of cancer cells in a subject, comprising administering to the subject a therapeutically effective amount of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer cell population expresses a target antigen. In some embodiments, the cancer cell population is from a tumor or hematological cancer ... cancer), pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenal cortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma. In some embodiments, the cancer cell population is from lung cancer, pancreatic cancer, gastric cancer, renal cancer, or liver cancer. In some embodiments, administration of the ADC, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, compared to the population in the absence of treatment. In some embodiments, administration of the ADC, composition, or pharmaceutical composition slows the expansion of the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, compared to the expansion in the absence of treatment.

[0655] Also provided herein is a method of determining whether a subject having or suspected of having cancer responds to treatment with the disclosed ADCs and compositions. An exemplary embodiment is a method of determining whether a subject having or suspected of having cancer responds to treatment with an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein) by preparing a biological sample from the subject; contacting the sample with an ADC; and detecting binding of the ADC to cancer cells in the sample. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample. In some embodiments, the method includes preparing a biological sample from the subject; contacting the sample with an ADC; and detecting one or more markers of cancer cell death in the sample (e.g., increased expression of one or more apoptotic markers, reduced expansion and proliferation of a cancer cell population in culture, etc.).

[0656] Therapeutic uses of the disclosed ADCs and compositions are further provided herein. An exemplary embodiment is an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject having or suspected of having cancer (e.g., a MET-expressing cancer). Another exemplary embodiment is the use of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein) in treating a subject having or suspected of having cancer (e.g., a MET-expressing cancer). Another exemplary embodiment is the use of an ADC, composition, or pharmaceutical composition (e.g., any of the exemplary ADCs, compositions, or pharmaceutical compositions disclosed herein) in a method of manufacturing a medicament for treating a subject having or suspected of having cancer (e.g., a MET-expressing cancer). Methods for identifying subjects having cancer that express a target antigen (e.g., MET) are known in the art and can be used to identify suitable patients for treatment with the disclosed ADC compounds or compositions.

[0657] The ADCs of the present disclosure may also be administered to non-human mammals expressing an antigen to which the ADC can bind, for veterinary purposes or as animal models of human disease. Regarding the latter, such animal models may be useful for evaluating the therapeutic efficacy (e.g., testing dosages and time courses of administration) of the disclosed ADCs.

[0658] The therapeutic compositions used in the practice of the aforementioned methods may be formulated into pharmaceutical compositions comprising a pharma- ceutically acceptable carrier suitable for the desired delivery method. An exemplary embodiment is a pharmaceutical composition comprising an ADC of the present disclosure and a pharma- ceutically acceptable carrier, e.g., suitable for a selected means of administration, e.g., intravenous administration. The pharmaceutical composition may also include one or more additional inactive and / or therapeutic agents (e.g., standard of care agents, etc.) suitable for treating or preventing, for example, cancer. The pharmaceutical composition may also include one or more carrier, excipient, and / or stabilizer components, etc. Methods for formulating such pharmaceutical compositions and suitable formulations are known in the art (see, e.g., "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA).

[0659] Suitable carriers include any material that, when combined with the therapeutic composition, retains the antitumor function of the therapeutic composition and is generally non-reactive with the patient's immune system. Pharmaceutically acceptable carriers include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate, etc., and combinations thereof. In many cases, isotonic agents, such as sugars, polyhydric alcohols, such as mannitol, sorbitol, or sodium chloride, are included in the composition. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the ADC.

[0660] The pharmaceutical compositions of the present disclosure can be administered by various methods known in the art. The route and / or mode of administration can vary depending on the desired outcome. In some embodiments, the therapeutic formulation is solubilized and administered via any route that can deliver the therapeutic composition to the cancer site. Potentially effective routes of administration include, but are not limited to, parenteral (e.g., intravenous, subcutaneous), intraperitoneal, intramuscular, intratumoral, intradermal, intraorgan, orthotopic, and the like. In some embodiments, administration is intravenous, subcutaneous, intraperitoneal, or intramuscular. The pharmaceutically acceptable carrier should be suitable for the route of administration, e.g., intravenous or subcutaneous administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., the ADC and / or any additional therapeutic agent, may be coated with a material that protects the compound from the action of acids and other natural conditions that may inactivate the compound. Administration can be either systemic or local.

[0661] The therapeutic compositions disclosed herein may be sterile and stable under the conditions of manufacture and storage, and may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration...

