Anti-B7-H3 antibodies and antibody drug conjugates

Abstract

The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs. 5 821 20 24 20 56 65 09 A ug 2 02 4 A B S T R A C T 2 0 2 4 2 0 5 6 6 5 0 9 A u g 2 0 2 4 5 8 2 1

Description

RELATED APPLICATIONS This application is a divisional application of Australian Patent Application No. 2017279550, filed 07 June 2017, which is a national phase entry of PCT / US2017 / 036445, which claims the benefit of U.S. Provisional Application No. 62 / 347,476 filed on 8 June 2016, and U.S. Provisional Application No. 62 / 366,511 filed on 25 July 2016. The entire contents of each of these applications are hereby incorporated by reference in their entirety. SEQUENCE LISTING Preceding applications contained a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 7, 2017, is named 117813-12620_ST25.txt and is 159,744 bytes in size. The instant application contains a sequence listing which has been submitted electronically as an XML document in the ST26 format and is hereby incorporated by reference in its entirety. Said XML copy, created on 8 August 2024, is named P0003440AUD1 ST.26 Sequence Listing and is 232,538 bytes in size. BACKGROUND OF THE INVENTION The B7 homology 3 protein (B7-H3) (also known as CD276 and B7RP-2, and referred to herein as "B7-H3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily. Human B7-H3 contains a putative signal peptide, V-like and C-like 1g domains, a transmembrane region and a cytoplasmic domain. Exon duplication in humans results in the expression of two B7-H3 isoforms having either a single IgV-IgC-like domain (2IgB7-H3 isoform) or a IgV-IgC-IgV-IgC-like domain (4IgB7-H3 isoform) containing several conserved cysteine residues. The predominant B7-H3 isoform in human tissues and cell lines is the 41gB7-H3 isofOlm (Steinberger et al., J. Immunol. 172(4): 2352-9 (2004)). B7-H3 has been reported as having both co-stimulatory and co-inhibitory signaling functions (see, e.g.,Chapoval etal., Nat. Immunol. 2: 269-74 (2001); Suh etal., Nat. Immunol. 4: 899-906 (2003); Prasad et al., J. Immunol. 173: 2500-6 (2004); and Wang et al., Eur. J. Immunol. 35: 428-38 (2005)). For example, in vitro studies have shown B7-H3's co-stimulatory function since B7-H3 was able to increase proliferation of cytotoxic T-lymphocytes (CTLs) and upregulate interferon gamma (IFN-y) production in the presence of anti-CD3 antibody to mimic the T cell receptor signal (Chapoval et al., 2001). Moreover, in vivo studies using cardiac allografts in B7-H3 -I- mice showed decreased production of key cytokine, chemokine and chemokine receptor mRNA transcdpts (e.g., IL-2, IFN—y, monocyte chemoattractant protein (MCP-1) and IFN-inducible protein (IP)-10) as compared to wild-type control (Wang et al., 2005). In contrast, B7-H3 co-inhibitory function has been observed, for example, in mice where B7-H3 protein inhibited T-cell activation and effector cytokine production (Suh et al., 2003). Although no ligands have been identified for human B7-H3, murine B7-H3 has been found to bind to the triggering receptor expressed on myeloid cells (TREM-) 1 2024205665   09 Aug 2024 like transcript 2 (TLT-2), a modulator of adaptive an innate immunity cellular responses. Binding of murine B7-H3 to TLT-2 on CD8+ T-cells enhances T-cell effector functions such as proliferation, [TEXT CONTINUES ON PAGE 2] la

Claims

1. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12 and a5           light chain variable region comprising a CDR3 having the amino acid sequence of SEQ IDNO: 15.

2. The antibody, or antigen binding portion thereof, of claim 1. wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having0           the amino acid sequence of SEQ ID NO: 140 and a light chain variable region comprising aCDR2 having the amino acid sequence of SEQ ID NO: 7.

3. The antibody, or antigen binding portion thereof, of claim 1 or 2, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising a CDR115           having the amino acid sequence of SEQ ID NO: 10 and a light chain variable regioncomprising a CDR1 having the amino acid sequence of either SEQ ID NO: 136 or 138.

4. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region20          comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chainvariable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

5. The antibody, or antigen binding portion thereof, of claim 4. wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising a CDR2 having25           the amino acid sequence of SEQ ID NO: 34, and a light chain variable region comprising aCDR2 having the amino acid sequence of SEQ ID NO: 38.

6. The antibody, or antigen binding portion thereof, of claim 4 or 5, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region comprising a CDR130           having the amino acid sequence of SEQ ID NO: 33 and a light chain variable regioncomprising a CDR1 having the amino acid sequence of either SEQ ID NO: 37.

7. The antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody, or antigen binding portion thereof, is an IgG isotype.

358. The antibody, or antigen binding portion thereof, of claim 7. wherein the antibody, or antigen binding portion thereof, is an IgGl or an IgG4 isotypc.2024205665   09 Aug 20249. The antibody, or antigen binding portion thereof, of any one of the preceding claims, wherein the antibody, or antigen binding portion thereof, has a KD of 1.5 x 10 8 or less as determined by surface plasmon resonance.5    10. An antibody, or antigen-binding portion thereof, that binds to hB7-H3, said antibody, orantigen-binding portion thereof, comprising eithera heavy chain variable region comprising a CDR set of SEQ ID NOs: 10, 11. and 12, and a light chain variable region comprising a CDR set of SEQ ID NOs:

14. 7, and 15, ora heavy chain variable region comprising a CDR set of SEQ ID NOs: 33, 34, and 35.0           and a light chain variable region comprising a CDR set of SEQ ID NOs: 37, 38, and 39.

11. The antibody, or antigen binding portion thereof, of claim 10, wherein the antibody, or antigen binding portion thereof, is humanized.15    12. The antibody, or antigen binding portion thereof, according to claim 11, further comprising ahuman acceptor framework.

13. The antibody, or antigen binding portion thereof, of claim 12, wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID20           Nos: 155.156, 164. 165, 166. and 167.

14. The antibody, or antigen binding portion thereof, of claim 13, wherein said human acceptor framework comprises at least one framework region amino acid substitution.25    15. The antibody, or antigen binding portion thereof, of claim 14. wherein the amino acidsequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.30    16. The antibody, or antigen binding portion thereof, of claim 14 or 15, wherein said humanacceptor framework comprises at least one framework region amino acid substitution at a key residue, said key residue selected from the group consisting of: a residue adjacent to a CDR;a glycosylation site residue;35            a rare residue;a residue capable of interacting with human B7-H3;a residue capable of interacting with a CDR;2024205665   09 Aug 2024a canonical residue;a contact residue between heavy chain variable region and light chain variable region;a residue within a V ernier zone; anda residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and5               a Kabat-dcfincd first heavy chain framework.

17. The antibody, or antigen binding portion thereof, of claim 16. wherein said key residue is selected from the group consisting of 48H. 67H, 69H, 71H, 73H, 94H. and 2L.0    18. The antibody, or antigen binding portion thereof, of claim 17, wherein the key residuesubstitution is in the variable heavy chain region and is selected from the group consisting of M48I, V67A, I69L, A71V, K73R. and R94G.

19. The antibody, or antigen binding portion thereof, of claim 17 or 18, wherein the key residue15            substitution is in the variable light chain region and is 12V.

20. An antibody, or antigen-binding portion thereof, that binds to hB7-H3 comprising a heavychain variable region comprising a CDR set of SEQ ID NOs: 25, 26, and 27, and a light chain variable region comprising a CDR set of SEQ ID NOs: 29, 30, and 31.2021. The antibody, or antigen binding portion thereof, of claim 20. wherein the antibody, or antigen binding portion thereof, is humanized.

22. The antibody, or antigen binding portion thereof, according to claim 21, further comprising a 25          human acceptor framework.

