Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.

Cancer immunology, immunotherapy : CII 2022 Oct

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Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic. © 2022. The Author(s).

Citation

Yosuke Sato, Cierra N Casson, Atsushi Matsuda, James I Kim, Judy Qiuju Shi, Shinji Iwasaki, Susan Chen, Brett Modrell, Chingkit Chan, Daniel Tavares, Douglas Austen, Koh Ida, Olga Tayber, Pyae Hein, Robert Comeau, Yafang Lin, Michael H Shaw. Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy. Cancer immunology, immunotherapy : CII. 2022 Oct;71(10):2421-2431