1-(chloromethyl)-2,3-dihydro-1H-benzo[E]indole dimer antibody-drug conjugate compounds, and methods of use and treatment

Patent metadata

Field	Value
Publication number	US-10442836-B2
Application number	US-201414305643-A
Country	US
Kind code	B2
Filing date	Jun 16, 2014
Priority date	Aug 12, 2013
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

The invention provides antibody-drug conjugates comprising an antibody conjugated to a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) dimer drug moiety via a linker, and methods of using the antibody-drug conjugates.

First claim

We claim:

1. An antibody-drug conjugate compound having the formula:
Ab-(L-D) p
wherein:
Ab is an antibody; wherein the antibody is a cysteine engineered, anti-CD22 antibody, wherein a cysteine group at the A118C site (EU numbering) of the heavy chain, also numbered as 121 by Sequential numbering or 114 by Kabat numbering, of the cysteine engineered antibody is attached to the linker L, and that comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein:
HVR-L1 comprises the amino acid sequence of SEQ ID NO:1;
HVR-L2 comprises the amino acid sequence of SEQ ID NO:2;
HVR-L3 comprises the amino acid sequence of SEQ ID NO:3;
HVR-H1 comprises the amino acid sequence of SEQ ID NO:4;
HVR-H2 comprises the amino acid sequence of SEQ ID NO:5; and
HVR-H3 comprises the amino acid sequence of SEQ ID NO:6;
L is a linker having the formula:
-Str-(Pep) m -(Sp) n -

where Str is a stretcher unit covalently attached to the antibody;
wherein Str has a formula selected from the group consisting of:

R 6 is selected from the group consisting of C 1 -C 10 alkylene, C 3 -C 8 carbocyclyl, O—(C 1 -C 8 alkyl), arylene, C 1 -C 10 alkylene-arylene, arylene-C 1 -C 10 alkylene, C 1 -C 10 alkylene-(C 3 -C 8 carbocyclyl), (C 3 -C 8 carbocyclyl)-C 1 -C 10 alkylene, C 3 -C 8 heterocyclyl, C 1 -C 10 alkylene-(C 3 -C 8 heterocyclyl), (C 3 -C 8 heterocyclyl)-C 1 -C 10 alkylene, C 1 -C 10 alkylene-C(O)N(R 8 )—C 2 -C 6 alkylene-N(R 8 ), N(R 8 )—(C 2 -C 6 alkylene), and (CH 2 CH 2 O) r —CH 2 ; where R 8 is H or C 1 -C 6 alkyl, and r is an integer ranging from 1 to 10;

R 7 is selected from C 1 -C 10 alkylene, C 1 -C 10 alkylene-O, N(R 8 )—(C 2 -C 6 alkylene)-N(R 8 ), N(R 8 )—(C 2 -C 6 alkylene), and (CH 2 CH 2 O) r —CH 2 ; where R 8 is H or C 1 -C 6 alkyl, and r is an integer ranging from 1 to 10; and

R 9 is selected from C 1 -C 10 alkylene, C 1 -C 10 alkylene-O, (C 2 -C 6 alkylene)-N(R 8 ), and (CH 2 CH 2 O) r —CH 2 ; where R 8 is H or C 1 -C 6 alkyl, and r is an integer ranging from 1 to 10;
Pep is an optional peptide unit of two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline;
Sp is an optional spacer unit covalently attached to a dimer drug moiety comprising para-aminobenzyl or para-aminobenzyloxycarbonyl;
m and n are independently selected from 0 and 1;
p is an integer from 1 to 8; and
D is the dimer drug moiety having the formula:

where
R 1 is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L;
R 2 is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L;
R a and R b are independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more F,
or R a and R b form a five or six membered heterocyclyl group;
T is a tether group selected from C 3 -C 12 alkylene, Y, (C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene), (C 2 -C 6 alkenylene)-Y—(C 2 -C 6 alkenylene), and (C 2 -C 6 alkynylene)-Y—(C 2 -C 6 alkynylene);
where Y is independently selected from O, S, NR 1 , aryl, and heteroaryl;
where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F;
or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to L;
D′ is a drug moiety having the formula:

where the wavy line indicates the site of attachment to T; and
X 1 and X 2 are independently selected from O and NR 3 , where R 3 is selected from H and C 1 -C 6 alkyl optionally substituted with one or more F.

2. The antibody-drug conjugate compound of claim 1 wherein R 6 is (CH 2 ) 5 .

3. The antibody-drug conjugate compound of claim 1 wherein m is 0 and n is 0.

4. The antibody-drug conjugate compound of claim 1 wherein m is 0 and n is 1.

5. The antibody-drug conjugate compound of claim 1 wherein L forms a disulfide bond with a cysteine amino acid of the antibody, and R 9 is C 2 -C 6 alkylene-O where alkylene is optionally substituted with F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F.

6. The antibody-drug conjugate compound of claim 1 wherein m is 1 and n is 1.

7. The antibody-drug conjugate compound of claim 1 wherein Pep is valine-citrulline.

8. The antibody-drug conjugate compound of claim 6 having the formula:

where AA1 and AA2 are independently selected from an amino acid side chain; p is an integer from 1 to 8.

9. The antibody-drug conjugate compound of claim 8 wherein the amino acid side chain is independently selected from H, —CH 3 , —CH 2 (C 6 H 5 ), —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , —CHCH(CH 3 )CH 3 , and —CH 2 CH 2 CH 2 NHC(O)NH 2 .

10. The antibody-drug conjugate compound of claim 9 having the formula:

11. The antibody-drug conjugate compound of claim 8 having the formula:

12. The antibody-drug conjugate compound of claim 11 having the formula:

13. The antibody-drug conjugate compound of claim 6 having the formula:

14. The antibody-drug conjugate compound of claim 13 having the formula:

15. The antibody-drug conjugate compound of claim 6 having the formula:

16. The antibody-drug conjugate compound of claim 15 having the formula:

17. The antibody-drug conjugate compound of claim 8 having the formula:

where R 7 is independently selected from H and C 1 -C 12 alkyl.

18. The antibody-drug conjugate compound of claim 1 where R a and R b form a five or six membered heterocyclyl group selected from N-methylpiperazinyl, morpholinyl, piperidyl, and pyrrolidinyl.

19. The antibody-drug co

Assignees

• Genentech Inc

Inventors

• Flygare John
• Pillow Thomas
• Safina Brian
• Verma Vishal
• Wei Binqing
• Denny William
• Giddens Anna
• Lee Ho
• Lu Guo-Liang
• Miller Christian
• REWCASTLE Gordon
• Tercel Moana
• Bonnet Muriel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/572

  Five-membered rings · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D209/60

  Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles · CPC title

• C07K5/06052 Primary

  Val-amino acid · CPC title