23. The antibody, or antigen binding portion thereof, of claim 22, wherein said human acceptor framework comprises an amino acid sequence selected from the gr oup consisting of SEQ ID NOs: 155 to 158.3024. The antibody, or antigen binding portion thereof, of claim 22 or 23, wherein said human acceptor framework comprises at least one framework region amino acid substitution.

25. The antibody, or antigen binding portion thereof, of claim 24, wherein the amino acid35           sequence of the framework is at least 65% identical to the sequence of said human acceptorframework and comprises at least 70 amino acid residues identical to said human acceptor framework.2024205665   09 Aug 202426. The antibody, or antigen binding portion thereof, of claim 24 or 25. wherein said human acceptor framework comprises at least one framework region amino acid substitution at a key residue, said key residue selected from the group consisting of:a residue adjacent to a CDR;5            a glycosylation site residue;a rare residue;a residue capable of interacting with human B7-H3;a residue capable of interacting with a CDR;a canonical residue;0           a contact residue between heavy chain variable region and light chain variable region;a residue within a Vernier zone; anda residue in a region that overlaps between a Chothia-defined variable heavy chain CDRl and a Kabat-defined first heavy chain framework.15    27. The antibody, or antigen binding portion thereof, of claim 26, wherein said key residue isselected from the group consisting of 69H, 46L, 47L, 64L, and 71L.

28. The antibody, or antigen binding portion thereof, of claim 27, wherein the key residue substitution is in the variable heavy chain region and is L69I.2029. The antibody, or antigen binding portion thereof, of claim 27 or 28. wherein the key residue substitution is in the variable light chain region and is selected from the group consisting of L46P, L47W. G64V, and F71H.25   30. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chainCDR 1 comprising an amino acid sequence as set forth in SEQ ID NO: 10, a heavy chainCDR2 comprising an amino acid sequence as set forth in SEQ ID NO:

140. a heavy chainCDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 12, a light chain CDRlcomprising an amino acid sequence as set forth in SEQ ID NO: 136 or 138, a light chain30          CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 7, and a light chainCDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 15.

31. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain CDR 1 comprising an amino acid sequence as set forth in SEQ ID NO: 33, a heavy chain35          CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 34, a heavy chainCDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 35, a light chain CDRlcomprising an amino acid sequence as set forth in SEQ ID NO: 37, a light chain CDR22024205665   09 Aug 2024comprising an amino acid sequence as set forth in SEQ ID NO:

38. and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 39.

32. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain5           variable domain comprising an amino acid sequence set forth in SEQ ID NO: 139 and a lightchain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 135.

33. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%0           identity to SEQ ID NO: 139, and / or a light chain comprising an amino acid sequence havingat least 90%. 95%, 96%. 97%, 98%, or 99% identity to SEQ ID NO: 135.

34. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 139 and a light 15           chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 137.

35. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%. 98%, or 99% identity to SEQ ID NO: 139, and / or a light chain comprising an amino acid sequence having 20          at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 137.

36. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 147 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 144.2537. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chain comprising an amino acid sequence having at least 90%. 95%, 96%, 97%. 98%, or 99% identity to SEQ ID NO: 147, and / or a light chain comprising an amino acid sequence having at least 90%. 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 144.3038. The antibody, or antigen-binding portion thereof, of any one of the preceding claims, wherein the antibody, or antigen binding portion thereof, binds cyno B7-H3.

39. The antibody, or antigen-binding portion thereof, of any one of the preceding claims, wherein 35            the antibody, or antigen binding portion thereof, has a dissociation constant (KD) to hB7-H3selected from the group consisting of: at most about 10 M; at most about 108 M; at most2024205665   09 Aug 2024about 1011 M; at most about 10 10 M; at most about 10 11 M; at most about 10 12 M; and at most 1013M.

40. The antibody, or antigen-binding portion thereof, of any one of the preceding claims, wherein 5           the antibody, or antigen binding portion thereof, comprises a heavy chain immunoglobulinconstant domain of a human IgM constant domain, a human IgGl constant domain, a human IgG2 constant domain, a human IgG3 constant domain, a human IgG4 constant domain, a human IgA constant domain, or a human IgE constant domain.0   41. The antibody of any one of the preceding claims, which is an IgG having four polypeptidechains which are two heavy chains and two light chains.

42. The antibody, or antigen-binding portion thereof, of claim 41. wherein the human IgGl constant domain comprises an amino acid sequence of SEQ ID NO: 159 or SEQ ID NO: 160.

543. The antibody, or antigen-binding portion thereof, of any one of the preceding claims, wherein the antibody, or antigen binding portion thereof, further comprises a light chain immunoglobulin constant domain comprising a human Ig kappa constant domain or a human Ig lambda constant domain.:

044. An anti-hB7-H3 antibody, or antigen-binding portion thereof, that competes with the antibody, or antigen binding portion thereof, of any one of the preceding claims.

45. A pharmaceutical composition comprising the anti-hB7-H3 antibody, or antigen binding 25            portion thereof, of any one of claims I -44. and a pharmaceutically acceptable carrier.

46. An anti-hB7-H3 Antibody Drug Conjugate (ADC) comprising an anti-hB7-H3 antibody of any one of claims 1 -44 conjugated to a drug via a linker.30   47.    The ADC of claim 46, wherein the drug is an auristatin or a pyrrolobenzodiazepine (PBD).

48. The ADC of claim 46. wherein the drug is a Bcl-xL inhibitor.

49. An anti-hB7-H3 antibody drug conjugate (ADC) comprising a drug linked to an anti-human35           B7-H3 (hB7-H3) antibody by way of a linker, wherein the drug is a Bcl-xL inhibitoraccording to structural formula (Ila), (lib). (He), or (lid):2024205665   09 Aug 2024(Ila)(lib)(He)(lid)wherein:2024205665   09 Aug 2024selected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl. Ci 4alkoxy, amino, cyano andhalomcthyl;substituted with one or more substituents independently selected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C, ^alkoxy, amino, cyano and halomethyl, wherein the Rl2-Z2b-, R'-Z2b-, #10    N(R4)-R' '-Z2b-, or #-R’-Z2b- substituents are attached to Ar2 at any Ar2 atom capable of beingsubstituted;Z1 is selected from N, CH, C-halo, C-CH3 and C-CN;and Z2b arc each , independently from one another, selected from a bond, NR6, CR6aR6b, O, S, S(O), S(O)2, -NR6C(O)-,-NR6aC(O)NR6b-, and -NR6C(O)O-;. wherein #. where attached to R', is attachedto R’ at any R' atom capable of being substituted;X’ is selected at each occurrence from -N(R10)-, -N(R10)C(O)-, -N(Rio)S(O)2-, -S(O)2N(R'°)-, and -O-;n is selected from 0-3;20           R10 is independently selected at each occurrence from hydrogen, lower alkyl, heterocycle,aminoalkyl, G-alkyl, and -(CH2)2-O-(CH2)2-O-(CH2)2-NH2;2024205665   09 Aug 2024G at each occurrence is independently selected from a polyol, a polyethylene glycol with between 4 and 30 repeating units, a salt and a moiety that is charged at physiological pH:SPa is independently selected at each occurrence from oxygen, -S(O)2N(H)-, -N(H)S(O)2-, -N(H)C(O)-, -C(O)N(H) -, -N(H)-, arylene, heterocyclene, and optionally substituted methylene;5 wherein methylene is optionally substituted with one or more of -NH(CH2)2G, NH2, Ci 8alkyl, and carbonyl;nr is selected from 0-12;R1 is selected from hydrogen, methyl, halo, halomethyl, ethyl, and cyano;R2 is selected from hydrogen, methyl, halo, halomethyl and cyano;0           R3 is selected from hydrogen, methyl, ethyl, halomethyl and haloethyl;R4 is selected from hydrogen, lower alkyl and lower heteroalkyl or is taken together with an atom of R13 to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms;R6, R6a and R6b ar e each, independent from one another, selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted cycloalkyl and 15 optionally substituted heterocyclyl, or are taken together with an atom from R4 and an atom horn R13 to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms;Rlla and R1 lb are each, independently of one another, selected from hydrogen, halo, methyl, ethyl, halomethyl, hydroxyl, methoxy, CN, and SCH3;R12 is optionally R’ or is selected from hydrogen, halo, cyano, optionally substituted alkyl. 20 optionally substituted heteroalkyl, optionally substituted heterocyclyl. and optionally substituted cycloalkyl;R13 is selected from optionally substituted Ci s alkylene, optionally substituted heteroalkylene, optionally substituted heterocyclene, and optionally substituted cycloalkylene; and# represents a point of attachment to a linker.25   50. The ADC of claim 49, which is a compound according to structural formula (I):(I)      ( D---L----Lk4—Abwherein:D is the Bcl-xL inhibitor drug of formula (Ila), (lib), (lie) or (lid);L is the linker;Ab is the anti-hB7-H3 antibody;30                   LK represents a covalent linkage linking the linker (L) to the anti-hB7-H3 antibody(Ab); andm is an integer ranging from 1 to 20.2024205665   09 Aug 202451. The ADC of claim 49 or 50, in which G at each occurrence is a salt or a moiety that is charged at physiological pH.