Claims

1. Antibody-drug conjugate of formula (1): A-(L-D) ｐ (1) [wherein Ab is an anti-Met antibody or an antigen-binding fragment thereof; L is a linker that covalently attaches Ab to D; p is an integer from 1 to 16; D is a Bcl-xL inhibitor compound of formula (I) or formula (II) covalently attached to said linker L: 【Chemistry 1】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, R １ and R ２ are each independently hydrogen; hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C ３ ~C ６ Cycloalkyl; trifluoromethyl; linear or branched C １ ~C ６ Alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a linear or branched C １ ~C ６ optionally substituted with an alkyl group; Or R １ and R ２ are the carbon atoms and C ３ ~C ６ Forming a cycloalkylene group, R ３ is hydrogen; ３ ~C ６ Cycloalkyl; linear or branched C １ ~C ６ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 2】 represents a group selected from R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ substituted by alkyl); linear or branched C optionally substituted by one or two hydroxyl groups; １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ； C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene -NR ｄ R ｅ ; C １ ~C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ ~C ６ Alkylene-phenyl, wherein the phenyl is １ ~C ６ substituted by an alkoxy group); 【Chemistry 3】 or represents a group selected from Or R ａ and R ｂ The nitrogen atom and ring B １ Forming; Or R ａ , R ｂ and R ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R ｄ and R ｅ The nitrogen atom and ring B ２ or Or R ｄ , R ｅ and R ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Het １ teeth, 【Chemistry 4】 represents a group selected from Het ２ teeth, 【Chemistry 5】 represents a group selected from A １ is -NH-, -N(C １ ~C ３ alkyl), O, S or Se; A ２ is N, CH or C(R ５ ) and G is, -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、 -OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , C optionally substituted with a hydroxyl group １ ~C ６ Alkyl, halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ - phenyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ -phenyl; or R Ｇ１ and R Ｇ２ Each combines with the atom to which it is attached to form C ３ ~C ８ forms a heterocycloalkyl; or alternatively, G is 【Chemistry 6】 R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl; C ２ ~C ６ Alkenyl; C ２ ~C ６ alkynyl; halogen or -CN, R ６ teeth, hydrogen; -C ２ ~C ６ Alkenyl; -X ２ -O-R ７ ; 【Chemistry 7】 -X ２ -NSO ２ -R ７ ; -C=C(R ９ )-Y １ -O-R ７ ; C ３ ~C ６ Cycloalkyl; C optionally substituted with a hydroxyl group ３ ~C ６ Heterocycloalkyl; C ３ ~C ６ Cycloalkylene-Y ２ -R ７ ; C ３ ~C ６ Heterocycloalkylene-Y ２ -R ７ base, Linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ base represents a group selected from R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ; or 【Chemistry 8】 Cy represents a group selected from ３ ~C ８ represents cycloalkyl, R ８ is hydrogen; linear or branched C １ ~C ６ Alkyl, -NR' ａ R' ｂ -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ -NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ , -X' ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemistry 9】 represents a group selected from R ９ is a linear or branched C １ ~C ６ Alkyl, trifluoromethyl, hydroxyl, halogen, C １ ~C ６ represents a group selected from alkoxy, R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, C １ ~C ３ Alkylene-R ８ , -O-C １ ~C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ ~C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ ~C ８ Cycloalkylene -CH ２ -R ８ , C ３ ~C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ , each independently represents a hydrogen atom or a methyl group; R １４ and R １５ , independently of each other, represent a hydrogen atom or a methyl group, or R １４ and R １５ forms a cyclohexyl with the carbon atom carrying it, R ｈ and R ｉ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ 1 or 2 hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene-NR' ｄ R' ｅ ; C １ ~C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene-OH;C １ ~C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 10】 or represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or Or R' ａ , R' ｂ and R' ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R' ｄ and R' ｅ The nitrogen atom and ring B ４ or Or R' ｄ , R' ｅ and R' ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Y １ is a linear or branched C １ ~C ４ represents alkylene, Y ２ represents bonding, -O-, -O-CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -, -CH ２ -O, -CH ２ -CO-, -CH ２ -SO ２ -, -C ２ H ５ -, -CO-, -CO-O-, -CO-CH ２ -, -CO-NH-CH ２ -, -SO ２ -, -SO ２ -CH ２ -, -NH-CO-, -NH-SO ２ and represents m=0, 1 or 2; p=1, 2, 3 or 4; B １ , B ２ , B ３ and B ４ are, independently of each other, C ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, straight-chain or branched C １ ~C ６ Alkyl, hydroxyl, -NH ２ , oxo or piperidinyl, The R ３ and R ８ one of the groups, if present, is covalently attached to said linker, such that the valency of the atom is not exceeded by one or more substituents attached thereto; or 【Chemistry 11】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, n=0, 1 or 2; --- represents a single bond or a double bond, A ４ and A ５ represent, independently of one another, a carbon or nitrogen atom, Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, R １ is hydrogen; hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C ３ ~C ６ Cycloalkyl; trifluoromethyl; linear or branched C １ ~C ６ Alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a linear or branched C １ ~C ６ optionally substituted with an alkyl group; R ２ represents hydrogen or methyl; R ３ is hydrogen; linear or branched C １ ~C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 12】 represents a group selected from R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ substituted by alkyl); linear or branched C optionally substituted by one or two hydroxyl groups; １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene -NR ｄ R ｅ ; C １ ~C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ ~C ６ Alkylene-phenyl, wherein the phenyl is １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 13】 represents a group selected from Or R ａ and R ｂ The nitrogen atom and ring B １ Forming; Or R ａ , R ｂ and R ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R ｄ and R ｅ The nitrogen atom and ring B ２ or Or R ｄ , R ｅ and R ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Het １ teeth, 【Chemistry 14】 represents a group selected from Het ２ teeth, 【Chemistry 15】 represents a group selected from A １ is -NH-, -N(C １ ~C ３ alkyl), O, S or Se; A ２ is N, CH or C(R ５ ) and G is, -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、 -OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , C optionally substituted with a hydroxyl group １ ~C ６ Alkyl, halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ - phenyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ -phenyl; or R Ｇ１ and R Ｇ２ , each of which is combined with the atom to which it is attached to form C ３ ~C ８ forms a heterocycloalkyl; or alternatively, G is 【Chemistry 16】 R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl; C ２ ~C ６ Alkenyl; C ２ ~C ６ alkynyl; halogen or -CN, R ６ teeth, hydrogen; -C ２ ~C ６ Alkenyl; -X ２ -O-R ７ ; 【Chemistry 17】 -X ２ -NSO ２ -R ７ ; -C=C(R ９ )-Y １ -O-R ７ ; C ３ ~C ６ Cycloalkyl; C optionally substituted with a hydroxyl group ３ ~C ６ Heterocycloalkyl; C ３ ~C ６ Cycloalkylene-Y ２ -R ７ ; C ３ ~C ６ Heterocycloalkylene-Y ２ -R ７ base, Linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ base represents a group selected from R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ; or 【Chemistry 18】 Cy represents a group selected from ３ ~C ８ represents cycloalkyl, R ８ is hydrogen; linear or branched C １ ~C ６ Alkyl, -NR' ａ R' ｂ -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-OR'c;-NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ , -X' ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemistry 19】 represents a group selected from: R ９ is a linear or branched C １ ~C ６ Alkyl, trifluoromethyl, hydroxyl, halogen, C １ ~C ６ represents a group selected from alkoxy, R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, halogen, C １ ~C ３ Alkylene-R ８ , -O-C １ ~C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ ~C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ ~C ８ Cycloalkylene -CH ２ -R ８ , C ３ ~C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ represent, independently of one another, a hydrogen atom or a methyl group, R １４ and R １５ are each independently a hydrogen atom or a methyl group, or R １４ and R １５ forms a cyclohexyl with the carbon atom carrying it, R ｈ and R ｉ , independently represent hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, X １ is trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ４ represents an alkylene group, X ２ is trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ 1 or 2 hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene-NR' ｄ R' ｅ ; C １ ~C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene-OH;C １ ~C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 20】 represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or Or R' ａ , R' ｂ and R' ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R' ｄ and R' ｅ The nitrogen atom and ring B ４ or Or R' ｄ , R' ｅ and R' ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Y １ is a linear or branched C １ ~C ４ represents alkylene, Y ２ represents bonding, -O-, -O-CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -, -CH ２ -O, -CH ２ -CO-, -CH ２ -SO ２ -, -C ２ H ５ -, -CO-, -CO-O-, -CO-CH ２ -, -CO-NH-CH ２ -, -SO ２ -, -SO ２ -CH ２ -, -NH-CO-, -NH-SO ２ and represents m=0, 1 or 2; p=1, 2, 3 or 4; B １ , B ２ , B ３ and B ４ , are each independently ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, straight-chain or branched C １ ~C ６ Alkyl, hydroxyl, -NH ２ , oxo or piperidinyl, The R ３ and R ８ One of the groups, if present, is covalently attached to said linker, and the valency of the atom is not exceeded by one or more of the substituents attached to it. and The anti-Met antibody or antigen-binding fragment thereof has the following amino acid sequence: HCDR1 of SEQ ID NO:5 or SEQ ID NO:11 or SEQ ID NO:39; HCDR2 of SEQ ID NO:6 or SEQ ID NO:12 or SEQ ID NO:40; HCDR3 of SEQ ID NO:7 or SEQ ID NO:13 or SEQ ID NO:41; A VH chain comprising at least one of and / or the following amino acid sequence: LCDR1 of SEQ ID NO:8 or SEQ ID NO:14 or SEQ ID NO:42; LCDR2 of SEQ ID NO:9 or SEQ ID NO:15 or SEQ ID NO:43; LCDR3 of SEQ ID NO: 10 or SEQ ID NO: 16 or SEQ ID NO: 44 A VL chain comprising at least one of [including]

2. The anti-Met antibody or antigen-binding fragment thereof has the amino acid sequence: HCDR1 of SEQ ID NO:5 or SEQ ID NO:11; HCDR2 of SEQ ID NO:6 or SEQ ID NO:12; HCDR3 of SEQ ID NO:7 or SEQ ID NO:13; A VH chain comprising at least one of and / or the following amino acid sequence: LCDR1 of SEQ ID NO:8 or SEQ ID NO:14; LCDR2 of SEQ ID NO:9 or SEQ ID NO:15; LCDR3 of SEQ ID NO: 10 or SEQ ID NO: 16 A VL chain comprising at least one of The antibody-drug conjugate of claim 1, comprising:

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

4. L, Attachment group; at least one bridging spacer group; and 4. The antibody-drug conjugate of claim 1, 2 or 3, comprising at least one cleavable group, optionally at least one cleavable group comprising a pyrophosphate group and / or a self-immolative group.

5. -(L-D) is a compound of the formula (A): 【Chemistry 21】 (In the formula, R １ is the attachment group; L １ is a bridging spacer group; E is a cleavable group. The antibody-drug conjugate of claim 4,

6. The cleavable group comprises a pyrophosphate group or the cleavable group comprises 【Chemical 22】 The antibody-drug conjugate of claim 4 or 5, comprising:

7. The bridging spacer group is (i) a polyoxyethylene (PEG) group; (ii) a PEG group selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15; (iii)-CO-CH ２ -CH ２ -PEG12-based; (iv) a butanoyl, pentanoyl, hexanoyl, heptanoyl, or octanoyl group; or (v) hexanoyl group The antibody-drug conjugate of claim 4 or 5, comprising:

8. (i) the attachment group is formed from at least one reactive group selected from a maleimide group, a thiol group, a cyclooctyne group, and an azide group; and optionally a) the maleimide group has the structure: 【Chemistry 23】 Have b) the azide group has the structure: -N=N ＋ = N － Have c) the cyclooctyne group has the structure: 【Chemistry 24】 (where: 【Chemistry 25】 is binding to said antibody; or d) the cyclooctyne group has the structure: 【Chemistry 26】 (where: 【Chemical 27】 is binding to said antibody; or (ii) the attachment group is 【Chemistry 28】 (where: 【Chemical 29】 is the bond to said antibody, The antibody-drug conjugate according to claim 7.

