Antibody drug conjugates for ablating hematopoietic stem cells

Patent metadata

Field	Value
Publication number	US-12171839-B2
Application number	US-202217833077-A
Country	US
Kind code	B2
Filing date	Jun 6, 2022
Priority date	Dec 21, 2016
Publication date	Dec 24, 2024
Grant date	Dec 24, 2024

Abstract

The present invention provides antibody drug conjugates, wherein an antibody or antibody fragment that specifically binds to human cKIT is linked to a drug moiety, optionally through a linker. The present invention further provides pharmaceutical compositions comprising the antibody drug conjugates; and methods of making and using such pharmaceutical compositions for ablating hematopoietic stem cells in a patient in need thereof.

First claim

What is claimed is:

1. A conjugate having the structure of Formula (C):

wherein:
A is an antibody fragment that specifically binds to human cKIT;
y is an integer from 1 to 10;
R 2 is C 1 -C 6 alkyl;
L 20 is -L 1 R 40 ;
Li is -((CH 2 ) m O) p (CH 2 ) m X 1 L 4 -, —((CH 2 ) m O) p (CH 2 ) m X 2 L 4 -, —((CH 2 ) m O) p (CH 2 ) m —, —(CH 2 ) m —, —(CH 2 ) m X 1 (CH 2 ) m —, —(CH 2 ) m NHC(═O)(CH 2 ) m —, —(CH 2 ) m NHC(═O)(CH 2 ) m C(═O)NH(CH 2 ) m —, —((CH 2 ) m O) p (CH 2 ) m NHC(═O)(CH 2 ) m , —((CH 2 ) m O) p CH 2 ) m C(═O)NH(CH 2 ) m —, X 3 X 4 C(═O)((CH 2 ) m O) p (CH 2 ) m —, —X 3 X 4 C(═O)(CH 2 ) m —, —X 3 C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m , —X 3 C(═O)(CH 2 ) m NHC(═O)((CH 2 ) m O) p (CH 2 ) m —, —(CH 2 ) m C(R 7 ) 2 —, —(CH 2 ) m C(R 7 ) 2 SS(CH 2 ) m NHC(═O)(CH 2 ) m or —(CH 2 ) m X 3 C(═O)(CH 2 ) m NHC(═O)((CH 2 ) m O) p (CH 2 ) m —;
L 4 is —((CH 2 ) m ;
X 1 is

 where the * indicates attachment point to L 4 ;
X 2 is

 where the * indicates attachment point to L 4 ;

X 3 is

X 4 is

R 40 is

 —NR 7 C(═O)CH 2 —, —NHC(═O)CH 2 —, —S(═O) 2 CH 2 CH 2 —, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 —, —NR 7 S(═O) 2 CH 2 CH 2 , —NR 7 C(═O)CH 2 CH 2 —, —NH—, —C(═O)—, —NHC(═O)—, —CH 2 NHCH 2 CH 2 —, —NHCH 2 CH 2 —, —S—,

each R 7 is independently selected from H and C 1 -C 6 alkyl;
each R 10 is independently selected from H, C 1 -C 6 alkyl, F, Cl, and —OH;
each R 11 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 12 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;
each R 15 is independently selected from H, —CH 3 and phenyl;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; and

wherein the antibody fragment that specifically binds to human cKIT is selected from any of the following:
(1) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 (Heavy Chain Complementarity Determining Region 1) comprising the amino acid sequence of SEQ ID NO: 1, (b) a HCDR2 (Heavy Chain Complementarity Determining Region 2) comprising the amino acid sequence of SEQ ID NO: 2, and (c) a HCDR3 (Heavy Chain Complementarity Determining Region 3) comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 (Light Chain Complementarity Determining Region 1) comprising the amino acid sequence of SEQ ID NO: 16, (e) a LCDR2 (Light Chain Complementarity Determining Region 2) comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 (Light Chain Complementarity Determining Region 3) comprising the amino acid sequence of SEQ ID NO: 18;
(2) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 19, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 21;
(3) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18;
(4) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 22, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18;
(5) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 27, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 28, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(6) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 30, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 45;
(7) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 32, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 28, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(8) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 33, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 35; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 46, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(9) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ I

Assignees

• Novartis Ag

Inventors

• Boitano Anthony Edward
• Burger Matthew
• Cellitti Susan E
• Cooke Michael P
• Finner Catrin
• Geierstanger Bernhard Hubert
• Jin Yunho
• Lee-Hoeflich Si Tuen
• Pham Hongngoc Thi
• Schleyer Siew Ho
• Tissot Kathrin
• Uno Tetsuo
• Wen Ben

Classifications

• A61K47/68033

  the drug being a maytansine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title