Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Improving Anti-CTLA-4 Therapies through Peptide Masking and Fragment Crystallizable Non-fucosylation: Preclinical Characterization of Three Novel Antibodies.
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Jhatakia Amy, Sun Xin, Vaccaro Alessandra, Wang Michael, Nasser Mohammed, Mukhopadhyay Anandaroop, Gupta Neha, Kang Kyeongah, Hu Wei, Newsome Courtni, Leung Cheuk Hong, Le John, Yazdani Mona, Guo Haiping, Chen Lili, Pradhan Monika, Lin Heather Y, Mandawe Remie, Findeisen Felix, Lohre Jack, Leung Leslie, Wei Yun, Dobroff Joshua, O'Brien Shaun, Xu Ke, Hammell Amy, Price Karen, Engelhardt John, Selby Mark, Korman Alan, Wilson Nicholas, Cascone Tina
Аннотация
PURPOSE: The anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab (IPI), has shown clinical benefit across multiple tumor types, both as monotherapy and in combination with nivolumab or chemotherapy. However, not all tumors respond, and peripheral effects can lead to immune-related adverse events. We characterized three novel anti-CTLA-4 antibodies: peptide-masked [PROBODY conditionally activatable therapeutic (PB)], non-fucosylated (NF), and combined NF-PB (BMS-986288).
EXPERIMENTAL DESIGN: We evaluated the preclinical characteristics, including pharmacodynamics, tolerability, antitumor activity and efficacy, and peripheral immune responses, of these novel anti-CTLA-4 antibodies using in vitro systems, animal models, and human data. This includes data from preclinical mouse models of colorectal cancer as well as non-small cell lung cancer.
RESULTS: NF demonstrated greater T-cell priming and antitumor activity than both IPI and the unmasked PB antibody in cell-based assays and mouse models. Whereas the intact PB antibody showed minimal CTLA-4 binding and peripheral immune activation, unmasking restored its functional activity to levels comparable with those of IPI. Unmasked anti-CTLA-4 NF-PB retained the effectiveness of anti-CTLA-4 NF, and both molecules demonstrated more profound antitumor activity, increased effector memory T-cell response, and prolonged survival in mouse models compared with IPI. Anti-CTLA-4 NF-PB demonstrated reduced peripheral immune responses compared with anti-CTLA-4 NF or IPI in non-human primates and patients with solid tumors.
CONCLUSIONS: Anti-CTLA-4 NF-PB has enhanced antitumor activity, efficacy, and reduced peripheral activity in preclinical models, and has the potential to provide therapeutic benefit in solid tumors. See related commentary by Galvez-Cancino et al., p. 3112.
EXPERIMENTAL DESIGN: We evaluated the preclinical characteristics, including pharmacodynamics, tolerability, antitumor activity and efficacy, and peripheral immune responses, of these novel anti-CTLA-4 antibodies using in vitro systems, animal models, and human data. This includes data from preclinical mouse models of colorectal cancer as well as non-small cell lung cancer.
RESULTS: NF demonstrated greater T-cell priming and antitumor activity than both IPI and the unmasked PB antibody in cell-based assays and mouse models. Whereas the intact PB antibody showed minimal CTLA-4 binding and peripheral immune activation, unmasking restored its functional activity to levels comparable with those of IPI. Unmasked anti-CTLA-4 NF-PB retained the effectiveness of anti-CTLA-4 NF, and both molecules demonstrated more profound antitumor activity, increased effector memory T-cell response, and prolonged survival in mouse models compared with IPI. Anti-CTLA-4 NF-PB demonstrated reduced peripheral immune responses compared with anti-CTLA-4 NF or IPI in non-human primates and patients with solid tumors.
CONCLUSIONS: Anti-CTLA-4 NF-PB has enhanced antitumor activity, efficacy, and reduced peripheral activity in preclinical models, and has the potential to provide therapeutic benefit in solid tumors. See related commentary by Galvez-Cancino et al., p. 3112.