| Autor: |
Kyle P Carter, Yao Y. Chiang, Vishal A. Manickam, Emily Benzie, Nicholas Wayham, David S. Johnson, Rena A. Mizrahi, Jasmeen Saini, Garry L. Coles, Savreet K. Sandhu, Eric A. Stone, Jan Fredrick Simons, Adam S. Adler, Ellen K. Wagner, Ashley Gras, Chelsea Edgar, LaRee Tracy, Brendan Tinsley, Jackson Leong, Kacy Stadtmiller, Ariel R Niedecken, Renee Leong, Yoong Wearn Lim, Bishal K. Gautam, Michael A. Asensio |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.07.12.452090 |
| Popis: |
Anti-CTLA-4 antibodies such as ipilimumab were among the first immune-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. In this study we present evidence that checkpoint inhibition is not a primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy is FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb) that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, the weak checkpoint inhibitor has superior anti-tumor activity compared to ipilimumab in a murine model. The weak checkpoint inhibitor also induces less Treg proliferation and has increased ability to inducein vitroFcR signaling andin vivodepletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of the weak checkpoint inhibitor likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that weak checkpoint inhibition was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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