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Improving anti–CTLA-4 therapies through peptide masking and fragment crystallizable nonfucosylation: preclinical characterization of three novel antibodies

ABSTRACT: Background The anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab, 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]), nonfucosylated (NF), and combined NF- PB (BMS-986288). Results NF demonstrated greater T-cell priming and antitumor activity than both ipilimumab 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 ipilimumab. 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 ipilimumab. Anti–CTLA-4 NF-PB demonstrated reduced peripheral immune responses than anti–CTLA-4 NF or ipilimumab in non-human primates and patients with solid tumors. Conclusion 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE315417 | GEO | 2026/01/05

REPOSITORIES: GEO

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