A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity
Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecif...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2316945 |
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| author | Diana I. Albu Benjamin J. Wolf Yan Qin Xianzhe Wang Amy Daniel Ulumben Mei Su Vivian Li Eirene Ding Jose Angel Gonzalo Jason Kong Ruturaj Jadhav Nelly Kuklin Alberto Visintin Bing Gong Thomas J. Schuetz |
| author_facet | Diana I. Albu Benjamin J. Wolf Yan Qin Xianzhe Wang Amy Daniel Ulumben Mei Su Vivian Li Eirene Ding Jose Angel Gonzalo Jason Kong Ruturaj Jadhav Nelly Kuklin Alberto Visintin Bing Gong Thomas J. Schuetz |
| author_sort | Diana I. Albu |
| collection | DOAJ |
| description | Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies. |
| format | Article |
| id | doaj-art-5e1ca35cffdd474daf5caef1c125a47e |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-5e1ca35cffdd474daf5caef1c125a47e2025-08-20T02:50:37ZengTaylor & Francis GroupOncoImmunology2162-402X2024-12-0113110.1080/2162402X.2024.2316945A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activityDiana I. Albu0Benjamin J. Wolf1Yan Qin2Xianzhe Wang3Amy Daniel Ulumben4Mei Su5Vivian Li6Eirene Ding7Jose Angel Gonzalo8Jason Kong9Ruturaj Jadhav10Nelly Kuklin11Alberto Visintin12Bing Gong13Thomas J. Schuetz14Compass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACompass Therapeutics Inc, Boston, MA, USACombinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.https://www.tandfonline.com/doi/10.1080/2162402X.2024.2316945Cancer immunotherapyimmuno-oncology |
| spellingShingle | Diana I. Albu Benjamin J. Wolf Yan Qin Xianzhe Wang Amy Daniel Ulumben Mei Su Vivian Li Eirene Ding Jose Angel Gonzalo Jason Kong Ruturaj Jadhav Nelly Kuklin Alberto Visintin Bing Gong Thomas J. Schuetz A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity OncoImmunology Cancer immunotherapy immuno-oncology |
| title | A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity |
| title_full | A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity |
| title_fullStr | A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity |
| title_full_unstemmed | A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity |
| title_short | A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity |
| title_sort | bispecific anti pd 1 and pd l1 antibody induces pd 1 cleavage and provides enhanced anti tumor activity |
| topic | Cancer immunotherapy immuno-oncology |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2316945 |
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