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EP-3972649-B1 - MCL-1 INHIBITOR ANTIBODY-DRUG CONJUGATES AND METHODS OF USE

EP3972649B1EP 3972649 B1EP3972649 B1EP 3972649B1EP-3972649-B1

Inventors

  • BURGER, MATTHEW, T.
  • KOTSCHY, ANDRAS
  • MARAGNO, Ana, Leticia
  • MCNEILL, Eric
  • PALERMO, MARK, G.
  • ROCCHETTI, Francesca
  • STARCK, Jérôme
  • YU, BING
  • ZHANG, QIANG
  • Proszenyák, Ágnes
  • SIPOS, Szabolcs
  • CHANRION, MAIA
  • CHEN, ZHUOLIANG
  • NAKAJIMA, KATSUMASA
  • D'ALESSIO, Joseph, Anthony
  • BLANKENSHIP, John, William
  • COLLAND, Frédéric
  • CSEKEI, MARTON
  • DELACOUR, Lea
  • DESOS, PATRICE
  • GENESTE, OLIVIER
  • HENLIN, JEAN-MICHEL
  • KOSTOVA, Vesela

Dates

Publication Date
20260513
Application Date
20200519

Claims (20)

  1. An antibody-drug conjugate of Formula (1): Ab-(L-D) p (1) wherein: Ab is an anti-CD74 antibody or an antigen-binding fragment thereof; p is an integer from 1 to 16; and -(L-D) is of the formula (C): wherein: R' is an attachment group; L 1 is a bridging spacer; L p is a peptide group comprising 1 to 6 amino acids; D is an Mcl-1 inhibitor, wherein (1) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (2) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (3) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (4) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (5) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (6) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (7) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (8) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (9) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (10) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (11) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (12) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; or (13) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (14) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (15) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; (16) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; or (17) D comprises: or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt of any of the foregoing; G 1 -L 2 -A is a self-immolative spacer; L 2 is a bond, a methylene, a neopentylene or a C 2 -C 3 alkenylene; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; L 3 is a spacer moiety; and R 2 is a hydrophilic moiety.
  2. The antibody-drug conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein -(L-D) is of Formula (D): wherein: R' is an attachment group; L 1 is a bridging spacer; Lp is a peptide group comprising 1 to 6 amino acids; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; L 3 is a spacer moiety; and R 2 is a hydrophilic moiety.
  3. The antibody-drug conjugate of claim 1 or 2, wherein (i) L 1 comprises: or *-CH(OH)CH(OH)CH(OH)CH(OH)-**, wherein each n is an integer from 1 to 12, wherein the * of L 1 indicates the point of direct or indirect attachment to Lp, and the ** of L 1 indicates the point of direct or indirect attachment to R 1 ; (ii) L 1 is and n is an integer from 1 to 12 or n is 1 or n is 12, wherein the * of L 1 indicates the point of direct or indirect attachment to Lp, and the ** of L 1 indicates the point of direct or indirect attachment to R 1 ; (iii) L 1 is and n is an integer from 1 to 12, wherein the * of L 1 indicates the point of direct or indirect attachment to Lp, and the ** of L 1 indicates the point of direct or indirect attachment to R 1 ; (iv) L 1 comprises wherein the * of L 1 indicates the point of direct or indirect attachment to Lp, and the ** of L 1 indicates the point of direct or indirect attachment to R 1 ; or (v) L 1 is a bridging spacer comprising: *-C(=O)(CH 2 ) m O(CH 2 ) m -**; *-C(=O)((CH 2 ) m O) t (CH 2 ) n -**; *-C(=O)(CH 2 ) m -**; *-C(=O)NH((CH 2 ) m O) t (CH 2 ) n -**; *-C(=O)O(CH 2 ) m SSC(R 3 ) 2 (CH 2 ) m C(=O)NR 3 (CH 2 ) m NR 3 C(=O)(CH 2 ) m -**; *-C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m -**; *-C(=O)(CH 2 ) m NH(CH 2 ) m -**; *-C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)-**; *-C(=O)(CH 2 ) m X 1 (CH 2 ) m -**; *-C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n -**; *-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n -**; *-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n -**; *-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**; *-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**; *-C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m -**; *-C(=O)(CH 2 ) m C(R 3 ) 2 -** or *-C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m -**, wherein the * of L 1 indicates the point of direct or indirect attachment to Lp, and the ** of L 1 indicates the point of direct or indirect attachment to R 1 ; X 1 is and each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30; and each R 3 is independently selected from H and C 1 -C 6 alkyl.
  4. The antibody-drug conjugate of any one of claims 1 to 3, wherein (1) R 2 is a hydrophilic moiety comprising polyethylene glycol, polyalkylene glycol, a polyol, a polysarcosine, a sugar, an oligosaccharide, a polypeptide, or C 2 -C 6 alkyl substituted with 1 to 3 groups; (2) R 2 is wherein n is an integer between 1 and 6, or (3) the hydrophilic moiety represented by R 2 comprises: (i) a polysarcosine, e.g., with the following moiety: wherein n is an integer between 3 and 25; and R is H, -CH 3 or - CH 2 CH 2 C(=O)OH; or (ii) a polyethylene glycol of formula: wherein R is H, - CH 3 , 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 , 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 , in which R a is H or C 1-4 alkyl optionally substituted with either OH or C 1-4 alkoxyl, and each of m and n is independently an integer between 2 and 25; or (4) the hydrophilic moiety represented by R 2 comprises
