Splicing modulator antibody-drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-12172986-B2
Application number	US-201917059635-A
Country	US
Kind code	B2
Filing date	May 31, 2019
Priority date	Jun 1, 2018
Publication date	Dec 24, 2024
Grant date	Dec 24, 2024

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. 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;
D is a splicing modulator of the formula:

or a pharmaceutically acceptable salt thereof, or of the formula:

or a pharmaceutically acceptable salt thereof;
L is a linker which covalently attaches Ab to D; and
p is an integer from 1 to 15.

2. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen binding fragment targets a neoplastic cell derived from a hematological malignancy selected from acute myeloid leukemia and multiple myeloma or a solid tumor selected from a B-cell malignancy, a leukemia, a lymphoma, and a myeloma.

3. The antibody-drug conjugate of claim 2 , wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, cervical cancer, pancreatic cancer, kidney cancer, colorectal cancer, and esophageal cancer.

4. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen binding fragment targets a HER2-expressing cell, wherein the antibody or antigen binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3); and/or wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 19, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:20.

5. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen binding fragment targets a CD138-expressing cell; wherein the antibody or antigen binding fragment comprises three heavy chain complementarity determining (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), and SEQ ID NO:9 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2), and SEQ ID NO:12 (LCDR3); and/or wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:21, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:22.

6. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen binding fragment targets an EPHA2-expressing cell; wherein the antibody or antigen binding fragment comprises three heavy chain complementarity determining (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 13 (HCDR1), SEQ ID NO: 14 (HCDR2), and SEQ ID NO:15 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 16 (LCDR1), SEQ ID NO: 17 (LCDR2), and SEQ ID NO: 18 (LCDR3); and/or wherein the antibody or antigen binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:23, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:24.

7. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen binding fragment comprises a human IgG heavy chain constant region and/or wherein the antibody or antigen binding fragment comprises a human Ig kappa light chain constant region.

8. The antibody-drug conjugate of claim 1 , wherein the linker L is a cleavable linker comprising a cleavable moiety, wherein the cleavable moiety comprises a cleavable peptide moiety or a cleavable glucuronide moiety.

9. The antibody-drug conjugate of claim 8 , wherein the cleavable peptide moiety comprises valine-alanine (Val-Ala) or valine-citrulline (Val-Cit).

10. The antibody-drug conjugate of claim 8 , wherein the linker attaches to the antibody or antigen binding fragment via a maleimide (Mal) moiety.

11. The antibody-drug conjugate of claim 10 , wherein the Mal moiety comprises a maleimidocaproyl (MC).

12. The antibody-drug conjugate of claim 11 , wherein the linker comprises MC-Val-Cit or MC-Val-Ala.

13. The antibody-drug conjugate of claim 12 , wherein the MC is joined to the antibody or antigen binding fragment via a cysteine residue on the antibody or antigen binding fragment.

14. The antibody-drug conjugate of claim 8 , wherein the linker comprises a spacer unit, wherein:
(a) the spacer unit comprises a polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises -(PEG) m - and m is an integer from 1 to 10, or
(b) the spacer unit comprises an alkyl moiety, wherein the alkyl moiety comprises —(CH 2 ) n — and n is an integer from 1 to 10.

15. The antibody-drug conjugate of claim 14 , wherein the spacer unit attaches to the antibody or antigen binding fragment via a maleimide (Mal) moiety (“Mal-spacer unit”).

16. The antibody-drug conjugate of claim 15 , wherein the Mal-spacer unit is joined to the antibody or antigen binding fragment via a cysteine residue on the antibody or antigen binding fragment.

17. The antibody-drug conjugate of claim 15 , wherein the Mal-spacer unit comprises an alkyl moiety, and/or a PEG moiety.

18. The antibody-drug conjugate of claim 8 , wherein a spacer unit attaches the cleavable moiety in the linker L to the splicing modulator.

19. The antibody-drug conjugate of claim 18 , wherein cleavage of the cleavable moiety releases the splicing modulator from the antibody or antigen binding fragment and linker.

20. The antibody-drug conjugate of claim 18 , wherein the spacer unit attaching the cleavable moiety in the linker to the splicing modulator is self-immolative.

21. The antibody-drug conjugate of claim 18 , wherein the spacer unit attaching the cleavable moiety in the linker to the splicing modulator comprises a p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC).

22. The antibody-drug conjugate of claim 21 , wherein the pAB or pABC attaches the cleavable moiety in the linker to the splicing modulator.

23. The antibody-drug conjugate of claim 21 , wherein the linker comprises Val-Cit-pAB, Val-Ala-pAB, Val-Cit-pABC or Val-Ala-pABC.

24. The antibody-drug conjugate of claim 1 , wherein the linker is a non-cleavable linker.

25. The antibody-drug conjugate of claim 1 , wherein the linker L comprises:

26. The antibody-drug conjugate of claim 1 , wherein the splicing modulator D is:

or a pharmaceutically acceptable salt thereof.

27. The antibody-drug conjugate of claim 1 , wherein the splicing modulator D is:

or a pharmaceutically acceptable salt thereof.

28. The antibody-drug conjugate of 1

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

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6851 Primary

  the antibody targeting a determinant of a tumour cell · CPC title