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-2016354485-A1
Application number	US-201615182444-A
Country	US
Kind code	A1
Filing date	Jun 14, 2016
Priority date	Dec 16, 2013
Publication date	Dec 8, 2016
Grant date	—

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; L is a linker having the formula:
-Str-(Pep) m -(Sp) n -
where Str is a stretcher unit covalently attached to the antibody; Pep is an optional peptide unit of two to twelve amino acid residues, Sp is an optional spacer unit covalently attached to a dimer drug moiety, and m and n are independently selected from 0 and 1; p is an integer from 1 to 8; 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 , or 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 selected from:

where the wavy line indicates the site of attachment to T;
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;
R 4 is H, CO 2 R, or a bond to L, where R is C 1 -C 6 alkyl or benzyl; and
R 5 is H or C 1 -C 6 alkyl; wherein the antibody binds to Napi2b and
the antibody 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:75;
HVR-L2 comprises the amino acid sequence of SEQ ID NO:76;
HVR-L3 comprises the amino acid sequence of SEQ ID NO:77.
HVR-H1 comprises the amino acid sequence of SEQ ID NO:78;
HVR-H2 comprises the amino acid sequence of SEQ ID NO:79; and
HVR-H3 comprises the amino acid sequence of SEQ ID NO:80; or
the antibody comprises a light chain hypervariable region comprising the amino acid sequence of SEQ ID NO:81 or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:82.

2 . The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

wherein 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.

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

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

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

6 . The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

wherein 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.

7 . The antibody-drug conjugate compound of claim 1 wherein Str has the formula:

wherein 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.

8 . The antibody-drug conjugate compound of claim 7 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 , or C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F.

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

10 . The antibody-drug conjugate compound of claim 1 wherein m is 1 and Pep comprises two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

11 . The antibody-drug conjugate compound of claim 10 wherein Pep is valine-citrulline.

12 . The antibody-drug conjugate compound of claim 1 wherein n is 1 and Sp comprises para-aminobenzyl or para-aminobenzyloxycarbonyl.

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

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

14 . The antibody-drug conjugate compound of claim 13 wherein the amino acid side chain is independently selected from H, —CH 3 , —CH 2 (C 6 Hs), —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 , or —CH 2 CH 2 CH 2 NHC(O)NH 2 .

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

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

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

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

19 . The antibody-drug conjugate compound of claim 18 having the formula:

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

21 . The antibody-drug conjugate compound of c

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• C07D209/60

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

• A61K47/6869

  the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · 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