Eribulin-based antibody-drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-10322192-B2
Application number	US-201815892921-A
Country	US
Kind code	B2
Filing date	Feb 9, 2018
Priority date	Mar 2, 2016
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Linker toxins and antibody-drug conjugates that bind to human oncology antigen targets such as folate receptor alpha and/or provide anti-tubulin drug activity are disclosed. The linker toxins and antibody-drug conjugates comprise an eribulin drug moiety and can be internalized into target antigen-expressing cells. The disclosure further relates to methods and compositions for use in the treatment of cancer by administering the antibody-drug conjugates provided herein.

First claim

The invention claimed is:

1. An antibody-drug conjugate of Formula (I):
Ab-(L-D) p   (I)

wherein
Ab is an internalizing anti-folate receptor alpha antibody or internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO:2 (HCDR1), SEQ ID NO:3 (HCDR2), and SEQ ID NO:4 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO:7 (LCDR1), SEQ ID NO:8 (LCDR2), and SEQ ID NO:9 (LCDR3), as defined by the Kabat numbering system; or three heavy chain complementarity determining regions (HCDRs) 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 (LCDRs) comprising amino acid sequences of SEQ ID NO:16 (LCDR1), SEQ ID NO:17 (LCDR2), and SEQ ID NO:18 (LCDR3), as defined by the IMGT numbering system;
D is eribulin;
L is a cleavable linker comprising Mal-(PEG) 2 -Val-Cit-pAB; and
p is an integer from 1 to 8.

2. The antibody-drug conjugate of claim 1 , 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; and wherein p is an integer from 3 to 4.

3. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant domain and a human Ig kappa light chain constant domain.

4. A pharmaceutical composition comprising the antibody-drug conjugate of claim 1 , and a pharmaceutically acceptable carrier.

5. A composition comprising multiple copies of the antibody-drug conjugate of claim 1 , wherein the average p of the antibody-drug conjugates in the composition is from about 3.2 to about 4.4.

6. A composition comprising multiple copies of an antibody-drug conjugate of Formula (I):
Ab-(L-D) p   (I)

wherein
Ab is an internalizing anti-folate receptor alpha antibody or internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO:2 (HCDR1), SEQ ID NO:3 (HCDR2), and SEQ ID NO:4 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO:7 (LCDR1), SEQ ID NO:8 (LCDR2), and SEQ ID NO:9 (LCDR3), as defined by the Kabat numbering system; or three heavy chain complementarity determining regions (HCDRs) 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 (LCDRs) comprising amino acid sequences of SEQ ID NO:16 (LCDR1), SEQ ID NO:17 (LCDR2), and SEQ ID NO:18 (LCDR3), as defined by the IMGT numbering system;
D is eribulin;
L is a cleavable linker comprising Mal-(PEG) 2 -Val-Cit-pAB; and
p is the average number of -L-D moieties per Ab, wherein the average p of the antibody-drug conjugates in the composition is from about 3.6 to about 4.4.

7. The composition of claim 6 , 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.

8. A method of treating a patient having a cancer that expresses folate receptor alpha, comprising administering to the patient a therapeutically effective amount of the antibody-drug conjugate of claim 1 .

9. The method of claim 5 , wherein the cancer is a gastric cancer, a serous ovarian cancer, a clear cell ovarian cancer, a non-small cell lung cancer, a colorectal cancer, a triple negative breast cancer, an endometrial cancer, a lung carcinoid, an osteosarcoma, a bladder cancer, or an urothelial cell carcinoma.

10. The method of claim 8 , wherein the cancer is a serous endometrial carcinoma.

11. A method of reducing or inhibiting growth of a folate receptor alpha-expressing tumor in a patient, comprising administering to the patient a therapeutically effective amount of the antibody-drug conjugate of claim 1 .

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Albone Earl F
• Cheng Xin
• Custar Daniel W
• Furuuchi Keiji
• Li Jing
• Majumder Utpal
• Uenaka Toshimitsu

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/92

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

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• C07K2317/77

  Internalization into the cell · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title