52. The ADC of claim 49 or 50, or in which G at each occurrence is a salt of a carboxylate, a sulfonate, a phosphonate, or ammonium.5   53. The ADC of claim 49 or 50, in which G at each occurrence is a moiety that is charged atphysiological pH selected from the group consisting of car boxylate, a sulfonate, a phosphonate, and an amine.

54. The ADC of claim 49 or 50, in which G at each occurrence is a moiety containing a polyethylene glycol with between 4 and 30 repeating units, or a polyol.0   55.    The ADC of claim 54, in which the polyol is a sugar.

56. The ADC of formula (Ila) or formula (lid) of claim 49 or 50, in which R' includes at least onesubstitutable nitrogen suitable for attachment to a linker.

57. The ADC of claim 56. in which G is selected at each occurrence from:hydrogen or a positively charged counterion.

58. The ADC of claim 49 or 50, in which R’ is selected fromoc ocLnOH OH789COoH2024205665   09 Aug 2024. and2024205665   09 Aug 2024OH , wherein # represents either a hydrogen atom in the Bcl-xL inhibitor drug of the ADCs of formula (lib) or (lie) or the point of attachment in the Bcl-xL inhibitor drug of the ADCs of formula (Ila) or (lid) to a linker L.The ADC of claim 49 or 50, in which Ar1 is selected from, andand is optionally substituted with one or more substituents independently selected from halo,cyano, methyl, and halomethyl.60.The ADC of claim 59, in which Ar1 isThe ADC of claim 49 or 50, in which Ar2 is, optionally substitutediowith one or more substituents.substituted with one or more substituents.

63. The ADC of claim 61, in which Ar is substituted with one or more solubilizinggroups.2024205665   09 Aug 202464.            The ADC of claim 63, in which each solubilizing group is, independently of theothers, selected from a moiety containing a polyol, a polyethylene glycol with between 4 and 30 repeating units, a salt, or a moiety that is charged at physiological pH.

65. The ADC of claim 62, in which Ar2 is substituted with one or more solubilizing5 groups.

66. The ADC of claim 65, in which each solubilizing group is, independently of theothers, selected from a moiety containing a polyol, a polyethylene glycol with between 4 and 30 repeating units, a salt, or a moiety that is charged at physiological pH.

67. The ADC of claim 49 or 50. in which Z1 is N.0   68.           The ADC of claim 49 or 50. in which Z2a is O.

69. The ADC of claim 49 or 50, in which R1 is methyl or chloro.

70. The ADC of claim 49 or 50, in which R" is hydrogen or methyl.

71. The ADC of claim 49 or 50, in which R" is hydrogen.

72. The ADC of claim 49 or 50, in which Z2b is O.15   73.           The ADC of claim 49 or 50, in which Z2b is NH or CH2.

74. The ADC of claim 49 or 50, which is a compound according to structural formula(Ha).

75. The ADC of claim 74, which includes a core selected from structures (C. 1)-(C.21):(C.l)(C.2)(C.4)(C.9)p de(C.13)796(C.16)2024205665   09 Aug 2024(C.19)(C.20)(C.21)76.            The ADC of claim 74, which is a compound according to structural formula (Ila. 1):(Ila.l)wherein:5            Y is optionally substituted Ci-Cs alkylene;r is 0 or 1; and2024205665   09 Aug 2024s is 1, 2 or 3.

77. The ADC of claim 74, which is a compound according to structural formula (IIa.2):(IIa.2)5 wherein:U is selected from N, O and CH, with the proviso that when U is O, then Va and R2la are absent;R20is selected from H and CrC4 alkyl;R21a and R2,b are each, independently from one another, absent or selected from H, Ci-C4 10 alkyl and G, where G is selected from a polyol, PEG4-30. a salt and a moiety that is charged at physiological pH;Va and Vh are each, independently from one another, absent or selected from a bond, and an optionally substituted alkylene;R20 is selected from H and Ci-C4 alkyl; and 15               s is 1,2 or 3.

78. The ADC of claim 74, which is a compound according to structural formula (IIa.3):20           Rb is selected from H, Ci-C4 alkyl and Jb-G or is optionally taken together with an atom of Tto form a ring having between 3 and 7 atoms;Ja and Jb are each, independently from one another, selected from optionally substituted CpCg alkylene and optionally substituted phenylene;2024205665   09 Aug 2024T is selected from optionally substituted CrC8 alkylene. CH2CH2OCH2CH2OCH2CH2, CH2CH2OCH2CH2OCH2CH2OCH2and a polyethylene glycol containing from 4 to 10 ethylene glycol units;G is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH; 5 ands is 1, 2 or 3.

79. The ADC of claim 49 or 50. which is a compound according to structural formula(lib).

80. The ADC of claim 79, which is a compound according to structural formula (Ilb.l):(Ilb.l)wherein:Y is optionally substituted C|-C8 alkylene;G is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH;15            r is 0 or 1; ands is 1, 2 or 3.

81. The ADC of claim 49 or 50, which is a compound according to structural formula(He).

82. The ADC of claim 81, which is a compound according to structural formula (lie.1):(nc.l) wherein:Ya is optionally substituted C,-C8alkylene;Yb is optionally substituted CrC8 alkylene;2024205665   09 Aug 2024R23 is selected from H and CrC4 alkyl; andG is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH.

83. The ADC of claim 81, which is a compound according to structural formula (IIc.2):5                                                        (IIc.2)wherein:Ya is optionally substituted Ci-C8 alkylene;Yb is optionally substituted Ci-C8 alkylene;Yc is optionally substituted CrC8 alkylene;10           R23 is selected from H and C1-C4 alkyl;R25 is Yb-G or is taken together with an atom of Yc to form a ring having 4-6 ring atoms; andG is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH.

