US2020325225A1PendingUtilityA1
Combination therapy with targeted 4-1bb (cd137) agonists

Assignee: HOFFMANN LA ROCHEPriority: Dec 19, 2016Filed: Mar 20, 2020Published: Oct 15, 2020
Est. expiryDec 19, 2036(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:Marina Bacac Christina Claus Claudia Ferrara Koller Christian Klein Sabine Lang Viktor Levitski Pablo Umana
C07K 2317/71C07K 2317/60C07K 2317/526C07K 16/3007C07K 16/2878C07K 16/2863C07K 16/2809C07K 16/2803C07K 14/5255A61K 39/395C07K 2317/55C07K 16/40A61P 35/00A61K 2300/00A61K 2039/507A61K 2039/54A61K 2039/545C07K 14/70575C07K 2317/565A61P 43/00C07K 2317/31A61K 2039/505
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References
Claims
Abstract

The present invention relates to combination therapies employing tumor targeted anti-CD3 bispecific antibodies and/or agents blocking PD-L1/PD-1 interaction in combination with 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.
Claims

exact text as granted — not AI-modified
1 .- 50 . (canceled) 
     
     
         51 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-CD3 bispecific antibody specific for a tumor-associated antigen and of a 4-1BB agonist. 
     
     
         52 . The method of  claim 51 , wherein the proliferative disease is cancer. 
     
     
         53 . The method of  claim 52 , wherein the cancer is selected from the group consisting of colon cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, breast cancer, kidney cancer, esophageal cancer, and prostate cancer. 
     
     
         54 . The method of  claim 51 , wherein the 4-1BB agonist comprises three ectodomains of 4-1BBL or fragments thereof. 
     
     
         55 . The method of  claim 54 , wherein each of the three ectodomains of 4-1BBL or fragments thereof independently comprises 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. 
     
     
         56 . The method of  claim 51 , wherein the T-cell activating anti-CD3 bispecific antibody specific for a tumor-associated antigen and the 4-1BB agonist are administered in combination with an agent blocking PD-L1/PD-1 interaction. 
     
     
         57 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-carcinoembroynic antigen (CEA)/anti-CD3 bispecific antibody and of a 4-1BB agonist. 
     
     
         58 . The method of  claim 57 , wherein the T-cell activating anti-CEA/anti-CD3 bispecific antibody comprises a first antigen binding domain comprising a heavy chain variable region (V H CD3) and a light chain variable region (V L CD3); and a second antigen binding domain comprising a heavy chain variable region (V H CEA) and a light chain variable region (V L CEA). 
     
     
         59 . The method of  claim 58 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:41, CDR-H2 sequence of SEQ ID NO:42, and CDR-H3 sequence of SEQ ID NO:43, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:44, CDR-L2 sequence of SEQ ID NO:45, and CDR-L3 sequence of SEQ ID NO:46, or
 (b) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:49, CDR-H2 sequence of SEQ ID NO:50, and CDR-H3 sequence of SEQ ID NO:51, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:52, CDR-L2 sequence of SEQ ID NO:53, and CDR-L3 sequence of SEQ ID NO:54.   
     
     
         60 . The method of  claim 58 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:47 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:48, or
 (b) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:55 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56.   
     
     
         61 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-folate receptor alpha (FolR1)/anti-CD3 bispecific antibody and of a 4-1BB agonist. 
     
     
         62 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-melanoma-associated chondroitin sulfate proteoglycan (MCSP)/anti-CD3 bispecific antibody and of a 4-1BB agonist. 
     
     
         63 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-CD3 bispecific antibody specific for a tumor-associated antigen and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to fibroblast activation protein (FAP). 
     
     
         64 . The method of  claim 63 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises three ectodomains of 4-1BBL or fragments thereof. 
     
     
         65 . The method of  claim 64 , wherein the at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 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.   
     
     
         66 . The method of  claim 63 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         67 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-CEA/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP. 
     
     
         68 . The method of  claim 67 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises three ectodomains of 4-1BBL or fragments thereof. 
     
     
         69 . The method of  claim 67 , wherein the T-cell activating anti-CEA/anti-CD3 bispecific antibody comprises a first antigen binding domain comprising a heavy chain variable region (V H CD3) and a light chain variable region (V L CD3); and a second antigen binding domain comprising a heavy chain variable region (V H CEA) and a light chain variable region (V L CEA). 
     
     
         70 . The method of  claim 69 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:41, CDR-H2 sequence of SEQ ID NO:42, and CDR-H3 sequence of SEQ ID NO:43, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:44, CDR-L2 sequence of SEQ ID NO:45, and CDR-L3 sequence of SEQ ID NO:46, or
 (b) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:49, CDR-H2 sequence of SEQ ID NO:50, and CDR-H3 sequence of SEQ ID NO:51, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:52, CDR-L2 sequence of SEQ ID NO:53, and CDR-L3 sequence of SEQ ID NO:54.   
     
     
         71 . The method of  claim 69 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:47 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:48, or
 (b) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:55 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56.   
     
     
         72 . The method of  claim 68 , wherein the at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 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.   
     
     
         73 . The method of  claim 67 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         74 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-FolR1/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP. 
     
     
         75 . The method of  claim 74 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises three ectodomains of 4-1BBL or fragments thereof. 
     
     
         76 . The method of  claim 75 , wherein the at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 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.   
     
     
         77 . The method of  claim 74 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         78 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-MCSP/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP. 
     
     
         79 . The method of  claim 78 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises three ectodomains of 4-1BBL or fragments thereof. 
     
     
         80 . The method of  claim 79 , wherein the at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 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.   
     