  5. The antibody-drug conjugate of any one of claims 1 to 4, wherein: (i) L 3 is a spacer moiety having the structure wherein: 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(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 N R b C(=O)-, -CH 2 N R 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-, wherein each R b is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; and X is a bond, triazolyl, or -CH 2 -triazolyl-; or (ii) L 3 is a spacer moiety having the structure wherein: 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(X-R 2 )C(=O)O-, -C(=O)N(X-R 2 )-, -CH 2 N(X-R 2 )C(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR b C(=O)-, -CH 2 NR b C(=O)NH-, -CH 2 NR b C(=O)NR b -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O- or -NH-, wherein each R b is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; and 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 -, or -CH 2 -triazolyl-C 1-4 alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, wherein each n independently is 1 2, or 3.
  6. The antibody-drug conjugate of any one of claims 1 to 5, wherein (i) the attachment group is formed by a reaction comprising at least one reactive group; (ii) the attachment group is formed by reacting: a first reactive group that is attached to the linker, and a second reactive group that is attached to the antibody or is an amino acid residue of the antibody; (iii) the attachment group is formed by a reaction comprising at least one reactive group, wherein at least one of the reactive groups comprises: a thiol, a maleimide, a haloacetamide, an azide, an alkyne, a cyclooctene, a triaryl phosphine, an oxanorbornadiene, a cyclooctyne, a diaryl tetrazine, a monoaryl tetrazine, a norbornene, an aldehyde, a hydroxylamine, a hydrazine, NH 2 -NH-C(=O)-, a ketone, a vinyl sulfone, an aziridine, an amino acid residue, -ONH 2 , -NH 2 , -N 3 , -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, -C(O)NHNH 2 , or wherein: each R 3 is independently selected from H and C 1 -C 6 alkyl; each R 4 is 2-pyridyl or 4-pyridyl; each R 5 is independently selected from H, C 1 -C 6 alkyl, F, Cl, and -OH; each R 6 is independently selected from 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 is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C 1-4 alkoxy substituted with - C(=O)OH and C 1-4 alkyl substituted with -C(=O)OH; (iv) the attachment group is formed by reacting that is attached to the linker and a second reactive group that is attached to the antibody or is an amino acid residue of the antibody, wherein the first reactive group and second reactive group comprise: a thiol and a maleimide, a thiol and a haloacetamide, a thiol and a vinyl sulfone, a thiol and an aziridine, an azide and an alkyne, an azide and a cyclooctyne, an azide and a cyclooctene, an azide and a triaryl phosphine, an azide and an oxanorbornadiene, a diaryl tetrazine and a cyclooctene, a monoaryl tetrazine and a norbornene, an aldehyde and a hydroxylamine, an aldehyde and a hydrazine, an aldehyde and NH 2 -NH-C(=O)-, a ketone and a hydroxylamine, a ketone and a hydrazine, a ketone and NH 2 -NH-C(=O)-, a hydroxylamine and an amine and or or a CoA or CoA analogue and a serine residue; or (v) the attachment group comprises a group selected from: amide; and disulfide, wherein: R 32 is H, C 1-4 alkyl, phenyl, pyrimidine or pyridine; R 35 is H, C 1-6 alkyl, phenyl or C 1-4 alkyl substituted with 1 to 3 -OH groups; each R 7 is independently selected from H, C 1-6 alkyl, fluoro, benzyloxy substituted with - C(=O)OH, benzyl substituted with -C(=O)OH, C 1-4 alkoxy substituted with -C(=O)OH and C 1-4 alkyl substituted with -C(=O)OH; R 37 is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 8 is H or methyl; and R 9 is H, -CH 3 or phenyl.
  7. The antibody-drug conjugate any one of claims 1 to 6, wherein (i) the peptide group comprises 1 to 4 amino acid residues, 1 to 3 amino acid residues, or 1 to 2 amino acid residues; (ii) the peptide group comprises amino acid residues selected from L-glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (lle), 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); (iii) the peptide group comprises Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, sulfo-Ala-Val, and/or sulfo-Ala-Val-Ala; or (iv) Lp is selected from:
  8. An antibody-drug conjugate of formula (1): Ab-(L-D) p (1) wherein: Ab is an anti-CD74 antibody or an antigen-binding fragment thereof; p is an integer from 1 to 16; and wherein -(L-D) comprises or is formed from a compound of formula: (1) wherein: R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (2) wherein: R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-* -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (3) wherein: R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (4) , wherein: each R is independently selected from H, -CH 3 , and -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (5) wherein: each R is independently selected from H, -CH 3 , and -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (6) wherein: Xa is -CH 2 -, -OCH 2 -, -NHCH 2 - or -NRCH 2 - and each R independently is H, -CH 3 or - CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, , -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (7) wherein: R is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (8) wherein: Xb is -CH 2 -, -OCH 2 -, -NHCH 2 - or -NRCH 2 - and each R independently is H, -CH 3 or - CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (9) wherein: A is a bond, -OC(=O)-*, 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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (10) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (11) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (12) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (13) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (14) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; (15) wherein: A is a bond, -OC(=O)-*, -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the * of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1; or (16) wherein: each R independently is H, -CH 3 or -CH 2 CH 2 C(=O)OH; A is a bond, -OC(=O)-* -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)-*, wherein each R a is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl and the of A indicates the point of attachment to D; and D is an Mcl-1 inhibitor as defined in claim 1.