84. The ADC of claim 49 or 50, wherein the Bcl-xL inhibitor is selected from the groupconsisting of the following compounds modified in that the hydrogen corresponding to the # position 15 of structural formula (Ila), (lib), (lie), or (lid) is not present forming a monoradical:6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-[ 1-( {3-(2-( {2-(2-(carboxymcthoxy)cthoxy]cthyl) amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.I1 ]dcc-l-yl) methyl)-5-methyl-1 H-pyrazol-4-yl]pyridine-2-carboxylic acid;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3.4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3,520   dimethyl-7-{ 2-((2-sulfoethyl)amino]ethoxy}tricyclo[3.3.].l3’7]dec-l-yl)methyl]-5-methyl-1H-pyrazol-4-yl} pyridine-2-carboxylic acid;2-{| (2-{| 2-( {3-[(4-{ 6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3.4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl}-5-methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13 ]dec-l-yl} oxy )e thy 1 ] amino} ethyl)su Ifonyl ] amino} -2 -deoxy-D-glucopyranose;25           6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoqumolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-( 2-((4-( [(3R,4R.5S.6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]methyl}benzyl)aminoJethoxy}tricyclo(3.3.1.13,7]dec-l-yl)methylJ-5-methyl-lH-pyrazol-4-yl}pyridine-2-carboxylic acid;2024205665   09 Aug 20246-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-{ 2-[(3-sulfopropyl)amino]ethoxy} tricyclo[3.3.1.117]dec-1 -yl)methyl]-5-methyl-1H-pyrazol-4-yl} pyridine-2-carboxylic acid;6-(8-( 1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1H )-y 1 ] -3- {1 -((3- {2-((2,35 dihydroxypropyl)amino]cthoxy}-5,7-dimcthyltricyclo[3.3.1.1 ,7]dcc-l-yl)mcthyl]-5-mcthyl-lH-pyrazol-4-yl}pyridine-2-carboxylic acid;2-(((4-( {[2-(( 3-((4-( 6-(8-( 1.3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl}-5-methyl-1 H-pyrazol-1 -yl)methyl]-5,7-dimethyltricyclo[3.3.1.1 ']dec-l-yl}oxy)ethyl]amino}methyl)phenyl]sulfonyl}amino)-2-deoxy-beta-D-glucopyranose;0            8-(1,3-benzothiazol-2-ylcarbamoyl)-2- {6-carboxy-5-[ 1 -({3-(2-( {2-( 1 -(beta-D-glucopyranuronosyl)-1H-1,2,3-triazol-4-yl]cthyl}amino)ethoxy (-5,7-dimethy ltricyclo[3.3.1.13 7 |dcc-l-yl}methyl)-5-methyl-lH-pyrazol-4-yl]pyridin-2-yl}-l,2,3,4-tetrahydroisoquinoline;3-( l-({3-[2-(2-{(4-(beta-D-allopyranosyloxy)benzyl]amino}ethoxy)ethoxy]-5,7-dimethyltricyclo|3.3.1.1’ ]dec-l -y 1}methyl)-5-methyl-1 H-pyrazol-4-ylJ-6-[8-( 1,3-benzothiazol-2-15 ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]pyridine-2-carboxylic acid;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-( 1-( [3,5-dimethyl-7-(2-(2-[(2-sulfoethyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.1 ’ ]dec-l-yl]methyl)-5-methyl-I H-pyrazol-4-yl)pyridinc-2-carboxylic acid;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl [-3-( 1-((3,520 dimethyl-7-{2-[(2-phosphonoethyl)amino]ethoxy)tricyclo[3.3.1.11 ]dec-l-yl)methyl]-5-methyl-lH-pyraz.ol-4-yl }pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydioisoquinolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-{2-[methyl(3-sulfo-L-alanyl)amino]ethoxy}tricyclo(3.3.1.r<7]dec-l-yl)methyl]-5-methyl-1 H-pyrazol-4-yl} pyridine-2-carboxylic acid;25            6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-{ 2-[(3-phosphonopropyl)amino]ethoxy }tricyclo[3.3.1.11 ]dec-l -yl)methyl]-5-methyl-l H-pyraz.ol-4-yl }pyridine-2-carboxylic acid;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-{2-[(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.1J7]dec-l-yl)methyl]-5-methyl-lH-30 pyrazol-4-yl}pyridine-2-carboxylic acid;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-(1-( [3,5-dimethyl-7-(2-{2-[(3-phosphonopropyl)amino|ethoxy)ethoxy)tricyclo[3.3.1 1’ ]dec-1 -yl]methy 1}-5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid:3-( 1 -((3-( 2-[L-alpha-aspartyl(methyl)amino]ethoxy }-5,7-dimethyltricyclo[3.3.1.13]dec-l-35    yl)methyl]-5-methyl-lH-pyrazol-4-yl}-6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridine-2-carboxylic acid;2024205665   09 Aug 20246-{4-[({2-[2-(2-aminoethoxy)ethoxy]ethyl) [2-({ 3-((4-( 6-(8-( 1.3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( I H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1 H-pyrazol-1 -yl)methyl]-5,7-dimethyltricyclo(3.3.1.1 |dec-l -yl |oxy)ethyl |amino)methyl (benzyl }-2,6-anhydro-L-gulonic acid;5            4-( {(2-(( 3-((4-( 6-(8-(1,3-bcnzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]-2-carboxypyridin-3-yl} -5-methyl-1 H-pyrazol-1 -yl)methyl]-5,7-dimethyltricyclof 3.3.1.1’ {dec-1 -yl }oxy)ethyl]amino}methyl)phenyl hexopyranosiduronic acid;6-( 1-(1,3-benzothiazol-2-ylcarbamoyl)-l,2,3,4-tetrahydroquinolin-7-yl]-3-{ l-((3,5-dimethyl-7-{2-[(2-phosphonoethyl)amino]ethoxy}tricyclo[3.3.1.1 7]dec-l-yl)methylJ-5-methyl-1 H-pyrazol-4-0 yl}pyridine-2-carboxylic acid;6-| l-(l,3-bcnzothiazol-2-ylcarbamoyl)-1.2,3.4-tctrahydroquinolin-7-yl]-3-{ l-[(3,5-dimethyl-7-(2-[methyl(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.13 7]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl} pyridine-2-carboxylic acid;3-( l-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.1' Jdec-l-yl)methyll-5-15    methyl-lH-pyrazol-4-yl )-6-(8-((1,3]thiazolo[5,4-b)pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]pyridine-2-carboxylic acid;3-(1 -((3,5-dimethyl-7- {2-[(2-sulfoethyl)amino]ethoxy) tricyclo[3.3.1.117]dec- l-yl)methyl ] -5-mcthyl-lH-pyrazol-4-yl )-6-(8-((1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridine-2-carboxylic acid;20           6-( 1-(1,3-benzothiazol-2-ylcarbamoyl)-l,2,3,4-tetrahydroquinolin-7-yl]-3-{ l-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy)tricyclo[3.3.1.r ]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl }pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3-(2-((2-carboxycthyl)amino]cthoxy} -5,7-dimcthyltricyclo[3.3.1.1 3‘ '|dcc-1 -yl)mcthyl]-5-mcthyl-1 H-pyrazol-25 4-yl )pyridine-2-carboxylic acid;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{1-((3,5-dimethyl-7-{2-[(3-phosphonopropyl)(piperidin-4-yl)amino]ethoxy}tricyclo[3.3.

1. T ]dec-l -yl)methylJ-5-methyl-lH-pyrazol-4-yl)pyridine-2-carboxylie acid;3-{ 1-((3-( 2-[D-alpha-aspartyl(mcthyl)amino)cthoxy}-5.7-dimethyltricyclo[3.3.1.1' (dec-130 yl)methyl]-5-methyl-lH-pyrazol-4-yl} -6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl )-3-(1-((3-(2-( [ 1-(carboxymethyl)piperidin-4-yl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.^, ]dec-l-yl]methyl}-5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid;35            N-[(5S)-5-amino-6-([2-({3-[(4-{6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl)-5-methyl-lH-pyrazol-l-yl)methyl]-5,7-2024205665   09 Aug 2024dimethyltricyclo(3.3.1.11 ]dec-l-yl(oxy)ethyl](methyl)amino}-6-oxohexyl]-N,N-dimethylmethanaminium;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{1-((3,5-dimethyl-7-{2-[piperidin-4-yl(2-sulfoethyl)anuno]ethoxy)tricyclo[3.3.1.13'7]dec-l-yl)methyl]-5-5 methyl-lH-pyrazol-4-yl)pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-5-(3-phosphonopropoxy )-3,4-dihydroisoquinolin-2( 1 H)-yl]-3-| l-({3.5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.137]dec-l-yl(methyl)-5-methyl-1 H-pyrazol-4-yl]pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-(l-{[3-(2-{[N-(2-0 carboxyethyl)-L-alpha-aspartyl]amino(ethoxy)-5,7-dimethyltricyclo[3.3.1.13 ]dec-l-yl]methyl}-5-methyl -1 H-pyrazol-4-yl)pyridine -2 -carboxylic acid;3-{ l-[(3-{2-[(2-aminoethyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.

