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.

Checkpoint inhibitors targeting PD-1 have shown unprecedented efficacy in some patients with cancer; however, coexpression 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 coexpressed by stem-like CD8 T cells, a population critical for the response to anti-PD-1 therapy, providing the rationale for their dual blockade. Yet, blocking LAG-3 can lead to the expansion of regulatory T cells (Treg), reducing the efficacy of anti-LAG-3 therapy on CD8 TILs. To address this limitation, we developed tobemstomig, a novel bispecific antibody (BsAb) 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 with monospecific antibodies targeting PD-1 and LAG-3 separately, which eroded the stem-like T-cell pool over time. SIGNIFICANCE: Constitutive LAG-3 expression on Tregs may limit anti-LAG-3 therapy efficacy by promoting Treg expansion, leading to suppression of tumor-specific CD8 T-cell responses. Tobemstomig, a BsAb preferentially targeting CD8, expands tumor-specific stem-like CD8 TILs and reduces intratumoral Tregs, resulting in superior, durable tumor inhibition in mice.