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

Autor: 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
Rok vydání: 2022
Předmět:
Zdroj: Cancer Immunology, Immunotherapy. 71:2421-2431
ISSN: 1432-0851
0340-7004
DOI: 10.1007/s00262-022-03170-z
Popis: 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.
Databáze: OpenAIRE
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