9. The antibody, 【Chemistry 30】 (where: 【Chemistry 31】 is binding to the antibody, 【Chemistry 32】 is the bond to the bridging spacer group The antibody-drug conjugate of claim 8, which is joined to the linker (L) by an attachment group selected from:

10. The bridging spacer group is -CO-CH ２ -CH ２ The antibody-drug conjugate of claim 9, which is -PEG12-.

11. The bridging spacer group is joined to a cleavable group; optionally, the cleavable group is -pyrophosphate-CH ２ -CH ２ -NH ２ The antibody-drug conjugate of claim 9 or 10,

12. The antibody-drug conjugate of any one of claims 9 to 11, wherein the cleavable group is conjugated to the Bcl-xL inhibitor (D).

13. The linker is Attachment group, at least one bridging spacer group; a peptide group, and At least one cleavable group The antibody-drug conjugate according to any one of claims 1 to 4, comprising:

14. -(L-D) is a compound of the formula (B): 【Chemical 33】 (In the formula, R １ is the attachment group; L １ is a bridging spacer; Lp is a peptide group containing 1 to 6 amino acid residues, or Lp is a group 【Chemical Formula 34】 Including; E is a cleavable group; L ２ is a bridging spacer; m is 0 or 1; D is a Bcl-xL inhibitor. The antibody-drug conjugate of claim 13,

15. (i) the attachment group is formed from at least one reactive group comprising a maleimide group, a thiol group, a cyclooctyne group, and / or an azide group, and optionally a) the maleimide group has the structure: 【Chemistry 35】 Have b) the azide group has the structure: -N=N ＋ = N － or c) the cyclooctyne group has the structure: 【Chemical 36】 (where: 【Chemical 37】 is binding to said antibody; or (ii) the attachment group is 【Chemical 38】 (where: 【Chemical 39】 is the bond to said antibody, The antibody-drug conjugate according to claim 13 or 14.

16. (i) at least one crosslink spacer comprises a PEG group, optionally selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEG11, PEG12, PEG13, PEG14, and PEG15; or (ii) at least one bridging spacer is ＊ —C(O)—CH ２ -CH ２ -PEG1- ＊＊ , ＊ —C(O)—CH ２ -PEG3- ＊＊ , ＊ —C(O)—CH ２ -CH ２ -PEG12 ＊＊ , ＊ -NH-CH ２ -CH ２ -PEG1- ＊＊ , polyhydroxyalkyl group, ＊ -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ )-C(O)- ＊＊ , and ＊ —C(O)—CH ２ -CH ２ -PEG12-NH-C(O)CH ２ -CH ２ - ＊＊ is selected from ＊＊ indicates a direct or indirect point of attachment of the at least one bridge spacer to the attachment group; ＊ indicates a direct or indirect point of attachment of the at least one cross-linking spacer to the peptide group; The antibody-drug conjugate according to any one of claims 13 to 15.

17. L １ but, ＊ —C(O)—CH ２ -CH ２ -PEG1- ＊＊ , ＊ —C(O)—CH ２ -PEG3- ＊＊ , ＊ —C(O)—CH ２ -CH ２ -PEG12 ＊＊ , ＊ -NH-CH ２ -CH ２ -PEG1- ＊＊ and polyhydroxyalkyl groups, ＊＊ is R １ L to １ indicates the direct or indirect attachment point of ＊ is L to Lp １ The antibody-drug conjugate according to any one of claims 13 to 16, exhibiting a direct or indirect attachment point of:

18. m is 1, L ２ is -C(O)-N(CH ３ )-CH ２ -CH ２ -N(CH ３ 20. The antibody-drug conjugate of claim 13, wherein the moiety is -C(O)-.

19. (i) the peptide group comprises 1-6, 1-4, 1-3 or 1-2 amino acid residues, optionally selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr); (ii) the peptide group comprises Val-Cit, Val-Ala, Val-Lys, Sulfo-Ala-Val-Ala, Gly-Gly-Gly, and / or Gly-Gly-Phe-Gly (SEQ ID NO:36); or (iii) the peptide group is 【Chemistry 40】 Selected from: The antibody-drug conjugate according to any one of claims 13 to 18.

20. (i) the cleavable group comprises a pyrophosphate and / or a self-immolative group; (ii) the cleavable group comprises a self-immolative group; or (iii) the cleavable group comprises a self-immolative group comprising para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate, or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium. The antibody-drug conjugate according to any one of claims 13 to 19.

21. m is 0 or 1, or m is 1 and the bridging spacer is 【Chemistry 41】 The antibody-drug conjugate of any one of claims 14 to 20, comprising:

22. -(L-D) is 【Chemistry 42-1】 【Chemistry 42-2】 【Chemistry 42-3】 【Chemistry 42-4】 【Chemistry 42-5】 【Chemistry 42-6】 The antibody-drug conjugate of any one of claims 14 to 21, which is formed from a compound selected from:

23. -(L-D) is 【Chemistry 43-1】 【Chemistry 43-2】 【Chemistry 43-3】 【Chemistry 43-4】 【Chemistry 43-5】 【Chemistry 43-6】 【Chemistry 43-7】 【Chemistry 43-8】 (where 【Chemistry 44】 is the bond to said antibody, The antibody-drug conjugate according to any one of claims 14 to 22.

24. -(L-D) is a compound of the formula (C): 【Chemistry 45】 (In the formula, R １ is the attachment group; L １ is a bridging spacer; L ｐ is a peptide group containing 1 to 6 amino acids; D is a Bcl-xL inhibitor; G １ -L ２ - A is a self-immolative spacer; L ２ is a bond, methylene, neopentylene or C ２ ~C ３ alkenylene; A is a bond, -OC(=O)- ＊ , 【Chemistry 46】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ is H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); L ３ is a spacer moiety; R ２ is the hydrophilic portion) That is, The antibody-drug conjugate of claim 1, 2 or 3.

25. -(LD) is a compound of the formula (D): 【Chemistry 47】 (In the formula, R １ is the attachment group; L １ is a bridging spacer; Lp is a peptide group containing 1 to 6 amino acids; A is a bond, -OC(=O)- ＊ , 【Chemistry 48】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); L ３ is a spacer moiety; R ２ is the hydrophilic moiety) 25. The antibody-drug conjugate of claim 24, which is:

26. (1) L １ but, 【Chemistry 49】 or ＊ -CH(OH)CH(OH)CH(OH)CH(OH)- ＊＊ Contains (wherein each n is an integer from 1 to 12, and L １の ＊ indicates a direct or indirect attachment point to Lp, and L １ of ＊＊ is R １ (indicating the direct or indirect point of attachment to the (2) L １ but, 【Chemistry 50】 and n is an integer from 1 to 12, or n is 1, or n is 12, where L １ of ＊ indicates the direct or indirect attachment point to Lp, L １ of ＊＊ is R １ (indicating the direct or indirect point of attachment to the (3) L １ but, 【Chemistry 51】 and n is an integer from 1 to 12 (where L １ of ＊ indicates the direct or indirect attachment point to Lp, L １ of ＊＊ is R １ (indicating the direct or indirect point of attachment to the (4) L １ but, 【Chemistry 52】 (where L １ of ＊ indicates the direct or indirect attachment point to Lp, L １ of ＊＊ is R １ (indicating a direct or indirect point of attachment to the (5) L １ but, ＊ -C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)O(CH ２ ) ｍ SSC(R ３ ) ２ (CH ２ ) ｍ C(=O)NR ３ (CH ２ ) ｍ NR ３ C(=O)(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)O(CH ２ ) ｍ P. (L.) ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ H ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ H ２ ) ｎ C(=O)- ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ X １ (CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ I'm sorry ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ I'm sorry ２ ) ｎ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ I'm sorry ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ I'm sorry ２ ) ｎ X １ (CH ２ ) ｎ - ＊＊ ; ＊ -C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ C(=O)NH(CH ２ ) ｍ - ＊＊ ; ＊ -C(=O)(CH ２ ) ｍ C(R ３ ) ２ - ＊＊ or ＊ -C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - ＊＊ wherein L is a bridging spacer comprising １ of ＊ indicates the direct or indirect attachment point to Lp, L １ of ＊＊ is R １ (indicating the direct or indirect point of attachment to the X １ but, 【Chemistry 53】 and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30; Each R ３ independently H and C １ ~C ６ selected from alkyl, The antibody-drug conjugate of claim 24 or 25.

