Tobemstomig, a novel bispecific antibody, preferentially blocks PD-1 and LAG-3 on CD8 TILs to expand stem-like T-cells for sustained tumor control

Abstract Checkpoint inhibitors targeting PD-1 have shown unprecedented efficacy in some cancer patients; however, co-expression of the immune-checkpoint LAG-3 by tumor infiltrating lymphocytes (TILs) might hinder such efficacy. PD-1 and LAG-3 are established markers of T-cell exhaustion in cancer and are co-expressed by stem-like CD8 T cells, a population critical for the response to anti-PD1 therapy, providing the rationale for their dual-blockade. Yet, blocking LAG-3 can lead to the expansion of regulatory T cells, reducing the efficacy of anti-LAG-3 therapy on CD8 TILs. To address this limitation, we developed tobemstomig, a novel bispecific antibody to preferentially and simultaneously block PD-1 and LAG-3 in cis on tumor-specific CD8 TILs, while sparing Tregs. It provided superior tumor growth inhibition in mouse models by replenishing stem-like cells and cytotoxic effector CD8 TILs, resulting in durable responses compared to monospecific antibodies targeting PD-1 and LAG-3 separately, which eroded the stem-like T cell pool over time.