Splicing modulator antibody-drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-12514926-B2
Application number	US-202418581307-A
Country	US
Kind code	B2
Filing date	Feb 19, 2024
Priority date	Jun 1, 2018
Publication date	Jan 6, 2026
Grant date	Jan 6, 2026

Abstract

Linker-drug compounds and antibody-drug conjugates that bind to human oncology targets are disclosed. The linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for use in the treatment of neoplastic disorders by administering the antibody-drug conjugates provided herein. In an embodiment, the splicing modulator comprises a pladienolide or a pladienolide derivative.

First claim

The invention claimed is:

1 . A compound of Formula (VI-A):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 9 are each independently chosen from absent, hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(=O)—(C 1 -C 6 alkyl) groups, and —CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(=O)—(C 1 -C 6 alkyl) groups;
R 4 , R 5 , and R 8 are each independently chosen from hydrogen, hydroxyl, —O—(C 1 -C 6 alkyl) groups, —O—C(=O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups;
R 6 and R 7 are each independently chosen from hydrogen, —O—R 17 , —O—C(=O)—R 17 , —O—C(=O)—NR 15 R 16 , C 1 -C 6 alkyl groups, and —NR 15 R 16 ;
R 10 is chosen from hydrogen, C 1 -C 6 alkyl groups, —C(=O)—(C 1 -C 6 alkyl) groups, and —CD 3 ;
R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(=O)—R 17 , and —C(=O)—O—R 17 ;
R 17 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups; and
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 alkyl) groups, —NR 15 R 16 , C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkylhydroxy groups, C 1 -C 6 alkylalkoxy groups, benzyl groups, and C 3 -C 8 heterocyclyl groups;
wherein at least one of R 6 and R 7 is hydrogen;
wherein R 1 and R 9 cannot both be absent; and
L is a linker.

2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:

3 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:

4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L comprises a cleavable peptide moiety.

5 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the cleavable peptide moiety comprises valine-citrulline (Val-Cit), valine-alanine (Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), or alanine-alanine-asparagine (Ala-Ala-Asn).

6 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises at least one spacer unit comprising: (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).

7 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises a maleimide (Mal) moiety.

8 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises maleimidocaproyl (MC).

9 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC).

10 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises MC-Val-Cit-pAB, MC-Val-Ala-pAB, MC-Glu-Val-Cit-pAB, MC-Ala-Ala-Asn-pAB, MC-Val-Cit-pABC, MC-Val-Ala-pABC, MC-Glu-Val-Cit-pABC, or MC-Ala-Ala-Asn-pABC.

11 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L comprises a cleavable glucuronide moiety.

12 . The compound or pharmaceutically acceptable salt of claim 11 , wherein the cleavable glucuronide moiety is cleavable by a glucuronidase.

13 . The compound or pharmaceutically acceptable salt of claim 11 , wherein the linker L comprises MC-β-glucuronide-pAB or MC-β-glucuronide-pABC.

14 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L is a non-cleavable linker comprising at least one spacer unit.

15 . The compound or pharmaceutically acceptable salt of claim 14 , wherein the linker L comprises a maleimide moiety.

16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein the at least one spacer unit comprises (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).

17 . The compound or pharmaceutically acceptable salt of claim 16 , wherein the linker L is chosen from:

and

18 . An antibody-drug conjugate of Formula (I):
Ab-(L-D) p   (I)
wherein: Ab is an antibody or antigen binding fragment which targets a neoplastic cell; L-D is a compound or pharmaceutically acceptable salt of claim 1 ; and p is an integer from 1 to 15.

19 . The antibody-drug conjugate of claim 18 , wherein L-D is a compound of formula:

or a pharmaceutically acceptable salt thereof.

20 . The antibody-drug conjugate of claim 18 , wherein L-D is a compound of formula:

or a pharmaceutically acceptable salt thereof.

21 . The antibody-drug conjugate of claim 18 , wherein the linker L comprises a cleavable peptide moiety.

22 . The antibody-drug conjugate of claim 21 , wherein the cleavable peptide moiety comprises valine-citrulline (Val-Cit), valine-alanine (Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), or alanine-alanine-asparagine (Ala-Ala-Asn).

23 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises at least one spacer unit comprising: (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).

24 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises a maleimide (Mal) moiety.

25 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises maleimidocaproyl (MC).

26 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC).

27 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises MC-Val-Cit-pAB, MC-Val-Ala-pAB, MC-Glu-Val-Cit-pAB, MC-Ala-Ala-Asn-pAB, MC-Val-Cit-pABC, MC-Val-Ala-pABC, MC-Glu-Val-Cit-pABC, or MC-Ala-Ala-Asn-pABC.

28 . The antibody-drug conjugate of claim 18 , wherein the linker L comprises a cleavable glucuronide moiety.

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Pazolli Ermira
• Buonamici Silvia
• Samarakoon Thiwanka
• Prajapati Sudeep
• Fishkin Nathan
• Palacino James
• Seiler Michael
• Zhu Ping
• Cook Andrew
• Smith Peter
• Liu Xiang
• Ellery Shelby
• Reynolds Dominic
• Yu Lihua
• Wu Zhenhua
• Peng Shouyong
• Calandra Nicholas
• Sheehan Megan
• Xiao Yonghong

Classifications

• G01N33/575

  for cancer · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K39/00

  Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) · CPC title

• G01N2500/10

  involving cells · CPC title

• G01N33/5011

  for testing antineoplastic activity · CPC title