Unlocking T Cell Potential: The Therapeutic Advancement of RG7769 in Overcoming Dual Checkpoint Resistance

The abstract highlights the development of RG7769, a novel bispecific antibody designed to target both PD-1 and TIM-3 immune checkpoints with high and low affinity, respectively. This avidity-driven heterodimeric CrossMabVH-VL is intended to specifically target T cells expressing PD-1 and/or TIM-3 while avoiding myeloid and NK cells. RG7769 is designed to resist drug shaving by macrophages in the tumor microenvironment (TME) and retains standard IgG pharmacokinetics.

The antibody demonstrates higher affinity for PD-1 than pembrolizumab and nivolumab, and X-ray crystallography reveals that it binds to a unique glycosylated epitope on PD-1, effectively blocking PD-1/PD-L1 and PD-1/PD-L2 interactions. RG7769's TIM-3 binding arm is selected for optimal functional activity, and the antibody shows reduced binding to TIM-3+ myeloid and NK cells while preferentially binding to dysfunctional T cells in the TME.

Compared to bivalent TIM-3 antibodies, RG7769 induces low antibody internalization on activated T cells, overcoming a significant limitation for TIM-3 antibodies. In functional assays, RG7769 enhances IFN-γ secretion by tumor-specific T-cells, increases ex vivo tumor-specific effector functions of T cells from melanoma patients, and boosts the anti-tumor activity of tumor-infiltrating lymphocytes (TILs) more effectively than the monospecific parental PD-1 antibody.

In vivo, RG7769 exhibits superior efficacy in controlling tumor growth in a transgenic mouse model compared to the parental PD-1 antibody. These preclinical findings support the potential of RG7769 as a monotherapy and combination therapy for solid and hematological tumors. A phase I clinical study is currently underway to evaluate the safety and efficacy of RG7769 in patients with advanced metastatic solid tumors.