  9. The antibody-drug conjugate of any one of claims 1 to 8, wherein A is a bond.
  10. The antibody-drug conjugate of any one of claims 1-9, wherein R is -CH 3 .
  11. The antibody-drug conjugate any one of claims 1 to 10, wherein -(L-D) is formed from a compound selected from Table A or an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and/or pharmaceutically acceptable salt thereof.
  12. The antibody-drug conjugate of claim 11, wherein the -(L-D) comprises or is formed from the following compound: or
  13. The antibody drug conjugate of any one of claims 1-11, wherein (1) the anti-CD74 antibody comprises an anti-CD74 antibody or antigen binding fragment comprising three heavy chain CDRs and three light chain CDRs as follows: (i) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:1, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:2, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:16, light chain CDR2 (LCDR2) consisting of SEQ ID NO:70, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (ii) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:4, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:2, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:16, light chain CDR2 (LCDR2) consisting of SEQ ID NO:70, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (iii) 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:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:19, light chain CDR2 (LCDR2) consisting of SEQ ID NO:20, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:21; (iv) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:7, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:8, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:9; light chain CDR1 (LCDR1) consisting of SEQ ID NO:22, light chain CDR2 (LCDR2) consisting of SEQ ID NO:20, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (v) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:1, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:2, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:35, light chain CDR2 (LCDR2) consisting of SEQ ID NO:70, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (vi) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:4, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:2, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:35, light chain CDR2 (LCDR2) consisting of SEQ ID NO:70, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (vii) 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:3; light chain CDR1 (LCDR1) consisting of SEQ ID NO:71, light chain CDR2 (LCDR2) consisting of SEQ ID NO:20, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:21.or (viii) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:7, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:8, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:9; light chain CDR1 (LCDR1) consisting of SEQ ID NO:17, light chain CDR2 (LCDR2) consisting of SEQ ID NO:20, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:18; (2) the anti-CD74 antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23; (ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:27;(iii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:31; (iv) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:36; (v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:40; or (vi) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:44; or (3) the anti-CD74 antibody comprises: (a) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:25; (b) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:25; (c) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:25; (d) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:29; (e) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:29; (f) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:29; (g) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:33; (h) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:33; (i) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:33; (j) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:38; (k) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:38; (l) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:38; (m) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:42; (n) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:42; (o) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:42; (p) the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:46; (q) the heavy chain amino acid sequence of SEQ ID NO:14 and the light chain amino acid sequence of SEQ ID NO:46; or (r) the heavy chain amino acid sequence of SEQ ID NO:15 and the light chain amino acid sequence of SEQ ID NO:46.
  14. The antibody drug conjugate of any one of claims 1-13, wherein the Ab is a Fc silent antibody.
  15. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 1 to 14, wherein the average p of the antibody-drug conjugates in the composition is from about 2 to about 16, e.g., about 2 to about 8, e.g., about 2 to about 4.
  16. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 14 or the composition of claim 15, and a pharmaceutically acceptable carrier.
