Bispecific antibodies against CD3 and CD20 for treating chronic lymphocytic leukemia

Patent metadata

Field	Value
Publication number	US-11858995-B2
Application number	US-202117559935-A
Country	US
Kind code	B2
Filing date	Dec 22, 2021
Priority date	Sep 10, 2020
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

Provided are methods of clinical treatment of chronic lymphoblastic leukemia (CLL) in human subjects using a bispecific antibody which binds to CD3 and CD20.

First claim

We claim:

1. A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising subcutaneously administering to the subject a bispecific antibody comprising:
(i) a first binding arm comprising a first antigen-binding region which binds to human CD3ε (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and
(ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14;
wherein the bispecific antibody is administered at a full dose ranging from 12-60 mg in 28-day cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1, and an intermediate dose of the bispecific antibody is administered on day 8 of cycle 1 before administration of the first full dose of the bispecific antibody on day 15 of cycle 1, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose; and
wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs.

2. The method of claim 1 , wherein after administration of the priming dose and the intermediate dose the bispecific antibody is administered at a full dose of 24 mg.

3. The method of claim 1 , wherein after administration of the priming dose and the intermediate dose the bispecific antibody is administered at a full dose of 48 mg.

4. The method of claim 1 , wherein the bispecific antibody is administered once every week (weekly administration) for 2.5 28-day cycles.

5. The method of claim 4 , wherein after the weekly administration, the bispecific antibody is administered once every two weeks (biweekly administration) for six 28-day cycles.

6. The method of claim 5 , wherein after the biweekly administration, the bispecific antibody is administered once every four weeks.

7. The method of claim 1 , wherein the priming dose is in the range of 0.05-0.35 mg.

8. The method of claim 1 , wherein said priming dose is 0.16 mg or about 0.16 mg.

9. The method of claim 1 , wherein said intermediate dose is in the range of 0.6-1.2 mg.

10. The method of claim 1 , wherein said intermediate dose is 0.8 mg or about 0.8 mg.

11. The method of claim 1 , wherein the bispecific antibody is administered in 28-day cycles, wherein:
a) in cycle 1, a priming dose is administered on day 1, an intermediate dose on day 8, and a full dose of 12-60 mg on days 15 and 22;
b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22;
c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and
d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1.

12. The method of claim 11 , wherein the full dose is 24 mg or about 24 mg.

13. The method of claim 11 , wherein the full dose is 48 mg or about 48 mg.

14. The method of claim 1 , wherein the CLL is relapsed and/or refractory CLL.

15. The method of claim 1 , wherein the subject is intolerant to a BTK inhibitor or wherein the subject has received at least two prior lines of antineoplastic therapy.

16. The method of claim 1 , wherein the CLL is refractory to a BTK inhibitor or wherein the CLL relapsed during treatment with a BTK inhibitor.

17. The method of claim 1 , wherein the subject has refractory and/or relapsed CLL after receiving the two prior antineoplastic therapies.

18. The method of claim 1 , wherein:
(i) the first antigen-binding region comprises a VH region comprising the amino acid sequence of SEQ ID NO: 6, and a VL region comprising the amino acid sequence of SEQ ID NO: 7; and
(ii) the second antigen-binding region comprises a VH region comprising the amino acid sequence of SEQ ID NO: 13, and a VL region comprising the amino acid sequence of SEQ ID NO: 14.

19. The method of claim 1 , wherein the first binding arm of the bispecific antibody is derived from a humanized antibody and comprises a λ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 22 and/or the second binding arm of the bispecific antibody is derived from a human antibody and comprises a κ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 23.

20. The method of claim 1 , wherein the bispecific antibody is a full-length antibody with a human IgG1 constant region.

21. The method of claim 1 , wherein the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein
(i) in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively, and/or
(ii) in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.

22. The method of claim 1 , wherein the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.

23. The method of claim 1 , wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.

24. The method of claim 1 , wherein the bispecific antibody is epcoritamab, or a biosimilar thereof, wherein the biosimilar comprises:
(i) a first binding arm comprising a VH region comprising the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and a VL region comprising the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and
(ii) a second binding arm comprising a VH region comprising the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and a VL region comprising the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14.

25. A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising subcutaneously administering to the subject a bispecific antibody comprising:
a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively, wherein the bispecific antibody is administered at a dose ranging from 12-60 mg in 28-day cycles, wherein:
a) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose

Assignees

• Genmab As

Inventors

• Elliott Brian
• Chen Jenny Jianlin
• Ahmadi Tahamtan
• Chiu Christopher W L
• Breij Esther C W
• Hiemstra Ida
• Jure-Kunkel Maria N

Classifications

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title

• C07K16/2887

  against CD20 · CPC title

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title