1. I3 (dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl (-6-(8-( 1.3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridine-2-carboxylic acid;15            6-[5-(2-aminoethoxy)-8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoqumolin-2(lH)-yl]-3-(1-(( 3,5-dimethyl-7-(2-( methylamino)ethoxy ]tricyclo(3.3.1.1’7 |dec-1 -yl) methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic acid;6-(8-(1,3-bcnzothiazol-2-ylcarbamoyl)naphthalen-2-yl]-3-{ l-((3,5-dimethyl-7-{2-[(3-sulfopropyl)amino]ethoxy}tricyclo(3.3.1.137]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl)pyridine-2-20 carboxylic acid;6-(8-( 1,3-henzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( I H)-yl]-3-{ 1 -((3-(2-((2-carboxyethyl)(piperidin-4-yl)aminoJethoxy)-5,7-dimethyltricyclo(3.3.1.13 7]dec-l-yl)methylJ-5-methyl-1 H-pyrazol-4-yl} pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydioisoquinolin-2(lH)-yl]-3-{ 1-((3,525 dimethyl-7- (2-[(3-sulfo-L-alanyl)(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.1 ’ (dec-1 -yl)methyl|-5-methyl-1 H-pyrazol-4-yl )pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(l H)-yl]-3-{l-[(3-{2-[{2-((2-carboxyethyl)amino]ethyl}(2-sulfoethyl)amino]ethoxy(-5,7-dimethyltricyclo[3.3.1.13 (dec-1-yl)methyl]-5-mcthyl-lH-pyrazol-4-yl) pyridine-2-carboxylic acid;30            3-(1 -((3,5-dimethyl-7-{2-[(3-phosphonopropyl)amino]ethoxy)tricyclo[3.3.1.13 (dec-1 -yl)methyl]-5-methyl-1 H-pyrazol-4-yl} -6-(8-(( 1,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridme-2-carboxylic acid;3-( 1 -[(3,5-dimethyl-7-{2-[(3-phosphonopropyl)amino]ethoxy)tricyclo[3.3.1.13 (dec-1 -yl)methyl]-5-methyl-l H-pyrazol-4-yl)-6-(8-(11,3]thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-3,4-35 dihydroisoquinolin-2(lH)-yl(pyridine-2-carboxylic acid;pyrazol-4-yl }pyridine-2-carboxylic acid;=CT o X6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydioisoquinolin-2(lH)-yl]-3-{ l-[(3-{2-[(1.3-dihydroxypiopan-2-yl)amino]ethoxy}-5J-dimethyltiicyclo[3.3.1.11 ]dec-l-yl)methyl]-5-methyl-l H-15 pyrazol-4-yl}pyridine-2-carboxylic acid;6-(5-(2 -aminoethoxy )-8-( 1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1H)-y 1 ] -3-( l-[(3,5-dimethyl-7-{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]dec-l-yl)methyl]-5-6-|8-(l,3-benzothiazol-2-ylcarbamoyl)-5-(carboxymethoxy)-3,4-dihydroisoquinolin-2(l H)-2024205665   09 Aug 20246-(8-(l,3-benzothiazol-2-ylcarbamoyl)-5-(3-sulfopropoxy)-3,4-dihydroisoquinolin-2(lH)-yl]-3-[l-({3,5-dimethyl-7-[2-(methylamino)ethoxy]tricyclo[3.3.1.13’7]dec-l-yl)methyl)-5-methyl-lH-pyrazol-4-yl]pyridine-2-carboxylic acid;3- (1 -)(3,5-dimethyl-7- {2-[(2-sulfoethyl)amino]ethoxy) tricyclo[3.3.1.13 7]dec- l-yl)methyl ] -55    mcthyl-1 H-pyrazol-4-yl )-6-(1 -([ l,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)-l, 2,3,4-tetrahydroquinolin-7-yl]pyridine-2-carboxylic acid;3-{ l-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy)tricyclo[3.3.1.137]dec-l-yl)niethyl]-5-methyl-1 H-pyrazol-4-yl )-6-)8-(11,3]thiazolo[4,5-b]pyridin-2-ylcarbamoyl)naphthalen-2-yl]pyridine-2-carboxylic acid;0            (1^)-1-() 2-)5-(1-{[3-(2-arninoethoxy)-5,7-dimcthyltricyclo[3.3.1.r,7]dec-l-yl]methyl )-5-methyl-17 / -pyrazol-4-yl)-6-carboxypyridin-2-yl]-8-(l,3-benzothiazol-2-ylcarbamoyl)-l,2,3,4-tetrahydroisoquinolin-5-yl) methyl)-1,5-anhydro-D-glucitol;6-)8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(l H)-yl )-3-( 1-)(3-(2-)(3-carboxypropyl)aminoJethoxy)-5,7-dimethyltricyclo[3.3.1.r jdec-l-yl)methyl]-5-methyl-lH-pyrazol-15 4-yl)pyridine-2-carboxylic acid;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)naphthalen-2-yl]-3-{ 1-)(3,5-dimethyl-7-( 2-)(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.1 3 ]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl }pyridine-2-carboxylic acid;6-)8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(l H)-yl]-3-( 1 -{[3-(2-{ [420   (beta-D-glucopyranosyloxy(benzyl)amino }ethoxy)-5,7-dimethyltricyclo)3.3.1.13 jdec-1 -yljmethyl}-5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid;3-(1-()3-(2-{[4-(beta-D-allopyranosyloxy)benzyl]amino)ethoxy)-5,7-dimethyltricyclo[3.3.1.1’ ]dec-l-yl]methyl}-5-mcthyl-lH-pyrazol-4-yl)-6-[8-( 1,3-bcnzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl)pyridine-2-carboxylic acid;25            3-{ l-[(3-(2-[azetidin-3-yl(2-sulfoethyl)aminoJethoxy}-5,7-dimethyltricyclo[3.3.1.137]dec-l-yl)methyl]-5-methyl-1 H-pyrazol-4-yl} -6-)8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-ylJpyridine-2-carboxylic acid;3-( 1-)(3-( 2-)(3-aminopropyl)(2-sulfocthyl)arnino]ethoxy )-5,7-dimcthyltricyclo[3.

