Combination therapy of anti-CD20/anti-CD3 bispecific antibodies and 4-1BB (CD137) agonists

Patent metadata

Field	Value
Publication number	US-11718680-B2
Application number	US-202016820504-A
Country	US
Kind code	B2
Filing date	Mar 16, 2020
Priority date	Dec 20, 2016
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

The present invention relates to combination therapies employing anti-CD20/anti-CD3 bispecific antibodies and 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules, the use of these combination therapies for the treatment of cancer and methods of using the combination therapies.

First claim

The invention claimed is:

1. A method for treating or delaying progression of a proliferative disease that expresses CD20 and CD19 in a subject, wherein the method comprises administering to the subject an effective amount of an anti-CD20/anti-CD3 bispecific antibody and a 4-1BB agonist, wherein the anti-CD20/anti-CD3 bispecific antibody comprises: (a) a first antigen binding domain comprising a heavy chain variable region (V H CD3) comprising CDR-H1 sequence of SEQ ID NO:56, CDR-H2 sequency of SEQ ID NO:57, and CDR-H3 sequence of SEQ ID NO:58; and a light chain variable region (V L CD3) comprising CDR-L1 sequence of SEQ ID NO:59, CDR-L2 sequence of SEQ ID NO:60, and CDR-L3 sequence of SEQ ID NO:61; and (b) a second antigen binding domain comprising a heavy chain variable region (V H CD20) comprising CDR-H1 sequence of SEQ ID NO:64, CDR-H2 sequence of SEQ ID NO:65, and CDR-H3 sequence of SEQ ID NO:66; and a light chain variable region (V L CD20) comprising CDR-L1 sequence of SEQ ID NO:67, CDR-L2 sequence of SEQ ID NO:68, and CDR-L3 sequence of SEQ ID NO:69; and wherein the 4-1BB agonist comprises: (c) three ectodomains of 4-1BBL that independently comprise an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO: 6, SEQ ID NO:7, and SEQ ID NO:8; and (d) a CD19 heavy chain variable region (V H CD19) comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 15, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 17; and a CD19 light chain variable region (V L CD19) comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:20; or a CD19 heavy chain variable region (V H CD19) comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11; and a CD19 light chain variable region (V L CD19) comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:14.

2. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist are administered together in a single composition or administered separately in two or more different compositions.

3. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist are administered intravenously or subcutaneously.

4. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody is administered concurrently with, prior to, or subsequently to the 4-1BB agonist.

5. The method of claim 1 , wherein the proliferative disease is cancer.

6. The method of claim 1 , wherein the proliferative disease is a B cell proliferative disorder.

7. The method of claim 6 , wherein the B cell proliferative disorder is selected from the group consisting of Non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), marginal zone lymphoma (MZL), Multiple myeloma (MM), and Hodgkin lymphoma (HL).

8. The method of claim 1 , wherein each of the three ectodomains of 4-1BBL or fragments thereof independently comprises an amino acid sequence of SEQ ID NO:1 or SEQ ID NO:5.

9. The method of claim 1 , wherein the 4-1BB agonist comprises at least one antigen binding domain and an IgG Fc domain.

10. The method of claim 9 , wherein the IgG Fc domain is an IgG1 Fc domain or an IgG4 Fc domain.

11. The method of claim 9 , wherein the 4-1BB agonist comprises at least one antigen binding domain and an Fc domain comprising one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function.

12. The method of claim 1 , wherein the 4-1BB agonist comprises a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises two ectodomains of 4-1BBL or fragments thereof that are connected to each other by a peptide linker and the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof.

13. The method of claim 1 , wherein the 4-1BB agonist comprises a polypeptide comprising three ectodomains of 4-1BBL or fragments thereof that are connected to each other by peptide linkers.

14. The method of claim 1 , wherein the 4-1BB agonist comprises:
(a) at least one antigen binding domain,
(b) a polypeptide comprising three ectodomains of 4-1BBL or fragments thereof that are connected to each other by peptide linkers, and
(c) an Fc domain composed of a first subunit and a second subunit capable of stable association, wherein the polypeptide comprising the three ectodomains of 4-1BBL or fragments thereof that are connected to each other by peptide linkers is fused to the N- or C-terminal amino acid of one of the two subunits of the Fc domain.

15. The method of claim 14 , wherein the polypeptide comprising the three ectodomains of 4-1BBL or fragments thereof that are connected to each other by peptide linkers is fused to the N- or C-terminal amino acid of one of the two subunits of the Fc domain through a peptide linker.

16. The method of claim 1 , wherein the first antigen binding domain comprises a CD3 heavy chain variable region (V H CD3) comprising the amino acid sequence of SEQ ID NO:62 and/or a CD3 light chain variable region (V L CD3) comprising the amino acid sequence of SEQ ID NO:63.

17. The method of claim 1 , wherein the second antigen binding domain comprises a CD20 heavy chain variable region (V H CD20) comprising the amino acid sequence of SEQ ID NO:70 and/or a CD20 light chain variable region (V L CD20) comprising the amino acid sequence of SEQ ID NO:71.

18. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody comprises a third antigen binding domain that binds to CD20.

19. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody comprises an Fc domain comprising one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function.

20. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist are administered at intervals from about one week to three weeks.

21. The method of claim 1 , wherein the subject is pretreated with a Type II anti-CD20 antibody prior to administration of the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist, and wherein the period of time between the pretreatment and the administration of the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist is sufficient for the reduction of B-cells in the individual in response to the Type II anti-CD20 antibody.

22. The method of claim 21 , wherein the Type II anti-CD20 antibody is obinutuzumab.

23. The method of claim 1 , wherein the anti-CD20/anti-CD3 bispecific antibody and the 4-1BB agonist are administered in combination with an agent blocking PD-L1/PD-1 interaction.

24. The method of claim 23 , wherein the agent blocking PD-L1/PD-1 interaction is an anti-PD-L1 antibody or an anti-PD1 antibody.

25. The method of claim 24 , wherein the agent bl

Assignees

• Hoffmann La Roche

Inventors

• Bacac Marina
• Ferrara Koller Claudia
• Klein Christian
• Perro Mario
• Sam Johannes
• Umaña Pablo
• Xu Wei

Classifications

• C07K2319/75

  containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones · CPC title

• C07K2317/66

  comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1 · CPC title

• C07K16/468

  Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies · CPC title

• C07K16/2809

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title