Cao, Shen, and Fu et al. created ProCTLA-4, a prodrug comprising a misfolded anti-CTLA-4 Ab, correctable by MMP cleavage in the TME. ProCTLA-4 exhibited high-affinity binding in TME (not LN/spleen), reduced toxicity (even combined with anti-PD-1 Ab), and greater efficacy than ipilimumab in “cold” murine tumor models. ProCTLA-4 depleted Treg (including ICOShigh super- inhibitory) cells preferentially in the TME to promote tumor-specific CD8+ T cell control of local and distal tumors and to prevent relapse. Enhancing ADCC boosted efficacy, but not toxicity. ProCTLA-4 showed superior safety and efficacy to BMS-986288, a phase II-tested CTLA-4 probody, particularly against ICB-resistant tumors.
Contributed by Paula Hochman
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.
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijin
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (7) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Changping District, Beijing, China. yangxinfu@tsinghua.edu.cn. (8) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn.