3. l.l’]dec-l-yl)mcthyl]-5-mcthyl-lH-pyrazol-4-yl )-6-)8-( l,3-benzothiazol-2-30 ylcarbatnoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]pyridine-2-carboxylic acid;6-) 1-(1,3-benzothiazol-2-ylcarbamoyl)-l,2,3,4-tetrahydroquinolin-7-yl]-3-{ 1-)(3-(2-)(2-carhoxyethyl)amino]ethoxy }-5,7-dimethyltricyclo[3.3.1.1 ’|dcc-1 -yljmethyl ]-5-methyl-l H-pyrazol-4-yl }pyridine-2-carboxylic acid;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-)(3-(235    )(N6,N6-dimethyl-L-lysyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13 (dec-1 -yl)methyl]-5-mcthyl-1 H-pyrazol-4-yl) pyridine-2-carboxylic acid;2024205665   09 Aug 20243-{ 1-((3-( 2-((3-aminopropyl)(methyI)amino]ethoxy}-5,7-dimethyltricyclo(3.3.1.r7]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl}-6-( 1-(1,3-benzothiazol-2-ylcarbamoyl)-l,2,3,4-tetrahydroquinolin-7-yl]pyridine-2-carboxylic acid;3- (1 -[(3- (2-[azetidin-3-yl(methyl)amino]ethoxy) -5,7-dimethyltricyclo[3.3.1.1 ]dec-1 -5 yl)mcthyl]-5-mcthyl-lH-pyrazol-4-yl}-6-[ 1-(1,3-bcnzothiazol-2-ylcarbamoyl)-l ,2,3,4-tetrahydroquinolin-7-yl]pyridine-2-carboxylic acid;Nfi-(37-oxo-2,5,8,l l,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-L-lysyl-N-(2-((3-((4-( 6-(8-( 1,3-benzothiazol-2-ylcarbamoyl)-3.4-dihydroisoquinolin-2( I H)-yl]-2-carboxypyridin-3-yl}-5-methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo(3.3.1.13'7]dec-l-yl}oxy)ethyl]-L-0 alaninamide;methyl 6-(4-(3- {[2-({3-((4- {6-(8-( 1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl)-5-methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1 ’ ]dec-l-yl}oxy)ethyl]amino}propyl)-lH-l,2.3-triazol-l-yl]-6-deoxy-beta-L-glucopyranoside;15            6-[8-(l,3-benzothiazol-2-ylcarbamoyl)naphthalen-2-yl]-3-{ l-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.137]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl )pyridine-2-carboxylic acid;6-(5-(1,3-bcnzothiazol-2-ylcarbamoyl)quinolin-3-yl]-3-{ l-((3,5-dimcthyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.rv]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl)pyridine-2-20 carboxylic acid;6-(4-(1,3-henzothiazol-2-ylcarbamoyl)quinolin-6-yl]-3-{ I-((3,5-dimethyl-7-{2-((2-sulfoethyl)aminojethoxy} tricyclo(3.3.1.13 7]dec-l -yl)methyl]-5-methyl-l H-pyrazol-4-yl }pyridine-2-carboxylic acid;6-(5-( 1,3-benzothiazol-2-ylcarbamoyl)quinolin-3-yl]-3- (1 -[ (3-( 2-((225 carboxyethyl)amino]ethoxy}-5.7-dimethyltricyclo(3.3.1.1l7]dec-l-yl)methyl]-5-methyl-IH-pyrazol-4-yl }pyridine-2-carboxylic acid;6-(1-(1,3-benzothiazol-2-ylcarbamoyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-3-{l-((3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy)tricyclo[3.3.1 1’ ]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl} pyridine-2-carboxylic acid;30            8-(l,3-benzothiazol-2-ylcarbamoyl)-2- {6-carboxy-5-[ 1 -((3-(2-( (3-(1 -(beta-D-glucopyranuronosyl)-lH-l,2,3-triazol-4-yl]propyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.13 ]dec-l-yl}methyl)-5-methyl-lH-pyiazol-4-yl]pyridin-2-yl}-l,2.3.4-tetrahydroisoquinoline;6-(7-(1,3-benzothiazol-2-ylcarbamoyl)-lH-indol-2-yl]-3-{ l-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy }tiicyclo[3.3.1.13 7]dec-l-yl)methyl]-5-methyl-l H-pyrazol-4-yl}pyridine-2-35 carboxylic acid;2024205665   09 Aug 20246-(8-(l,3-benzothiazol-2-ylcarbamoyl)-6-[3-(methylamino)propyl]-3.4-dihydroisoquinolin-2( I H)-yl]-3-{ 1 -((3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy }tricyclo[3.3.1.1 ' Jdec-1 -yl)methyl]-5-methyl-1 H-pyrazol-4-yl}pyridine-2-carboxylic acid;5-((2-({3-[(4-{6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoqumolin-2(lH)-yl]-2-5    carboxypyridin-3-yl )-5-mcthyl-l H-pyrazol-l-yl)mcthyl]-5,7-dimcthyltricyclo[3.3.1.r]dcc-l-yl }oxy)ethyl]aniino} -5-deoxy-D-arabinitol;1-( (2-({ 3-((4-(6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl) -5-methyl-1 H-pyrazol-1 -yl)methyl]-5,7-dimethyltricyclo[3.3.1.1 7]dec-1 -yl}oxy)ethyl]amino}-l,2-dideoxy-D-arabino-hexitol;0           6-(4-( l,3-benzothiazol-2-ylcarbamoyl)isoquinolin-6-yl]-3-( l-[(3,5-dimcthyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl}pyridine-2-carboxylic acid;6-[8-(1.3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl 1-3-(1-( [3-(2-{ [3-hydroxy-2-(hydroxymethyl (propyl |amino)ethoxy)-5.7-dimcthyltricyclo[3.3.

1. l’|dcc-1 -yl [methyl J-15    5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid;l-((2-({3-[(4-{6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl) -5-methyl-1 H-pyrazol-l-yl)mcthyl]-5,7-dimethyltricyclo[3.3.1.1 7]dec-l-yl }oxy)ethyl]amino} -1,2-didcoxy-D-erythro-pentitol;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-( 1-((3,520 dimethyl-7-(2-{ [(2S.3S)-2,3.4-trihydroxybutyl]amino)ethoxy)tricyclo[3.3.1 .r7]dec-l-yl|methyl}-5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1H )-y 1 J-3-( 1 - {(3-(2-{[(2S,3S,4R,5R,6R)-2,3,4,5,6,7-hexahydroxyheptyl]amino}cthoxy)-5,7-dimcthyltricyclo(3.3.1.11 ]dec-1 -yl]mcthyl) -5-methyl-1 H-pyrazol-4-yl)pyridinc-2-carboxylic acid;25            6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3-(2-(((3-[(l,3-dihydroxypropan-2-yl)amino]propyl}sulfonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13 ]dec-l -yl)methyl]-5-methyl-1 H-pyrazol-4-yl }pyridine-2-carboxylic acid;6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3-(2-((3-{[l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino}-3-oxopropyr)amino]ethoxy)-5,7-30 dimethyltricyclo[3.3.1.13 ]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl)pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(l / / )-yl |-3-( 1-{[3-(2-{ [(35)-3.4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyltricyclo(3.3.1.1' ]dec-l-yl]methyl}-5-methyl-1 / / -pyrazol-4-yl)pyridine-2-carboxylic acid;4-( {[2-( {3-[(4-{ 6-(8-( 1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( I H)-yl]-2-35    carboxypyridin-3-yl) -5-methyl-1 H-pyrazol-l-yl)methylJ-5,7 -dimethyltricyclo(3.3.1.1 ’ 7]dec-l-yl }oxy)ethyl]amino}methyl)phenyl beta-D-glucopyranosiduronic acid;2024205665   09 Aug 20243-{ 12-( {3-((4-( 6-(8-( l,3-benzothiazol-2-ylcarbamoyl)naphthalen-2-yl]-2-carboxypyridin-3-yl }-5-methyl-1 H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo(3.3.1.I3 ]dec-l -yl}oxy)ethyl]amino}propyl beta-D-glucopyranosiduronic acid;6-(4-(1,3-benzothiazol-2-ylcarbamoyl)-2-oxidoisoquinolin-6-yl]-3-(l-({ 3,5-dimethyl-7-(2-5 (mcthylamino)ethoxy]tricyclo(3.3.1.1 ’ ']dcc-l-yl(mcthyl)-5-mcthyl-lH-pyrazol-4-yl]pyridinc-2-carboxylic acid;6-(8-[(1.3-benzothiazol-2-yl)carbamoyl]-3.4-dihydroisoquinolin-2(lH)-yl )-3-( 1-((3.5-dimethyl-7-(2-[(2-sulfoethyl)aminoJacetamido)tricyclo(3.3.1.1 ]decan-l-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid;0            6-(8-(1,3-bcnzothiazoI-2-ylcarbamoyl)-3.4-dihydroisoquinolin-2(l / f)-yl]-3-( 1-( [3,5-dimcthyl-7-((2-[(2-sulfoethyl)amino]ethyl)sulfanyl)tricyclo[3.3.1.1 ’ ]dec-l-yl]methyl)-5-methyl-lW-pyrazol-4-yl)pyridine-2-caiboxylic acid; and6-{ 8-((1,3-benzothiazol-2-yl)caibamoyl]-3,4-dihydroisoquinolin-2(l / f)-yl}-3-{ 1-((3,5-dimethyl-7-(3-[(2-sulfoethyl)aminoJpropyl) tricyclo[3.3.1.1’ |decan-l -yl)methyl]-5-methyl-1H-15 pyrazol-4-yl)pyridine-2-carboxylic acid,85.            The ADC of any one of claims 49-84, in which the linker is cleavable by a lysosomalenzyme.