     
         81 . The method of  claim 78 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP comprises:
 (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 polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         82 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-CD3 bispecific antibody specific for a tumor-associated antigen and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA. 
     
     
         83 . The method of  claim 82 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA comprises:
 (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:55 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56, and   (b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         84 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-CEA/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA. 
     
     
         85 . The method of  claim 84 , wherein the T-cell activating anti-CEA/anti-CD3 bispecific antibody comprises a first antigen binding domain comprising a heavy chain variable region (V H CD3) and a light chain variable region (V L CD3); and a second antigen binding domain comprising a heavy chain variable region (V H CEA) and a light chain variable region (V L CEA). 
     
     
         86 . The method of  claim 85 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:41, CDR-H2 sequence of SEQ ID NO:42, and CDR-H3 sequence of SEQ ID NO:43, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:44, CDR-L2 sequence of SEQ ID NO:45, and CDR-L3 sequence of SEQ ID NO:46, or
 (b) a heavy chain variable region (V H CEA) comprising CDR-H1 sequence of SEQ ID NO:49, CDR-H2 sequence of SEQ ID NO:50, and CDR-H3 sequence of SEQ ID NO:51, and/or a light chain variable region (V L CEA) comprising CDR-L1 sequence of SEQ ID NO:52, CDR-L2 sequence of SEQ ID NO:53, and CDR-L3 sequence of SEQ ID NO:54.   
     
     
         87 . The method of  claim 85 , wherein the second antigen binding domain comprises (a) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:47 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:48, or
 (b) a heavy chain variable region (V H CEA) comprising the amino acid sequence of SEQ ID NO:55 and/or a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56.   
     
     
         88 . The method of  claim 84 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA comprises:
 (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:55 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56, and   (b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         89 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-FolR1/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA. 
     
     
         90 . The method of  claim 89 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA comprises:
 (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:55 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56, and   (b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         91 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a T-cell activating anti-MCSP/anti-CD3 bispecific antibody and of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA. 
     
     
         92 . The method of  claim 91 , wherein the 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA comprises:
 (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:55 and a light chain variable region (V L CEA) comprising the amino acid sequence of SEQ ID NO:56, and   (b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises an 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 the second polypeptide comprises 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.   
     
     
         93 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to a tumor-associated antigen and of an agent blocking PD-L1/PD-1 interaction. 
     
     
         94 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to FAP and of an agent blocking PD-L1/PD-1 interaction. 
     
     
         95 . A method for treating or delaying progression of a proliferative disease in a subject, wherein the method comprises administering to the subject an effective amount of a 4-1BB agonist comprising at least one antigen binding domain capable of specific binding to CEA and of an agent blocking PD-L1/PD-1 interaction. 
     
     
         96 . A pharmaceutical product comprising (A) a first composition comprising as active ingredient a T-cell activating anti-CD3 bispecific antibody and a pharmaceutically acceptable carrier; and (B) a second composition comprising as active ingredient a 4-1BB agonist and a pharmaceutically acceptable carrier. 
     
     
         97 . The pharmaceutical product of  claim 96 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         98 . The pharmaceutical product of  claim 96 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         99 . A pharmaceutical product comprising (A) a first composition comprising as active ingredient a T-cell activating anti-CEA/anti-CD3 bispecific antibody and a pharmaceutically acceptable carrier; and (B) a second composition comprising as active ingredient a 4-1BB agonist and a pharmaceutically acceptable carrier. 
     
     
         100 . The pharmaceutical product of  claim 99 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         101 . The pharmaceutical product of  claim 99 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         102 . A pharmaceutical product comprising (A) a first composition comprising as active ingredient a T-cell activating anti-FolR1/anti-CD3 bispecific antibody and a pharmaceutically acceptable carrier; and (B) a second composition comprising as active ingredient a 4-1BB agonist and a pharmaceutically acceptable carrier. 
     
     
         103 . The pharmaceutical product of  claim 102 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         104 . The pharmaceutical product of  claim 102 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         105 . A pharmaceutical product comprising (A) a first composition comprising as active ingredient a T-cell activating anti-MCSP/anti-CD3 bispecific antibody and a pharmaceutically acceptable carrier; and (B) a second composition comprising as active ingredient a 4-1BB agonist and a pharmaceutically acceptable carrier. 
     
     
         106 . The pharmaceutical product of  claim 105 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         107 . The pharmaceutical product of  claim 105 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         108 . A pharmaceutical composition comprising a T-cell activating anti-CD3 bispecific antibody and a 4-1BB agonist. 
     
     
         109 . The pharmaceutical composition of  claim 108 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         110 . The pharmaceutical composition of  claim 108 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         111 . A pharmaceutical composition comprising a T-cell activating anti-CEA/anti-CD3 bispecific antibody and a 4-1BB agonist. 
     
     
         112 . The pharmaceutical composition of  claim 111 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         113 . The pharmaceutical composition of  claim 111 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         114 . A pharmaceutical composition comprising a T-cell activating anti-FolR1/anti-CD3 bispecific antibody and a 4-1BB agonist. 
     
     
         115 . The pharmaceutical composition of  claim 114 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         116 . The pharmaceutical composition of  claim 114 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA. 
     
     
         117 . A pharmaceutical composition comprising a T-cell activating anti-MCSP/anti-CD3 bispecific antibody and a 4-1BB agonist. 
     
     
         118 . The pharmaceutical composition of  claim 117 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to FAP. 
     
     
         119 . The pharmaceutical composition of  claim 117 , wherein the 4-1BB agonist comprises at least one antigen binding domain capable of specific binding to CEA.
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