Bispecific antibody against CD3 and CD20 in combination therapy for treating diffuse large B-cell lymphoma

Patent metadata

Field	Value
Publication number	US-11548952-B2
Application number	US-202117560006-A
Country	US
Kind code	B2
Filing date	Dec 22, 2021
Priority date	Sep 10, 2020
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

Provided are methods of clinical treatment of diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and/or refractory DLBCL eligible for autologous stem cell transplant) in human subjects using a bispecific antibody which binds to CD3 and CD20 in combination with standard of care regimen of R-DHAX/C (rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin).

First claim

The invention claimed is:

1. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of (a) rituximab, (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin, wherein the bispecific antibody comprises:
(i) a first binding arm comprising a first antigen-binding region which binds to human CD3c (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 dose of 24 mg or 48 mg, and wherein rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin, and the bispecific antibody are administered in 21-day cycles,
wherein the bispecific antibody, rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin are administered in the same cycle for the first 3 cycles, and the bispecific antibody is administered alone for subsequent cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1 and an intermediate dose is administered on day 8 of cycle 1 before the dose of 24 mg or 48 mg on day 15 of cycle 1.

2. The method of claim 1 , wherein the bispecific antibody is administered at a dose of 24 mg.

3. The method of claim 1 , wherein the bispecific antibody is administered at a dose of 48 mg.

4. The method of claim 1 , wherein the bispecific antibody is administered once every week (weekly administration) for three and one-third 21-day cycles.

5. The method of claim 4 , wherein the subject planned to receive autologous stem cell transplant (ASCT) and wherein after the weekly administration, if high-dose therapy (HDT) for ASCT does not occur following the fourth 21-day cycle, then the bispecific antibody is administered once every two weeks (biweekly administration) as a monotherapy in 28-day cycles until ASCT is performed or for five 28-day cycles, whichever is earlier, and wherein if after five 28-day cycles of biweekly administration ASCT has not been performed, then the bispecific antibody is administered once every four weeks in 28-day cycles until ASCT is performed.

6. The method of claim 1 , wherein the priming dose is 0.16 mg and wherein the intermediate dose is 0.8 mg.

7. The method of claim 1 , wherein rituximab is administered once every three weeks for three 21-day cycles.

8. The method of claim 1 , wherein dexamethasone is administered once a day from day 1 to day 4 of the 21-day cycles and wherein dexamethasone is administered for three 21-day cycles.

9. The method of claim 1 , wherein cytarabine is administered twice every three weeks and wherein the administration of cytarabine twice every three weeks is performed for three 21-day cycles.

10. The method of claim 1 , wherein cytarabine is administered a total of twice over days 1-3 of a 21-day cycle and wherein the second administration of cytarabine is performed 12 hours after initiation of the first administration of cytarabine.

11. The method of claim 1 , wherein oxaliplatin is administered once every three weeks for three 21-day cycles.

12. The method of claim 1 , wherein carboplatin is administered once every three weeks for three 21-day cycles.

13. The method of claim 1 , wherein:
(a) the bispecific antibody is administered in 21-day cycles as follows:
(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; and
(ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15;

(b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3;
(c) oxaliplatin/carboplatin is administered in 21-day cycles on day 1 in cycles 1-3;
(d) cytarabine is administered in 21-day cycles on day 1 or days 1-2 or day 2 or days 2-3 in cycles 1-3; and
(e) dexamethasone is administered in 21-day cycles on days 1-4 in cycles 1-3.

14. The method of claim 1 , wherein rituximab is administered at a dose of 375 mg/m 2 , dexamethasone is administered at a dose of 40 mg/day, cytarabine is administered at a dose of 2 g/m 2 , oxaliplatin is administered at a dose of 100 mg/m 2 , and carboplatin is administered at a dose of AUC=5 mg/ml/min, as determined using Calvert's formula.

15. The method of claim 13 , wherein the bispecific antibody is administered once every two weeks in 28-day cycles from cycle 5 to cycle 9 or to when ASCT is performed, whichever is earlier, and wherein if ASCT is not performed by the end of cycle 9, the bispecific antibody is administered once every four weeks in 28-day cycles from cycle 10 to when ASCT is performed.

16. The method of claim 1 , wherein the bispecific antibody is administered subcutaneously.

17. The method of claim 1 , wherein rituximab is administered intravenously, and/or wherein dexamethasone is administered intravenously or orally, and/or wherein cytarabine is administered intravenously, and/or wherein oxaliplatin is administered intravenously, and/or wherein carboplatin is administered intravenously.

18. The method of claim 1 , wherein
(a) the DLBCL is double-hit or triple-hit DLBCL, and/or
(b) the DLBCL is follicular lymphoma Grade 3B, and/or
(c) the subject has relapsed after or is refractory to at least one prior therapy.

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

20. 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 wherein 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.

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

22. 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
(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 cor

Assignees

• Genmab As

Inventors

• Elliott Brian
• Ahmadi Tahamtan

Classifications

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• C07K16/2887 Primary

  against CD20 · CPC title

• C07K2317/31

  multispecific · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/2809 Primary

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