27. R ２ Polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 【Chemical 54】 C substituted with ２ ~C ６ Alkyl, or -OC(=O)NHS(O) ２ N.H.C.H. ２ CH ２ OCH ３ , -NHC(=O)C １～４ Alkylene-P(O)(OCH ２ CH ３ ) ２ and C substituted with 1 to 2 substituents independently selected from —COOH groups. ２ ~C ６ The antibody-drug conjugate of any one of claims 24 to 26, wherein the hydrophilic moiety comprises an alkyl.

28. R ２ but, 【Chemistry 55】 (wherein n is an integer from 1 to 6). 【Chemistry 56】 The antibody-drug conjugate according to any one of claims 24 to 27,

29. The hydrophilic portion is (i) the part: 【Chemistry 57】 (wherein n is an integer from 3 to 25, and R is H, -CH ３ or -CH ２ CH ２ C(═O)OH; or (ii) Formula: 【Chemistry 58】 (wherein R is H, -CH ３ , C.H. ２ CH ２ NHC(=O)OR ａ , -CH ２ CH ２ NHC(=O)R ａ , or -CH ２ CH ２ C(=O)OR ａ and R' is OH, -OCH ３ , -CH ２ CH ２ NHC(=O)OR ａ , -CH ２ CH ２ NHC(=O)R ａ , or -OCH ２ CH ２ C(=O)OR ａ and R ａ is H, or OH or C １～４ C optionally substituted with any one of alkoxyl １～４ alkyl, and each of m and n is independently an integer from 2 to 25. The antibody-drug conjugate of claim 24 or 25, comprising:

30. The hydrophilic portion is 【Chemistry 59】 The antibody-drug conjugate of any one of claims 24 to 28, comprising:

31. (i) L ３ But the structure 【Chemistry 60】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(=O)C(R ｂ ) ２ NHC(=O)O-、 -NHC(=O)C(R ｂ ) ２ HUNTER ｂ ) ２ HUNTER ２ N(X-R ２ )C(=O)O-、-C(=O)N(X-R ２ )-、-CH ２ N(X-R ２ )C(=O)-、-C(=O)NR ｂ -、-C(=O)NH-、-CH ２ NR ｂ C(=O)-、-CH ２ NR ｂ C(=O)NH-,-CH ２ NR ｂ P.S. ｂ -、-NHC(=O)-, -NHC(=O)NH-, -OC(=O)NH-、 -S (O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl); X is a bond, triazolyl, or -CH ２ -triazolyl-, X is R ２ connected to or a spacer moiety having the formula: (ii) L ３ But the structure 【Chemistry 61】 (In the formula, Wは、-CH ２ -、-CH ２ O-、-CH ２ N(R ｂ )C(=O)O-、-NHC(=O)C(R ｂ ) ２ NHC(=O)O-、 -NHC(=O)C(R ｂ ) ２ NH-、-NHC(=O)C(R ｂ ) ２ NHC(=O)-、-CH ２ N(X-R ２ )C(=O)O-、-C(=O)N(X-R ２ )-、 -CH ２ N(X-R ２ )C(=O)-、-C(=O)NR ｂ -、-C(=O)NH-、-CH ２ NR ｂ C(=O)-、-CH ２ NR ｂ C(=O)NH-、 -CH ２ NR ｂ P.S. ｂ -、-NHC(=O)-, -NHC(=O)NH-, -OC(=O)NH-、 -S (O) ２ NH-, -NHS(O) ２ -, -C(=O)-, -C(=O)O-, or -NH-, where each R ｂ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; X is -CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-, -C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-, -(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-, -(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ --, --CH ２ -Triazolyl-C １～４ Alkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -, -C ４～６ Cycloalkylene-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -wherein each n is independently 1, 2, or 3; X is R ２ connected to is a spacer moiety having the formula: The antibody-drug conjugate according to any one of claims 24 to 30.

32. The antibody-drug conjugate of any one of claims 4 to 31, wherein the attachment group is formed by a reaction involving at least one reactive group.

33. The attachment group is a first reactive group attached to the linker; and A second reactive group that is attached to the antibody or is an amino acid residue of the antibody. and optionally, (i) at least one of the reactive groups is Thiol, Maleimide, Haloacetamides, Azide, Alkynes, Cyclooctene, Triarylphosphines, oxanobornadiene, Cyclooctyne, Diaryltetrazines, Monoaryltetrazines, Norbornene, aldehyde, Hydroxylamine, Hydrazine, NH ２ -NH-C(=O)-、 Ketones, vinyl sulfone, Aziridine, Amino acid residues, 【Chemistry 62】 、-ONH ２ 、-NH ２ 、 【Chemistry 63】 、-N ３ 、 【Chemistry 64】 、-SH、-SR ３ 、-SSR ４ 、-S(=O) ２ (CH=CH ２ )、-(CH ２ ) ２ S(=O) ２ (CH=CH ２ )、-NHS(=O) ２ (CH=CH ２ )、-NHC(=O)CH ２ Br、-NHC(=O)CH ２ I、 【Chemistry 65】 (O)NHNH ２ 、 【Hua 66-1】 【Hua 66-2】 Contains; (where: Each R ３ are independently H and C １ ~C ６ alkyl; Each R ４ is 2-pyridyl or 4-pyridyl; Each R ５ are independently H, C １ ~C ６ selected from alkyl, F, Cl, and -OH; Each R ６ are independently H, C １ ~C ６ Alkyl, F, Cl, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -N(CH ３ ) ２ , -CN, -NO ２ and -OH; Each R ７ are independently H, C １～６ Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH １～４ Alkoxy and -C(=O)OH substituted C １～４ alkyl); and / or (ii) the first reactive group and the second reactive group are Thiols and maleimides, Thiols and haloacetamides, Thiols and vinyl sulfones, Thiols and aziridines, Azides and alkynes, Azide and cyclooctyne, Azide and cyclooctene, Azides and triarylphosphines, Azides and oxanobornadienes, diaryltetrazines and cyclooctenes, Monoaryltetrazines and norbornenes, Aldehydes and hydroxylamines, Aldehydes and hydrazines, Aldehydes and NH ２ -NH-C(=O)-, Ketones and hydroxylamines, Ketones and hydrazines, Ketones and NH ２ -NH-C(=O)-, Hydroxylamine and 【Chemistry 67】 , amines and 【Chemistry 68】 ,or CoA or CoA analog and serine residue Including, The antibody-drug conjugate according to any one of claims 4 to 32.

34. The attachment group is 【Chemistry 69-1】 【Chemistry 69-2】 【Chemistry 69-3】 【Chemistry 69-4】 Contains a group selected from (where: R ３２ is H, C １～４ alkyl, phenyl, pyrimidine or pyridine; R ３５ is H, C １～６ C substituted with alkyl, phenyl or 1 to 3 -OH groups １～４ is alkyl; Each R ７ are independently H, C １～６ Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH １～４ Alkoxy and -C(=O)OH substituted C １～４ alkyl; R ３７ is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R ８ is H or methyl; R ９ is H, -CH ３ or phenyl), The antibody-drug conjugate according to any one of claims 4 to 33.

35. 35. The antibody-drug conjugate of any one of claims 24 to 34, wherein the peptide group comprises 1 to 4, or 1 to 3, or 1 or 2 amino acid residues, optionally wherein the amino acid residues are selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr).

36. 35. The antibody-drug conjugate of any one of claims 24 to 34, wherein the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Sulfo-Ala-Val-Cit, Sulfo-Ala-Val-Ala, Gly-Gly-Gly, and / or Gly-Gly-Phe-Gly (SEQ ID NO: 36).