86. The ADC of claim 85, in which the lysosomal enzyme is Cathepsin B.

87. The ADC of anyone of claims 49-84. in which the linker comprises a segment20 according to structural formula (IVa), (IVb), (IVc), or (IVd):(IVa)(IVb)2024205665   09 Aug 2024(IVc)(IVd)wherein:peptide represents a peptide (illustrated N—<, wherein peptide includes the amino and carboxy “termini”) a cleavable by a lysosomal enzyme;T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or5 combinations thereof;Ra is selected from hydrogen, Ci6 alkyl, SO,H and CH2SO3H;Ry is hydrogen or Ci4 alkyl-(O)r-(C| 4 alkylene)s-G' orC| 4 alkyl-(N)-[(C| 4 alkylene)-G']2;Rz is CM alkyl-(O)r-(CM alkylene)s-G2;G1 is SO3H, CO2H, PEG 4-32, or sugar moiety;10          G2 is SO3H, CO2H, or PEG 4-32 moiety;r is 0 or 1;s is 0 or 1;p is an integer ranging from 0 to 5;q is 0 or 1;15             x is 0 or 1;y is 0 or 1;represents the point of attachment of the linker to the Bcl-xL inhibitor; and* represents the point of attachment to the remainder of the linker.

88. The ADC of claim 87, in which peptide is selected from the group consisting of Val-20 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-Vai; 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.

89. The ADC of claim 85, in which the lysosomal enzyme is P-glucuronidasc orp-galactosidase.2024205665   09 Aug 202490.The ADC of any one of claims 49-84, in which the linker comprises a segmentaccording to structural formula (Va), (Vb), (Vc), (Vd), or (Ve):(Va)(Vb)(Vc)OH OH(Vd)2024205665   09 Aug 2024(Ve)wherein:q is 0 or 1;r is 0 or 1;X1 is CH2, O or NH;5              represents the point of attachment of the linker to the drug; and* represents the point of attachment to the remainder of the linker.

91. The ADC of any one of claims 49-84, in which the linker comprises a segmentaccording to structural formulae (Villa), (Vlllb), or (VIIIc):(hydrolyzed form)(Villa)10 (Vlllb)(VIIIc)or a hydrolyzed derivative thereof, wherein:2024205665   09 Aug 2024Rq is H or-O-(CH2CH2O)n-CH3;x is 0 or 1;y is 0 or 1;G3 is -CH2CH2CH2SO3H or -CH2CH2O-(CH2CH2O)irCH3;5         Rw is -O-CH2CH2SO3H or -NH(CO)-CH2CH2O-(CH2CH2O)I2-CH3;* represents the point of attachment to the remainder of the linker; andrepresents the point of attachment of the linker to the antibody.

92. The ADC of any one of claims 49-84, in which the linker comprises a polyethyleneglycol segment having from 1 to 6 ethylene glycol units.0   93.            The ADC of any one of claims 50-84, in which m is 2,3 or 4.

94. The ADC of claim 86, in which linker L is selected from IVa or IVb.

95. The ADC of any one of claims 49-84, in which linker L is selected from the groupconsisting of IVa. 1-IVa.8, IVb. I-IVb. 19, IVc.l-IVc.7, IVd.l-IVd.4, Va.l-Va.12, Vb.l-Vb.10, Vc.l-Vc.ll, Vd.l-Vd.6, Ve.l-Ve.2, Vla.l, Vlc.l-Vlc.2, Vld.l-Vld.

4. VIla.l-VIIa.4, Vllb.l-Vllb.8,15    Vile. 1 -VIIc.6 in either the closed or open form.

96. The ADC of any one of claims 50-84, in which the linker L is selected from the groupconsisting of IVb.

2. IVc.

5. IVc.6, IVc.7, IVd.

4. Vb.

9. VIIa.1, VIIa.3, VIIc.l, VIIc.

4. and VIIc.5, wherein the maleimide of each linker has reacted with the antibody Ab, forming a covalent attachment as either a succinimide (closed form) or succinamide (open form).20   97.            The ADC of any one of claims 49-84, in which the linker L is selected from the groupconsisting of IVb.

2. IVc.

5. IVc.6, IVd.4, VIIa.l, VIIa.3, VIIc.l, VIIc.4, VIIc.5, wherein the maleimide of each linker has reacted with the antibody Ab, forming a covalent attachment as either a succinimide (closed form) or succinamide (open form).

98. The ADC of any one of claims 49-84, in which the linker L is selected from the group25 consisting of IVb.2, VIIa.

3. IVc.

6. and VIIc.l, wherein is the attachment point to drug D and @ is the attachment point to the LK, wherein when the linker is in the open form as shown below, @ can be either at the a-position or P-position of the car boxylic acid next to it:2024205665   09 Aug 20242024205665   09 Aug 2024IVb.2 (open form)99.           The ADC of any one of claims 50-84, in which LK is a linkage formed with an amino5 group on the anti-hB7H3 antibody Ab.

100. The ADC of claim 98, in which LK is an amide or a thiourea.

101. The ADC of any one of claims 50-84, in which LK is a linkage formed with asulfhydryl group on the anti-hB7-H3 antibody Ab.

102. The ADC of claim 101, in which LK is a thiocther.10   103.          The ADC of any one of claims 50-84, in which:LK is selected from the group consisting of amide, thiourea and thioether: andm is an integer ranging from 1 to 8.

104. The ADC of claim 50, in which:D is the Bcl-xL inhibitor as defined in claim 84;2024205665   09 Aug 2024L is selected from the group consisting of linkers IVa.l-IVa.

8. IVb. l-IVb.19, IVc.l-IVc.7, IVd. l-IVd.4, Va.l-Va.12, Vb.l-Vb.10, Vc.l-Vc.l 1, Vd.l-Vd.6, Ve.l-Ve.2, VIa.l, VIc.l-Vlc.2, Vid. l-Vld.4, Vila. 1 -Vlla.4, V 11b. 1 -Vlib.8, and Vllc.l-Vllc.6, wherein each linker has reacted with the antibody, Ab, forming a covalent attachment;5            LK is thiocther; andm is an integer ranging from 1 to 8.

105. The ADC of claim 50, in which:D is the Bcl-xL inhibitor selected from the group consisting of the following compounds modified in that the hydrogen corresponding to the # position of structural formula (Ila), (11b), (lie), 0 or (lid) is not present, forming a monoradical:6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1-((3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.r ]dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl} pyridine-2-carboxylic acid;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-{ 1 -((3-(2-((215 carboxyethyl)amino]ethoxy}-5.7-dimethyltricyclo[3.3.1.r'' |dec-l-yl)methyl]-5-methyl-lH-pyrazol-4-yl }pyridine-2-carboxylic acid;6-(8-(1,3-benzothiazol-2-ylcarbamoyl)naphthalen-2-yl]-3-{ 1-((3,5-dimethyl-7-( 2-((2-sulfocthyl)amino]ethoxy(tiicyclo(3.3.1.117]dcc-l-yl)mcthyl]-5-mcthyl-lH-pyrazol-4-yl (pyridine-2-carboxylic acid;20            l-{ [2-( {3-((4-( 6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3.4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl) -5-methyl-1 H-pyrazol-1 -yl)methyl]-5,7-dimethyltricyclo(3.3.1.1 1 '(dec-1-yl}oxy)ethyl]amino}-l,2-dideoxy-D-arabino-hexitol;6-(8-( l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3-( 1-( [3-(2-{ [3-hydroxy-2-(hydroxymethyl)propyl]amino)ethoxy)-5,7-dimethyltricyclo[3.3.1.T17]dec-l-yl]methyl)-25 5-methyl-1 H-pyrazol-4-yl)pyridine-2-carboxylic acid; and6-(8-( 1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-y 1 ]-3-( 1 - {[3-(2- {[(35)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1 .r (dec-1-yljmethyl}-5-methyl-1 / 7-pyrazol-4-yl)pyridine-2-carboxylic acid;L is selected from the group consisting of linkers IVb.2, IVc.5, IVc.

