Anti-CTLA-4 antibodies are one of the only three types of immune checkpoint inhibitors (together with anti-PD-1 and anti-PD-L1 antibodies) with proven monotherapy value in cancer therapy. Despite demonstrated efficacy, their broad application in monotherapies and combinational therapies are hampered by the safety profiles. Evidence in animal models suggests that efficacy of anti-CTLA-4 antibodies is at least partially due to depletion of regulatory T cells (Treg) via ADCC function, whereas clinically adverse events are positively correlated with systemic exposure.
Here we embarked to develop the next generation anti-CTLA-4 antibody with better efficacy and safety profile. Fully human Heavy Chain only antibody (HCAb) 4003-2 was generated using the Harbour HCAb transgenic mouse platform. 4003-2 specifically binds to CTLA-4 and blocks its binding to B7.1/B7.2. It was optimized to have enhanced ADCC function that affords superior ability to deplete Treg cells both in vitro and in vivo. 4003-2 showed in murine tumor models significantly more potent anti-tumor activity than other CTLA4 antibodies, at least partly driven by substantially enhanced depletion of intra-tumoral Treg cells. In addition, due to its shorter serum half-life, 4003-2 has less systemic drug exposure in vivo at efficacious doses, suggesting potentially improvement of safety profile in clinical applications.
The augmented efficacy and safety profile of 4003-2 present it as an excellent candidate for the development of next generation anti-CTLA4 therapy.
Citation Format: George Liu, Xin Gan, Yun He, Jiuqiao Zhao, Huayan Duan, Yiping Rong. A heavy chain only antibody against CTLA4 with outstanding preclinical efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4098.