37. Lp is 【Chemistry 70】 The antibody-drug conjugate according to any one of claims 24 to 36, selected from:

38. -(LD) is a compound of the formula: （１） 【Chemistry 71】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemical Formula 72】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （２） 【Chemical Formula 73】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemical 74】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （３） 【Chemistry 75】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemical 76】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （４） 【Chemical Formula 77】 (In the formula, Each R is independently H, —CH ３ , and -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemical 78】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （５） 【Chemical Formula 79】 (In the formula, Each R is independently H, —CH ３ , and -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 80】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （６） 【Chemistry 81】 (In the formula, Xa is -CH ２ --, --OCH ２ --NHCH ２ -or- NRCH ２ -, and each R is independently H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 82】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （７） 【Chemistry 83】 (In the formula, R is H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 84】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （８） 【Chemistry 85】 (In the formula, Xb is -CH ２ --, --OCH ２ --, --NHCH ２ -or- NRCH ２ -, and each R is independently H, -CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 86】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （９） 【Chemistry 87】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 88】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１０） 【Chemistry 89】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 90】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１１） 【Chemistry 91】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 92】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１２） 【Chemistry 93】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 94】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１３） 【Chemistry 95】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 96】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１４） 【Chemistry 97】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 98】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; （１５） 【Chemistry 99】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 100】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; or （１６） 【Chemistry 101】 (In the formula, Each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 102】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor; or （１７） 【Chemistry 103】 (In the formula, Each R is independently H, —CH ３ or -CH ２ CH ２ C(=O)OH; A is a bond, -OC(=O)- ＊ , 【Chemistry 104】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); n is an integer from 2 to 24; D is a Bcl-xL inhibitor; or （１８） 【Chemistry 105】 (In the formula, A is a bond, -OC(=O)- ＊ , 【Chemistry 106】 , -OC(=O)N(CH ３ ) CH ２ CH ２ N (CH ３ ) C(=O)- ＊ Or -OC(=O)N(CH ３ ) C(R ａ ) ２ C(R ａ ) ２ N (CH ３ ) C(=O)- ＊ and (Here, each R ａ are independently H, C １ ~C ６ Alkyl, and C ３ ~C ８ cycloalkyl; ＊ indicates the point of attachment to D); D is a Bcl-xL inhibitor.

38. The antibody-drug conjugate of any one of claims 24 to 37, comprising or formed from:

39. A is a bond and / or R is -CH ３ or -CH ２ CH ２ The antibody-drug conjugate of any one of claims 24 to 38, wherein said conjugate is COOH.

40. A is -OC(=O)- ＊ and / or R is -CH ３ or -CH ２ CH ２ The antibody-drug conjugate of any one of claims 24 to 38, wherein said conjugate is COOH.

41. -(L-D) is 【Chemistry 107-1】 【Chemistry 107-2】 【Chemistry 107-3】 【Chemistry 107-4】 【Chemistry 107-5】 【Chemistry 107-6】 【Chemistry 107-7】 【Chemistry 107-8】 【Chemistry 107-9】 【Chemistry 107-10】 【Chemistry 107-11】 【Chemistry 107-12】 【Chemistry 107-13】 【Chemistry 107-14】 【Chemistry 107-15】 The antibody-drug conjugate of any one of claims 24 to 40, which is formed from a compound selected from:

42. D is a compound of formula (I): 【Chemistry 108】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, R １ and R ２ are each independently hydrogen; hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C ３ ~C ６ Cycloalkyl; trifluoromethyl; linear or branched C １ ~C ６ Alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a linear or branched C １ ~C ６ optionally substituted with an alkyl group; Or R １ and R ２ are the carbon atoms and C ３ ~C ６ Forming a cycloalkylene group, R ３ is hydrogen; ３ ~C ６ Cycloalkyl; linear or branched C １ ~C ６ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 109】 represents a group selected from R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ substituted by alkyl); linear or branched C optionally substituted by one or two hydroxyl groups; １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ； C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene -NR ｄ R ｅ ; C １ ~C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ ~C ６ Alkylene-phenyl, wherein the phenyl is １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 110】 or represents a group selected from Or R ａ and R ｂ The nitrogen atom and ring B １ Forming; Or R ａ , R ｂ and R ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R ｃ , R ｄ , R ｅ , R ｆ , independently represent hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R ｄ and R ｅ The nitrogen atom and ring B ２ or Or R ｄ , R ｅ and R ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Het １ teeth, 【Chemistry 111】 represents a group selected from Het ２ teeth, 【Chemistry 112】 represents a group selected from A １ is -NH-, -N(C １ ~C ３ alkyl), O, S or Se; A ２ is N, CH or C(R ５ ) and G is, -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、 -OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , C optionally substituted with a hydroxyl group １ ~C ６ Alkyl, halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ - phenyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ -phenyl; or R Ｇ１ and R Ｇ２ Each combines with the atom to which it is attached to form C ３ ~C ８ forms a heterocycloalkyl; or alternatively, G is 【Chemistry 113】 R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl; C ２ ~C ６ Alkenyl; C ２ ~C ６ alkynyl; halogen or -CN, R ６ teeth, hydrogen; -C ２ ~C ６ Alkenyl; -X ２ -O-R ７ ; 【Chemistry 114】 -X ２ -NSO ２ -R ７ ; -C=C(R ９ )-Y １ -O-R ７ ; C ３ ~C ６ Cycloalkyl; C optionally substituted with a hydroxyl group ３ ~C ６ Heterocycloalkyl; C ３ ~C ６ Cycloalkylene-Y ２ -R ７ ; C ３ ~C ６ Heterocycloalkylene-Y ２ -R ７ basis, Linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ base represents a group selected from R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ; or 【Chemistry 115】 Cy represents a group selected from ３ ~C ８ represents cycloalkyl, R ８ is hydrogen; linear or branched C １ ~C ６ Alkyl, -NR' ａ R' ｂ -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ -NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ , -X' ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemistry 116】 represents a group selected from R ９ is a linear or branched C １ ~C ６ Alkyl, trifluoromethyl, hydroxyl, halogen, C １ ~C ６ represents a group selected from alkoxy, R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, C １ ~C ３ Alkylene-R ８ , -O-C １ ~C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ ~C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ ~C ８ Cycloalkylene -CH ２ -R ８ , C ３ ~C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ represent, independently of one another, a hydrogen atom or a methyl group, R １４ and R １５ are each independently a hydrogen atom or a methyl group, or R １４ and R １５ forms a cyclohexyl with the carbon atom carrying it, R ｈ and R ｉ , independently represent hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ 1 or 2 hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene-NR' ｄ R' ｅ ; C １ ~C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene-OH;C １ ~C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 117】 or represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or Or R' ａ , R' ｂ and R' ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R' ｄ and R' ｅ The nitrogen atom and ring B ４ or Or R' ｄ , R' ｅ and R' ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Y １ is a linear or branched C １ ~C ４ represents alkylene, Y ２ represents bonding, -O-, -O-CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -, -CH ２ -O, -CH ２ -CO-, -CH ２ -SO ２ -, -C ２ H ５ -, -CO-, -CO-O-, -CO-CH ２ -, -CO-NH-CH ２ -, -SO ２ -, -SO ２ -CH ２ -, -NH-CO-, -NH-SO ２ and represents m=0, 1 or 2; p=1, 2, 3 or 4; B １ , B ２ , B ３ and B ４ , are each independently ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, straight-chain or branched C １ ~C ６ Alkyl, hydroxyl, -NH ２、 may be substituted by one or two groups selected from oxo or piperidinyl; The R ３ and R ８ One of the groups, if present, is covalently attached to said linker, and the valency of the atom is not exceeded by one or more of the substituents attached to it. The antibody-drug conjugate of any one of claims 1 to 41, comprising:

43. R １ is linear or branched C １～６ alkyl, R ２ The antibody-drug conjugate of claim 42, wherein is H.

44. D is a compound of formula (II): 【Chemistry 118】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, n=0, 1 or 2; --- represents a single bond or a double bond, A ４ and A ５ represent, independently of one another, a carbon or nitrogen atom, Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, R １ is hydrogen; hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C ３ ~C ６ Cycloalkyl; trifluoromethyl; linear or branched C １ ~C ６ Alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a linear or branched C １ ~C ６ optionally substituted with an alkyl group; R ２ represents hydrogen or methyl; R ３ is hydrogen; linear or branched C １ ~C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 119】 represents a group selected from R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ substituted by alkyl); linear or branched C optionally substituted by one or two hydroxyl groups; １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ； C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene -NR ｄ R ｅ ; C １ ~C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ ~C ６ Alkylene-phenyl, wherein the phenyl is １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 120】 or represents a group selected from Or R ａ and R ｂ The nitrogen atom and ring B １ Forming; Or R ａ , R ｂ and R ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R ｄ and R ｅ The nitrogen atom and ring B ２ or Or R ｄ , R ｅ and R ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Het １ teeth, 【Chemistry 121】 represents a group selected from Het ２ teeth, 【Chemistry 122】 represents a group selected from A １ is -NH-, -N(C １ ~C ３ alkyl), O, S or Se; A ２ is N, CH or C(R ５ ) and G is, -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、 -OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , C optionally substituted with a hydroxyl group １ ~C ６ Alkyl, halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ - phenyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ -phenyl; or R Ｇ１ and R Ｇ２ Each combines with the atom to which it is attached to form C ３ ~C ８ forms a heterocycloalkyl; or alternatively, G is 【Chemistry 123】 R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl; C ２ ~C ６ Alkenyl; C ２ ~C ６ alkynyl; halogen or -CN, R ６ teeth, hydrogen; -C ２ ~C ６ Alkenyl; -X ２ -O-R ７ ; 【Chemical 124】 -X ２ -NSO ２ -R ７ ; -C=C(R ９ )-Y １ -O-R ７ ; C ３ ~C ６ Cycloalkyl; C optionally substituted with a hydroxyl group ３ ~C ６ Heterocycloalkyl; C ３ ~C ６ Cycloalkylene-Y ２ -R ７ ; C ３ ~C ６ Heterocycloalkylene-Y ２ -R ７ base, Linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ base represents a group selected from R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ; or 【Chemistry 125】 Cy represents a group selected from ３ ~C ８ represents cycloalkyl, R ８ is hydrogen; linear or branched C １ ~C ６ Alkyl, -NR' ａ R' ｂ -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-OR'c;-NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ、 -X' ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemistry 126】 represents a group selected from R ９ is a linear or branched C １ ~C ６ Alkyl, trifluoromethyl, hydroxyl, halogen, C １ ~C ６ represents a group selected from alkoxy, R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, halogen, C １ ~C ３ Alkylene-R ８ , -O-C １ ~C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ ~C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ ~C ８ Cycloalkylene -CH ２ -R ８ , C ３ ~C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ , each independently represents a hydrogen atom or a methyl group; R １４ and R １５ , independently of each other, represent a hydrogen atom or a methyl group, or R １４ and R １５ forms a cyclohexyl with the carbon atom carrying it, R ｈ and R ｉ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, X １ is trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ４ represents an alkylene group, X ２ is trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ 1 or 2 hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene-NR' ｄ R' ｅ ; C １ ~C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene-OH;C １ ~C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 127】 or represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or Or R' ａ , R' ｂ and R' ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R' ｄ and R' ｅ The nitrogen atom and ring B ４ or Or R' ｄ , R' ｅ and R' ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, Y １ is a linear or branched C １ ~C ４ represents alkylene, Y ２ represents bonding, -O-, -O-CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -, -CH ２ -O, -CH ２ -CO-, -CH ２ -SO ２ -, -C ２ H ５ -, -CO-, -CO-O-, -CO-CH ２ -, -CO-NH-CH ２ -, -SO ２ -, -SO ２ -CH ２ -, -NH-CO-, -NH-SO ２ and represents m=0, 1 or 2; p=1, 2, 3 or 4; B １ , B ２ , B ３ and B ４ , are each independently ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, straight-chain or branched C １ ~C ６ Alkyl, hydroxyl, -NH ２ , oxo or piperidinyl, The R ３ and R ８ One of the groups, if present, is covalently attached to said linker, and the valency of the atom is not exceeded by one or more of the substituents attached to it. The antibody-drug conjugate of any one of claims 1 to 41, comprising:

45. A １ and A ５ Both represent nitrogen atoms, R １ is a linear or branched C １～６ alkyl; R ２ The antibody-drug conjugate of claim 44, wherein: is H; n is 1; and represents a single bond.

46. Gが、-C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen, C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ - phenyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, phenyl and -(CH ２ ) １～４ -phenyl; or R Ｇ１ and R Ｇ２ Each combines with the atom to which it is attached to form C ３ ~C ８ forms a heterocycloalkyl; or alternatively, G is 【Chemistry 128】 R Ｇ４ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl, An antibody-drug conjugate according to any one of claims 1 to 45.

47. D is a compound of formula (IA) or (IIA): 【Chemistry 129】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, Z １ represents a bond or -O-; R ３ is hydrogen; ３ ~C ６ Cycloalkyl; linear or branched C １ ~C ６ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ and -X １ -O-R ｃ represents a group selected from R ａ and R ｂ are each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; １ ~C ６ Alkyl; and C １ ~C ６ Alkylene-SO ２ O － represents a group selected from R ｃ is hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Het ２ teeth, 【Chemistry 130】 represents a group selected from A １ is -NH-, -N(C １ ~C ３ alkyl), O, S or Se; A ２ is N, CH or C(R ５ ) and G is, -C(O)OH、-C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、 -OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , C optionally substituted with a hydroxyl group １ ~C ６ Alkyl, halogen, -NO ２ -CN; - R in each occurrence Ｇ１ and R Ｇ２ are each independently hydrogen and C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ selected from the group consisting of alkyl; - R Ｇ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ is alkyl; or R Ｇ１ and R Ｇ２ Each combines with the atom to which it is attached to form C ３ ~C ８ Forming a heterocycloalkyl; R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, R ５ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ represents a group selected from alkyl; halogen or -CN, R ６ teeth, -X ２ -O-R ７ and Linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ base represents a group selected from R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ； or 【Chemistry 131】 Cy represents a group selected from ３ ~C ８ represents cycloalkyl, R ８ is hydrogen; linear or branched C １ ~C ６ Alkyl, -NR' ａ R' ｂ ; -NR' ａ -CO-OR' ｃ -NR' ａ -CO-R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ -NH-X' ２ -N ＋ R' ａ R' ｂ R' ｃ ;-O-X' ２ -NR' ａ R' ｂ ;-X' ２ -NR' ａ R' ｂ : -NR' ｃ -X' ２ -N ３ and 【Chemistry 132】 represents a group selected from R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl, R １１ is hydrogen, C １ ~C ３ Alkylene-R ８ , -O-C １ ~C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ ~C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ ~C ８ Cycloalkylene -CH ２ -R ８ , C ３ ~C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from R １２ and R １３ represent, independently of one another, a hydrogen atom or a methyl group, R １４ and R １５ are each independently a hydrogen atom or a methyl group, or R １４ and R １５ forms a cyclohexyl with the carbon atom carrying it, R ｈ and R ｉ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ -phenyl, wherein the phenyl is a linear or branched C １ ~C ６ 1 or 2 hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-SO ２ OH;C １ ~C ６ Alkylene-SO ２ O － ; C １ ~C ６ Alkylene-COOH; １ ~C ６ Alkylene-PO(OH) ２ ; C １ ~C ６ Alkylene-NR' ｄ R' ｅ ; C １ ~C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ ~C ６ Alkylene -O-C １ ~C ６ Alkylene-OH;C １ ~C ６ Alkylene-phenyl, wherein the phenyl is selected from the group consisting of hydroxyl and C １ ~C ６ Optionally substituted by an alkoxy group; Base: 【Chemistry 133】 or represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or Or R' ａ , R' ｂ and R' ｃ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, Or R' ｄ and R' ｅ The nitrogen atom and ring B ４ or Or R' ｄ , R' ｅ and R' ｆ The nitrogen atom and the bridging C ３ ~C ８ forming a heterocycloalkyl, m=0, 1 or 2; p=1, 2, 3 or 4; B ３ and B ４ are, independently of each other, C ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, straight-chain or branched C １ ~C ６ Alkyl, hydroxyl, -NH ２ , oxo or piperidinyl). The antibody-drug conjugate of any one of claims 1 to 41, comprising:

48. Gが、-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) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、 -NR Ｇ１ S (O) ２ R Ｇ２ , -NR Ｇ１ C (=NR Ｇ２ ) N.R. Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) N.R. Ｇ１ R Ｇ２ , halogen, -NO ２ 48. The antibody-drug conjugate of claim 47, wherein the antibody-drug conjugate is selected from the group consisting of -CN, -CN, and -CN.