  17. An antibody-drug conjugate of any one of claims 1 to 14, the composition of claim 15, or the pharmaceutical composition of claim 16 for use in treating a subject having a cancer, optionally wherein (1) the cancer expresses CD74; or (2) the cancer is a tumor or a hematological cancer, preferably, the cancer is a breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or spleen cancer.
  18. An antibody-drug conjugate of any one of claims 1 to 14, the composition of claim 15, or the pharmaceutical composition of claim 16 for use in reducing or inhibiting the growth of a tumor in a subject, optionally wherein (1) the tumor expresses CD74; or (2) the tumor is a breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or spleen cancer.
  19. An antibody-drug conjugate of any one of claims 1 to 14, the composition of claim 15, or the pharmaceutical composition of claim 16 for use according to claim 18, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor 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%.
  20. An antibody-drug conjugate of any one of claims 1 to 14, the composition of claim 15, or the pharmaceutical composition of claim 16 for use in reducing or slowing the expansion of a cancer cell population in a subject, optionally wherein (1) the cancer cell population expresses CD74; or (2) the cancer cell population is from a tumor or a hematological cancer, preferably the cancer cell population is from a breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or spleen cancer.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is appended hereto. Said ASCII copy, created on June 25, 2020, is named 132043-00220_SL.txt and is 76,528 bytes in size. FIELD OF THE INVENTION The present disclosure relates to antibody-drug conjugates (ADCs) comprising an Mcl-1 inhibitor and an anti-CD74 antibody or antigen-binding fragment thereof that binds an antigen target, e.g., an antigen expressed on a tumor or other cancer cell. The disclosure further relates to methods and compositions useful in the treatment and/or diagnosis of cancers that express the target antigen CD74 and/or are amenable to treatment by modulating Mcl-1 expression and/or activity, as well as methods of making those compositions. Linker-drug conjugates comprising an Mcl-1 inhibitor drug moiety and methods of making same are also disclosed. BACKGROUND OF THE INVENTION Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis. Apoptotic-type cell death generally involves morphological changes such as condensation of the nucleus and DNA fragmentation, as well as biochemical changes such as the activation of caspases that can cause damage to key structural components of the cell. Regulation of apoptosis is complex and typically involves the activation or repression of several intracellular signaling pathways (Cory et al. (2002) Nature Review Cancer 2:647-656). Deregulation of apoptosis is associated with certain pathologies. For instance, increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and ischemia. Conversely, deficits in apoptosis can play a role in the development of cancers and chemoresistance, autoimmune diseases, inflammatory diseases, and viral infections. The absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan et al. (2000) Cell 100:57-70). Anti-apoptotic proteins of the Bcl-2 family are associated with numerous types of cancer, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, and pancreatic cancer. Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic Bcl-2 family member, is a regulator of cell survival. Amplification of the Mcl-1 gene and/or overexpression of the Mcl-1 protein has been observed in multiple cancer types and is commonly implicated in tumor development (Beroukhim et al. (2010) Nature 463(7283):899-905). Mcl-1 is one of the most frequently amplified genes in human cancer and is also a critical survival factor that has been shown to mediate drug resistance to a variety of anti-cancer agents. Mcl-1 is believed to promote cell survival by binding to and neutralizing the deathinducing activities of pro-apoptotic proteins such as Bim, Noxa, Bak, and Bax. Inhibition of Mcl-1 releases these pro-apoptotic proteins, often leading to the induction of apoptosis in tumor cells dependent on Mcl-1 for survival. Therapeutically targeting Mcl-1 or proteins upstream and/or downstream of it in an apoptotic signaling pathway, therefore, may represent promising strategies to treat various malignancies and to overcome drug resistance in certain human cancers. CD74 (DHLAG) is an established and attractive target for antibody drug conjugates due to its restricted expression on normal tissues and significant upregulation in a range of hematological malignancies. CD74 functions as a chaperone that is necessary for the assembly and trafficking of MHC class II complexes as well as a receptor for macrophage migration inhibitory receptor (MIF). In oncology, it has been well established that CD74 is significantly upregulated at both the RNA and protein level in a range of B-cell and myeloid cell malignancies including acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Additionally CD74 is known to rapidly internalize upon antibody engagement and traffic to the lysosome as well as to to be rapidly repopulated on the surface of tumor cells following internalization. Antibodies and antibody drug conjugates targeting CD74 have been shown previously to demonstrate anti-tumor activity in preclinical models of cancer. CRISTINA L. ABRAHAMS ET AL: "Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001 ", ONCOTARGET, vol. 9, no. 102, 28 December 2018 (2018-12-28), pages 37700-37714 is a study of the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies S. V. GOVINDAN ET AL: "Milatuzumab-SN-38 Conjugates for the Treatment of CD74+ Cancers", MOLECULAR CANCER THERAPEUTICS, vol. 12, no. 6, 1 June 2013 (2013-06-01), pages 968-978, examines the humanized anti-CD74 antibody, milatuzuma