6. IVc.7, IVd.4, Vb.9, 30 Vc.l 1, VIIa.

1. VIla.3, VIIc.l, VIIc.4, and Vile.5 in either closed or open forms;LK is thioether; andm is an integer ranging from 2 to 4.

106. The ADC of claim 50, selected from the group consisting of huAb3v2.5-CZ,huAb3v2.5-TX, huAb3v2.5-TV, huAb3v2.5-YY, huAb3v2.5-AAA, huAb3v2.5-AAD, huAb.3v2.6-35 CZ, huAb3v2.6-TX, huAb3v2.6-TV, huAb3v2.6-YY, huAb3v2.6-AAD, huAbl3vl-CZ, huAbl3vl-TX, huAbl3vl-TV, huAb!3vl-YY, huAbl3vl-AAA, huAbl3vl-AAD, wherein CZ, TX, TV. YY,2024205665   09 Aug 2024AAA, and AAD are synthons disclosed in Table B. and wherein the conjugated synthons are either inopen or closed form.107.The ADC of claim 50, selected from the group consisting of formulae i-vi:2024205665   09 Aug 2024wherein m is an integer from 1 to 6.

108. The ADC of claim 107, wherein m is an integer from 2 to 6.

109. The ADC of any one of claims 49-108, wherein the anti-hB7-H3 antibody comprisesa heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO:12, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavy chain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; a10 light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:

7. and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136 or 138.2024205665   09 Aug 2024110.          The ADC of any one of claims 49-108, wherein the antibody comprises a heavy chainvariable region comprising the amino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 135.

111. The ADC of any one of claims 49-108, wherein the antibody comprises either a5 heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 137; or a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 144.

112. The ADC of any one of claims 49-108, wherein the antibody comprises a light chain0 CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain CDR1domain comprising the amino acid sequence set forth in SEQ ID NO: 37; and a heavy chain CDR3domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavy chain CDR2domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavy chain CDR115 domain comprising the amino acid sequence set forth in SEQ ID NO: 33.

113. The ADC of any one of claims 49-108, wherein the antibody is an IgG having fourpolypeptide chains which are two heavy chains and two light chains.

114. A pharmaceutical composition comprising an effective amount of an ADC accordingto any one of claims 46-113, and a pharmaceutically acceptable carrier.20   115.           A pharmaceutical composition comprising an ADC mixture comprising a plurality ofthe ADC of any one of claims 46-113, and a pharmaceutically acceptable canier.

116. The pharmaceutical composition of claim 115, wherein the ADC mixture has anaverage drug to antibody ratio (DAR) of 1.5 to 4.

117. The pharmaceutical composition of claim 115, wherein the ADC mixture comprises25 at least 75% ADCs each having a DAR of 2.

118. A method for treating cancer, comprising administering a therapeutically effectiveamount of the ADC of any one of claims 46-113 to a subject in need thereof.

119. The method of claim 118, wherein the cancer is selected from the group consisting ofsmall cell lung cancer, non small cell lung cancer, breast cancer, ovarian cancer, a glioblastoma,30 prostate cancer, pancreatic cancer, colon cancer, gastric cancer, melanoma, hepatocellular carcinoma, head and neck cancer, acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and kidney cancer120.           The method of claim 119, wherein the cancer is a squamous cell carcinoma.

121. The method of claim 120, wherein the squamous cell carcinoma is squamous lung35 cancer or squamous head and neck cancer.

122. The method of claim 119, wherein the cancer is triple negative breast cancer.

123. The method of claim 119, wherein the cancer is non-small cell lung cancer.2024205665   09 Aug 2024124.           A method for inhibiting or decreasing solid tumor growth in a subject having a solidtumor, said method comprising administering an effective amount of the ADC of any one of claims 46-114 to the subject having the solid tumor, such that the solid tumor growth is inhibited or decreased.5    125.           The method of claim 124, wherein the solid tumor is a non-small cell lung carcinoma.

126. The method of any one of claims 119-125, wherein the ADC is administered incombination with an additional agent or an additional therapy.

127. The method of claim 126, wherein the additional agent is selected from the groupconsisting of an anti-PDl antibody (e.g. pembrolizumab), an anti-PD-Ll antibody (e.g.,0 atezolizumab), an anti-CTLA-4 antibody (e.g. ipilimumab), a MEK inhibitor (e.g. trametinib), an ERK inhibitor, a BRAF inhibitor (e.g. dabrafenib). osimertinib, erlotinib, gefitinib, sorafenib, a CDK9 inhibitor (e.g. dinaciclib), a MCL-1 inhibitor, temozolomide, a Bcl-xL inhibitor, a Bcl-2 inhibitor (e.g., venetoclax), ibrutinib, a mTOR inhibitor (e.g. everolimus), a PI3K inhibitor (e.g. buparlisib), duvelisib, idelalisib, an AKT inhibitor, a HER2 inhibitor (e.g. lapatinib), a taxane (e.g. docetaxel,15 paclitaxel, nab-paclitaxel), venetoclax, an ADC comprising an auristatin, an ADC comprising a PBD (e.g. rovalpituzumab tesirine), an ADC comprising a maytansinoid (e.g. TDM1), a TRAIL agonist, a proteasome inhibitor (e.g. bortezomib), and a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.

128. The method of claim 125, wherein the additional therapy is radiation.20    129.           The method of claim 125, wherein the additional agent is a chemotherapeutic agent.

130. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3(hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 168 and a light chain comprising the amino acid sequence of SEQ ID NO: 169.25    131.           An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3(hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 170 and a light chain comprising the amino acid sequence of SEQ ID NO: 171.

132. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H330   (hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chaincomprising the amino acid sequence of SEQ ID NO: 172 and a light chain comprising the amino acid sequence of SEQ ID NO: 173.

133. The method of any one of claims 118-129, wherein the cancer is characterized ashaving an activating EGFR mutation.35    134.           The method of claim 133, wherein the activating EGFR mutation is selected from thegroup consisting of an exon 19 deletion mutation, a single-point substitution mutation L858R in exon 21, a T790M point mutation, and combinations thereof.2024205665   09 Aug 2024135.           A process for the preparation of an ADC according to structural formula (I):(I)            ( D---L----Lk4—Ab'                  / mwherein:D is the Bcl-xL inhibitor drug of formula (Ila), (lib). (lie), or (lid);L is the linker;5           Ab is an hB7-H3 antibody, wherein the hB7-H3 antibody comprises the heavy and light chainCDRs of huAb3v2.5, huAb3v2.6, or huAbl3vl;LK represents a covalent linkage linking linker L to antibody Ab; andm is an integer ranging from 1 to 20;the process comprising:0           treating an antibody in an aqueous solution with an effective amount of a disulfide reducingagent at 30-40 °C for at least 15 minutes, and then cooling the antibody solution to 20-27 °C;adding to the reduced antibody solution a solution of water / dimethyl sulfoxide comprising asynthon selected from the group of 2.1 to 2.176 (Table B);adjusting the pH of the solution to a pH of 7.5 to 8.5;15            allowing the reaction to run for 48 to 80 hours to form the ADC;wherein the mass is shifted by 18 + 2 amu for each hydrolysis of a succinimide to asuccinamide as measured by election spray mass spectrometry; andwherein the ADC is optionally purified by hydrophobic interaction chromatography.

136. The process of claim 135, wherein m is 2.20   137. An ADC prepared by the process of claim 135 or 136.

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