49. R ７ is a linear or branched C １ ~C ６ Alkyl group; ３ ~C ６ ) Cycloalkylene-R ８ ;or 【Chemistry 134】 (where Cy is C ３ ~C ８ represents cycloalkyl) The antibody-drug conjugate of any one of claims 1 to 48, wherein the antibody-drug conjugate represents a group selected from:

50. R ７ but, 【Chemistry 135】 The antibody-drug conjugate of any one of claims 1 to 48, wherein the antibody-drug conjugate represents a group selected from:

51. D is a compound of formula (IB), (IC), (IIB) or (IIC): 【Chemistry 136】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing, For formula (IB) or (IC), R ３ is hydrogen; linear or branched C １ ~C ６ Alkyl ； -X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ and -X １ -O-R ｃ represents a group selected from For formula (IIB) or (IIC), Z １ represents a bond, R ３ represents hydrogen; or Z １ represents -O-; R ３ is -X １ -NR ａ R ｂ represents R ａ and R ｂ are each independently hydrogen; a linear or branched C optionally substituted with one or two hydroxyl groups; １ ~C ６ Alkyl; and C １ ~C ６ Alkylene-SO ２ O － represents a group selected from: R ｃ is hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, R ６ is -X ２ -O-R ７ or linear or branched C １ ~C ６ Heteroarylene -R optionally substituted with an alkyl group ７ represents a group, R ７ teeth, 【Chemistry 137】 represents a group selected from R ８ is -NR' ａ R' ｂ ;-O-X' ２ -NR' ａ R' ｂ and -X' ２ -NR' ａ R' ｂ represents a group selected from R １０ represents fluorine, R １２ and R １３ represent, independently of one another, a hydrogen atom or a methyl group, R １４ and R １５ are each independently a hydrogen or a methyl group, X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen, C １ ~C ６ A linear or branched C optionally substituted with one or two groups selected from alkoxy. １ ~C ６ represents an alkylene group, X' ２ is a linear or branched C １ ~C ６ represents alkylene, R' ａ and R' ｂ are each independently hydrogen; one or two hydroxyl or C １ ~C ６ A linear or branched C optionally substituted with an alkoxy group １ ~C ６ Alkyl; C １ ~C ６ Alkylene-NR' ｄ R' ｅ represents a group selected from Or R' ａ and R' ｂ The nitrogen atom and ring B ３ or R' ｄ , R' ｅ are each independently hydrogen or a linear or branched C １ ~C ６ represents an alkyl group, B ３ is C ３ ~C ８ represents a heterocycloalkyl group, which (i) may be a monocyclic or bicyclic group (wherein bicyclic groups include fused, bridged, or spiro ring systems); (ii) may contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; and (iii) may be selected from fluorine, bromine, chlorine, linear or branched C １ ~C ６ may be substituted with one or two groups selected from alkyl, hydroxyl, and oxo; The antibody-drug conjugate of any one of claims 1 to 41, comprising:

52. R ７ The following group: 【Chemistry 138】 The antibody-drug conjugate according to any one of claims 1 to 51, wherein

53. R ７ but, 【Chemistry 139】 The antibody-drug conjugate of any one of claims 1 to 51, wherein the antibody-drug conjugate represents a group selected from:

54. R ８ but, 【Chemistry 140】 represents a group selected from 【Chemistry 141】 represents a bond to the linker, The antibody-drug conjugate according to any one of claims 42 to 53.

55. B ３ is selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group; ３ ~C ８ The antibody-drug conjugate of any one of claims 42 to 54, which displays a heterocycloalkyl group.

56. D is one of the following attached to L: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any one of the foregoing.

57. The antibody-drug conjugate of any one of claims 1 to 41, wherein D comprises a group represented by a formula selected from the formulas in Table A2.

58. The antibody-drug conjugate of any one of claims 1 to 41, wherein -(LD) is formed from a compound in Table B, or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt of any of the foregoing.

59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-MET antibody or antigen-binding fragment thereof comprises at least two, three, four or five CDR sequences selected from the group consisting of: HCDR1 of SEQ ID NO:5 or SEQ ID NO:11 or SEQ ID NO:39; HCDR2 of SEQ ID NO:6 or SEQ ID NO:12 or SEQ ID NO:40; HCDR3 of SEQ ID NO:7 or SEQ ID NO:13 or SEQ ID NO:41; LCDR1 of SEQ ID NO:8 or SEQ ID NO:14 or SEQ ID NO:42; LCDR2 of SEQ ID NO:9 or SEQ ID NO:15 or SEQ ID NO:43; and LCDR3 of SEQ ID NO:10 or SEQ ID NO:16 or SEQ ID NO:

44.

60. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-MET antibody or antigen-binding fragment thereof comprises at least two, three, four or five CDR sequences selected from the group consisting of HCDR1 of SEQ ID NO:5 or SEQ ID NO:11, HCDR2 of SEQ ID NO:6 or SEQ ID NO:12, HCDR3 of SEQ ID NO:7 or SEQ ID NO:13, LCDR1 of SEQ ID NO:8 or SEQ ID NO:14, LCDR2 of SEQ ID NO:9 or SEQ ID NO:15, and LCDR3 of SEQ ID NO:10 or SEQ ID NO:

16.

61. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:5, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:6, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:7; light chain CDR1 (LCDR1) consisting of SEQ ID NO:8, light chain CDR2 (LCDR2) consisting of SEQ ID NO:9, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:

10.

62. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:11, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:12, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:13; light chain CDR1 (LCDR1) consisting of SEQ ID NO:14, light chain CDR2 (LCDR2) consisting of SEQ ID NO:15, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:

16.

63. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 39, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 41; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 42, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 43, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:

44.

64. The antibody-drug conjugate of any one of claims 2 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO:1 and the light chain variable region amino acid sequence of SEQ ID NO:

2.

65. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO:3 and the light chain variable region amino acid sequence of SEQ ID NO:

4.

66. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO:37 and the light chain variable region amino acid sequence of SEQ ID NO:

38.

67. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 17, or a sequence that is at least 95% identical to SEQ ID NO: 17, and a light chain amino acid sequence of SEQ ID NO: 18, or a sequence that is at least 95% identical to SEQ ID NO:

18.

68. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 19, or a sequence that is at least 95% identical to SEQ ID NO: 19, and a light chain amino acid sequence of SEQ ID NO: 20, or a sequence that is at least 95% identical to SEQ ID NO:

20.

69. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:21, or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22, or a sequence that is at least 95% identical to SEQ ID NO:

22.

70. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO:23, or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24, or a sequence that is at least 95% identical to SEQ ID NO:

24.

71. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45, or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to SEQ ID NO:

46.

72. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 47, or a sequence that is at least 95% identical to SEQ ID NO: 47, and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to SEQ ID NO:

48.

73. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificities of a first anti-Met antibody 9006 and a second anti-Met antibody 9338, or antigen-binding portions thereof.

74. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificities of a first anti-Met antibody 9006 and a second anti-Met antibody 8902, or antigen-binding portions thereof.

75. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificities of a first anti-Met antibody 9338 and a second anti-Met antibody 8902, or antigen-binding portions thereof.

76. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificity of a first anti-Met antibody 9006 and an antigen-binding portion of a second antibody, or the antigen-binding portion thereof.

77. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificity of a first anti-Met antibody 9338 and an antigen-binding portion of a second antibody, or the antigen-binding portion thereof.

78. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule having the binding specificity of a first anti-Met antibody 8902 and an antigen-binding portion of a second antibody, or the antigen-binding portion thereof.

79. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising: an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively.

80. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising: an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 39, 40, 41, 42, 43, and 44, respectively.

81. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising: an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively; and an antigen-binding portion of an antibody whose HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NOs: 39, 40, 41, 42, 43, and 44, respectively.

82. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 2, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:

4.

83. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 2, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 37 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:

38.

84. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:4, and an antigen-binding portion of a second antibody having a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:37 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:

38.

85. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:25, or a sequence that is at least 95% identical to SEQ ID NO:25, and a light chain amino acid sequence of SEQ ID NO:26, or a sequence that is at least 95% identical to SEQ ID NO:26, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO:27, or a sequence that is at least 95% identical to SEQ ID NO:27, and a light chain amino acid sequence of SEQ ID NO:28, or a sequence that is at least 95% identical to SEQ ID NO:

28.

86. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO: 17, or a sequence that is at least 95% identical to SEQ ID NO: 17, and a light chain amino acid sequence of SEQ ID NO: 18, or a sequence that is at least 95% identical to SEQ ID NO: 18, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO: 45, or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to SEQ ID NO:

46.

87. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO: 19, or a sequence that is at least 95% identical to SEQ ID NO: 19, and a light chain amino acid sequence of SEQ ID NO: 20, or a sequence that is at least 95% identical to SEQ ID NO: 20, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO: 45, or a sequence that is at least 95% identical to SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46, or a sequence that is at least 95% identical to SEQ ID NO:

46.

88. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising antigen-binding portions of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:21 or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22 or a sequence that is at least 95% identical to SEQ ID NO:22, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO:23 or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24 or a sequence that is at least 95% identical to SEQ ID NO:

24.

89. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising an antigen-binding portion of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:21 or a sequence that is at least 95% identical to SEQ ID NO:21, and a light chain amino acid sequence of SEQ ID NO:22 or a sequence that is at least 95% identical to SEQ ID NO:22, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO:47 or a sequence that is at least 95% identical to SEQ ID NO:47, and a light chain amino acid sequence of SEQ ID NO:48 or a sequence that is at least 95% identical to SEQ ID NO:

48.

90. 59. The antibody-drug conjugate of any one of claims 1 to 58, wherein the anti-Met antibody or antigen-binding fragment is a bispecific binding molecule, the bispecific binding molecule comprising antigen-binding portions of a first antibody having a heavy chain amino acid sequence of SEQ ID NO:23, or a sequence that is at least 95% identical to SEQ ID NO:23, and a light chain amino acid sequence of SEQ ID NO:24, or a sequence that is at least 95% identical to SEQ ID NO:24, and a second antibody having a heavy chain amino acid sequence of SEQ ID NO:47, or a sequence that is at least 95% identical to SEQ ID NO:47, and a light chain amino acid sequence of SEQ ID NO:48, or a sequence that is at least 95% identical to SEQ ID NO:

48.

91. 91. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 1 to 90, wherein the average p of the antibody-drug conjugate in the composition is from about 2 to about 16, such as from about 2 to about 8, such as from about 2 to about 4.

92. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 90 or the composition of claim 91, and a pharma- ceutically acceptable carrier.

93. 92. A method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 90, a composition according to claim 91, or a pharmaceutical composition according to claim 92.

94. 94. The method of claim 93, wherein the cancer expresses MET.

95. The cancer is a tumor or blood cancer, and optionally the cancer is selected from the group consisting of melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer.

95. The method of claim 93 or 94, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma.

96. 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 of any one of claims 1 to 90, a composition of claim 91, or a pharmaceutical composition of claim 92.

97. 97. The method of claim 96, wherein the tumor expresses MET.

98. 98. The method of claim 96 or 97, wherein the tumor is melanoma, uveal melanoma, kidney cancer including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer including non-small cell lung cancer and small cell lung cancer, gastric cancer including stomach cancer, pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, or thymoma.

99. 93. A method of reducing or inhibiting a hematological cancer in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate of any one of claims 1 to 90, a composition of claim 91, or a pharmaceutical composition of claim 92.

100. 100. The method of claim 99, wherein the hematological cancer expresses MET.

101. 101. The method of claim 99 or 100, 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 myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

102. The method of any one of claims 96-101, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor or hematological cancer by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

103. A method of reducing a cancer cell population or slowing its expansion and growth in a subject, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate described in any one of claims 1 to 90, a composition described in claim 91, or a pharmaceutical composition described in claim 92.

104. 104. The method of claim 103, wherein the cancer cell population expresses MET.

105. The cancer cell population is derived from a tumor or blood cancer, and optionally the cancer cell population is derived from melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer.

105. The method of claim 103 or 104, wherein the cancer is derived from pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma.

106. The method of any one of claims 103-105, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, 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%.

107. The method of any one of claims 93 to 106, wherein the antibody-drug conjugate is administered as a monotherapy.

108. The method of any one of claims 93 to 106, wherein the antibody-drug conjugate is administered as an adjunct to another therapeutic agent or to radiation therapy.

109. The method of claim 108, 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.

110. 107. The method of any one of claims 93-106, further comprising administering to said subject in need thereof at least one additional therapeutic agent.

111. The method of claim 110, wherein the one additional therapeutic agent is a Bcl-2 inhibitor, an Mcl-1 inhibitor, a taxane, a vinca alkaloid, a MEK inhibitor, an ERK inhibitor, a topoisomerase inhibitor, a nucleoside analog, an antimitotic drug, a RAF inhibitor, a c-MET inhibitor, or an EGFR-tyrosine kinase inhibitor.

112. 111. The method of claim 110, wherein the one additional therapeutic agent is selected from venetoclax, compound A2, vincristine, topotecan, docetaxel, paclitaxel, LTT463, trametinib, gemcitabine, monomethyl auristatin E, antibody-drug conjugates comprising monomethyl auristatin E, LXH254, and osimertinib.

113. The method of claim 112, wherein the one additional therapeutic agent is an antibody-drug conjugate comprising monomethylauristatin E.

114. The one additional therapeutic agent has the following structure: 【Chemistry 142】 wherein Ab is an anti-MET antibody.

115. The method of claim 110, wherein said one additional therapeutic agent is a second antibody-drug conjugate according to any one of claims 1 to 90.

116. 91. A method of inhibiting Bcl-xL activity in a cell expressing Bcl-xL, comprising contacting the cell with an antibody-drug conjugate of any one of claims 1 to 90 capable of binding to the cell under conditions such that the antibody-drug conjugate binds to the cell.

117. A method of determining whether a subject having or suspected of having cancer will respond to treatment with an antibody-drug conjugate of any one of claims 1 to 90, a composition of claim 91, or a pharmaceutical composition of claim 92, comprising providing a biological sample from the subject; contacting the sample with the antibody-drug conjugate; and detecting binding of the antibody-drug conjugate to cancer cells in the sample.

118. 118. The method of claim 117, wherein the cancer cells in the sample express MET.

119. The method of claim 117 or claim 118, wherein the cancer expresses MET.

120. The cancer is a tumor or blood cancer, and optionally the cancer is selected from the group consisting of melanoma, uveal melanoma, kidney cancer, including papillary renal cell carcinoma, thyroid cancer, mesothelioma, hepatocellular carcinoma of the liver, lung cancer, including non-small cell lung cancer and small cell lung cancer, gastric cancer, including stomach cancer.

120. The method of any one of claims 117 to 119, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, esophageal cancer, cholangiocarcinoma, head and neck cancer including oral cancer, cervical and endocervical cancer, bladder and urothelial cancer, uterine cancer, ovarian cancer, breast cancer, prostate cancer, sarcoma, testicular cancer, glioblastoma, adrenocortical carcinoma, brain cancer, splenic cancer, thymoma, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, acute myeloid leukemia, bone marrow cancer, chronic lymphocytic leukemia, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, or myeloma.

121. The method of any one of claims 117 to 120, wherein the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.

122. 91. A method of producing an antibody-drug conjugate according to any one of claims 1 to 90, comprising reacting an anti-Met antibody or antigen-binding fragment with a cleavable linker conjugated to a Bcl-xL inhibitor under conditions allowing conjugation.

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