A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41073424.
- Also identified by DOI 10.1038/s41467-025-64081-y and PMC identifier 12514261.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
CTLA-4 is a promising target for immune checkpoint inhibition in cancer therapy, with CTLA-4 blockade achieving prolonged overall survival for responding patients. However, the progressively elevated doses of anti-CTLA-4 agents, aimed at achieving better efficacy, result in increased toxicities, limiting their clinical applications. Here, we generate a prodrug design of the anti-CTLA-4 antibody, named ProCTLA-4, by folding the Fab fragment of the antibody in a tumor-associated protease-based manner. In preclinical mouse models, ProCTLA-4 effectively depletes suppressive regulatory T cells within the tumor microenvironment and enhances tumor-associated antigen-specific CD8<sup>+</sup> T cell responses, while exhibiting reduced toxicity compared to currently available CTLA-4 blockade approaches. Furthermore, compared to the currently used Probody therapeutics for anti-CTLA-4 (BMS986288), ProCTLA-4 has more advantages in efficacy amplification, such as in poor immunogenic melanoma. Our design establishes an alternative paradigm for antibody agents that limits the emergence of immune-related adverse events (irAE) while increasing therapeutic efficacy.
Medical subject headings
- CTLA-4 Antigen
- Immune Checkpoint Inhibitors