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A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice
Weian Cao1,2, Junfan Chen1,2, Yutong Fu1,2
1School of Basic Medical Sciences, Tsinghua University, Beijing, China.
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+ 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.
Insights
A novel prodrug antibody, ProCTLA-4, enhances cancer immunotherapy by targeting CTLA-4. This approach reduces toxicity and improves efficacy compared to existing treatments, offering a promising new strategy for immune checkpoint inhibition.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade is a key cancer immunotherapy strategy.
- High-dose anti-CTLA-4 agents improve efficacy but increase toxicities, limiting clinical use.
Purpose of the Study:
- To develop a prodrug anti-CTLA-4 antibody (ProCTLA-4) with improved efficacy and reduced toxicity.
- To evaluate ProCTLA-4's performance in preclinical cancer models.
Main Methods:
- Engineered an anti-CTLA-4 antibody fragment (Fab) into a prodrug (ProCTLA-4) activated by tumor-associated proteases.
- Tested ProCTLA-4 in preclinical mouse models of cancer.
Main Results:
- ProCTLA-4 effectively depleted regulatory T cells in the tumor microenvironment.
- Enhanced CD8+ T cell responses against tumor antigens.
- Demonstrated reduced toxicity compared to current CTLA-4 blockade therapies.
- Showed superior efficacy amplification over existing anti-CTLA-4 Probody therapeutics, particularly in poorly immunogenic melanoma.
Conclusions:
- ProCTLA-4 represents a novel prodrug antibody design for cancer immunotherapy.
- This approach offers a paradigm for limiting immune-related adverse events while enhancing therapeutic efficacy.
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