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

Patent metadata

Field	Value
Publication number	US-11845805-B2
Application number	US-202117558430-A
Country	US
Kind code	B2
Filing date	Dec 21, 2021
Priority date	Sep 10, 2020
Publication date	Dec 19, 2023
Grant date	Dec 19, 2023

Abstract

Provided are methods of clinical treatment of diffuse large B-cell lymphoma (DLBCL) (e.g., previously untreated, high-risk DLBCL) in human subjects using a bispecific antibody which binds to CD3 and CD20 in combination with standard of care regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

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) cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone, 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 heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the CDR1, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 6, and the VL comprises the CDR1, CDR2 and CDR3 sequences that are in the VL 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 and a VL, wherein the VH comprises the CDR1, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 13, and the VL comprises the CDR1, CDR2 and CDR3 sequences that are in the VL sequence of SEQ ID NO: 14;
wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles; and wherein
(a) a priming dose of the bispecific antibody is administered on day 1 of cycle 1 of the 21-day cycles, an intermediate dose of the bispecific antibody is administered on day 8 of cycle 1 of the 21-day cycles, a dose of 24 mg or 48 mg of the bispecific antibody is administered on day 15 of cycle 1 of the 21-day cycles, and a dose of 24 or 48 mg of the bispecific antibody is administered weekly starting on day 1 of cycle 2 of the 21-day cycles;
(b) rituximab is administered once every three weeks for six or eight 21-day cycles, and
(c) cyclophosphamide is administered once every three weeks for six or eight 21-day cycles, and
(d) doxorubicin is administered once every three weeks for six or eight 21-day cycles, and
(e) vincristine is administered once every three weeks for six or eight 21-day cycles, and
(f) prednisone is administered once a day from day 1 to day 5 of each 21-day cycles for six or eight 21-day cycles.

2. The method of claim 1 , wherein the bispecific antibody is administered at a weekly dose of 24 mg starting on day 1 of cycle 2 of the 21-day cycles.

3. The method of claim 1 , wherein the bispecific antibody is administered at a weekly dose of 48 mg starting on day 1 of cycle 2 of the 21-day cycles.

4. The method of claim 1 , wherein the weekly administration of 24 mg or 48 mg of the bispecific antibody is performed for three and one-third 21-day cycles.

5. The method of claim 4 , wherein after the weekly administration of the bispecific antibody for three and one-third 21-day cycles, the bispecific antibody is administered once every three weeks for two or four 21-day cycles.

6. The method of claim 5 , wherein after the administration of the bispecific antibody once every three weeks for two or four 21-day cycles, the bispecific antibody is administered once every four weeks in 28-day cycles for up to one year total duration of treatment with the bispecific antibody.

7. The method of claim 1 , wherein (a) the priming dose of the bispecific antibody is 0.16 mg, (b) intermediate dose of the bispecific antibody is 0.8 mg, or (c) the priming dose of the bispecific antibody is 0.16 mg and the intermediate dose of the bispecific antibody is 0.8 mg.

8. The method of claim 1 , wherein rituximab is administered at a dose of 375 mg/m 2 , cyclophosphamide is administered at a dose of 750 mg/m 2 , doxorubicin is administered at a dose of 50 mg/m 2 , vincristine is administered at a dose of 1.4 mg/m 2 , and prednisone is administered at a dose of 100 mg/day.

9. The method of claim 1 , wherein:
(a) the bispecific antibody is administered 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;
(ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15;
(iii) in cycles 5 and 6, a dose of 24 mg or 48 mg is administered on day 1;

(b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and
(c) prednisone is administered on days 1-5 in cycles 1-6.

10. The method of claim 9 , wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7.

11. The method of claim 1 , wherein:
(a) the bispecific antibody is administered 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;
(ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15;
(iii) in cycles 5-8, a dose of 24 mg or 48 mg is administered on day 1;

(b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and
(c) prednisone is administered on days 1-5 in cycles 1-8.

12. The method of claim 11 , wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9.

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

14. The method of claim 1 , wherein rituximab is administered intravenously, wherein cyclophosphamide is administered intravenously, wherein doxorubicin is administered intravenously, wherein vincristine is administered intravenously and wherein prednisone is administered intravenously or orally.

15. 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 an International Prognostic Index (IPI) score or Revised-IPI score>3, and/or
(d) the subject has not received prior therapy for DLBCL or follicular lymphoma Grade 3B.

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

17. 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.

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

19. The method of claim 1 , wherein the bispecific antibody comprises an inert Fc region.

20. 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 corresponding to K409

Assignees

• Genmab As

Inventors

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

Classifications

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07K16/2887 Primary

  against CD20 · CPC title

• A61K31/475

  having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375) · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title