IP Library › Granted Patent US 12,281,153
Granted Patent B2
US 12,281,153 · App. 17/017,942 · Granted Apr 22, 2025

Combination therapy with targeted 4-1BB (CD137) agonists

Inventors: Christina Claus (Ennetbaden, CH); Claudia Ferrara Koller (Zug, CH); Christian Klein (Bonstetten, CH); Johannes Sam (Baden, CH); Pablo Umana (Wollerau, CH)
Assignee: Hoffmann-La Roche Inc.
C07K14/70575A61K39/39541A61K39/39558A61P35/00C07K16/2878C07K16/3007C07K16/32C07K16/40A61K2039/507C07K2317/31C07K2319/30C07K2319/33
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Quick Facts
Patent No.
US 12,281,153
App. No.
17/017,942
Granted
Apr 22, 2025
Kind
B2
Abstract

The present invention relates to combination therapies employing 4-1BB (CD137) agonists, in particular 4-1BBL trimer containing antigen binding molecules, in combination with HER-2 targeting agents, the use of these combination therapies for the treatment of cancer, and methods of using the combination therapies.

Claims (35)

1. A method for treating or delaying progression of a HER2-positive cancer in a subject comprising administering to the subject an effective amount of a 4-1BB agonist and an effective amount of a HER-2 targeting agent, wherein the HER-2 targeting agent is trastuzumab, pertuzumab, and/or trastuzumab emtansine, wherein the 4-1BB agonist is an antigen binding molecule comprising at least one antigen binding domain capable of specific binding to a tumor-associated antigen,

wherein the 4-1BB agonist is a molecule comprising three ectodomains of 4-1BBL or 4-1BB-binding fragments thereof and wherein the ectodomains of 4-1BBL comprise the amino acid sequence 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 or SEQ ID NO:8 and an IgG1 Fc domain comprising the amino acid substitutions L234A, L235A and P329G, as numbered according to EU numbering.

2. The method of claim 1 , wherein the 4-1BB agonist and the HER-2 targeting agent are administered together in a single composition or administered separately in two or more different compositions.

3. The method of claim 1 , wherein the 4-1BB agonist and the HER-2 targeting agent are administered intravenously or subcutaneously.

4. The method of claim 1 , wherein the 4-1BB agonist is administered concurrently with, prior to, or subsequently to the HER-2 targeting agent.

5. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising at least one antigen binding domain capable of specific binding to a tumor-associated antigen.

6. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising at least one antigen binding domain capable of specific binding to a tumor-associated antigen selected from the group consisting of Fibroblast activation protein (FAP) and Carcinoembryonic Antigen (CEA).

7. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising three ectodomains of 4-1BBL or fragments thereof and at least one antigen binding domain capable of specific binding to Fibroblast activation protein (FAP).

8. The method of claim 1 , wherein the antigen binding domain capable of specific binding to a tumor-associated antigen is an antigen binding domain capable of specific binding to FAP comprising:

(a) a heavy chain variable region (V H FAP) 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 light chain variable region (V L FAP) 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, or

(b) a heavy chain variable region (V H FAP) 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 a light chain variable region (V L FAP) 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.

9. The method of claim 1 , wherein the antigen binding domain capable of specific binding to a tumor-associated antigen is an antigen binding domain capable of specific binding to FAP comprising a heavy chain variable region (V H FAP) comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region (V L FAP) comprising the amino acid sequence of SEQ ID NO:22 or wherein the antigen binding domain capable of specific binding to FAP comprises a heavy chain variable region (V H FAP) comprising the amino acid sequence of SEQ ID NO:23 and a light chain variable region (V L FAP) comprising the amino acid sequence of SEQ ID NO:24.

10. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising:

(a) at least one antigen binding domain capable of specific binding to FAP,

(b) a first 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 in that the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof.

11. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising:

(a) at least one Fab domain capable of specific binding to FAP comprising a heavy chain variable region (V H FAP) comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region (V L FAP) comprising the amino acid sequence of SEQ ID NO:22 or a heavy chain variable region (V H FAP) comprising the amino acid sequence of SEQ ID NO:23 and a light chain variable region (V L FAP) comprising the amino acid sequence of SEQ ID NO:24, and

(b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32 and in that the second polypeptide comprises the 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.

12. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising a first heavy chain comprising the amino acid sequence of SEQ ID NO:41, a first light chain comprising the amino acid sequence of SEQ ID NO:42, a second heavy chain comprising the amino acid sequence of SEQ ID NO:43 and a second light chain comprising the amino acid sequence of SEQ ID NO:44.

13. The method of claim 1 , wherein the 4-1BB agonist is an anti-FAP/anti-4-1BB bispecific antibody.

14. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising three ectodomains of 4-1BBL or fragments thereof and at least one antigen binding domain capable of specific binding to CEA.

15. The method of claim 1 , wherein the antigen binding domain capable of specific binding to a tumor-associated antigen is an antigen binding domain capable of specific binding to CEA comprising (a) a heavy chain variable region (V H CEA) comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:33, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:34, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:35, and a light chain variable region (V L CEA) comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:37, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:38.

16. The method of claim 1 , wherein the antigen binding domain capable of specific binding to a tumor-associated antigen is an antigen binding domain capable of specific binding to CEA comprising a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:39 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:40.

17. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising:

(a) at least one antigen binding domain capable of specific binding to CEA,

(b) a first 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 in that the second polypeptide comprises one ectodomain of 4-1BBL or a fragment thereof.

18. The method of claim 1 , wherein the 4-1BB agonist is an antigen binding molecule comprising:

(a) at least one Fab domain capable of specific binding to CEA comprising a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:39 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:40, and

(b) a first and a second polypeptide that are linked to each other by a disulfide bond, wherein the antigen binding molecule is characterized in that the first polypeptide comprises the amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32 and in that the second polypeptide comprises the 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.

19. The method of claim 1 , wherein the 4-1BB agonist is an anti-CEA/anti-4-1BB bispecific antibody.

20. The method of claim 1 , wherein the 4-1BB agonist and the HER-2 targeting agent are administered together in a single composition or administered separately in two or more different compositions.

21. The method of claim 1 , wherein the 4-1BB agonist acts synergistically with the HER-2 targeting agent.

22. The method of claim 1 , wherein said cancer is gastric cancer.

23. The method of claim 7 , wherein said cancer is gastric cancer.

24. The method of claim 8 , wherein said cancer is gastric cancer.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2022
From: CLAUS, CHRISTINA; FERRARA KOLLER, CLAUDIA; KLEIN, CHRISTIAN; SAM, JOHANNES; UMANA, PABLO
To: ROCHE GLYCART AG
Reel/Frame 061702/0300 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2022
From: ROCHE GLYCART AG
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 061702/0329 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2022
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 061702/0338 →
Priority Claims (1)
EP 18161340 · Mar 13, 2018 · regional
Continuity (2)
Continuation PCTEP2019056067 · Mar 12, 2019
Related Publication 20210095002A1 · Apr 1, 2021
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