An innovative engineered IL-10 monomer strengthens T cell-mediated anti-tumor responses through anti-PD-1 cis-delivery.

Immune checkpoint blockade (ICB) therapy exerts anti-tumor efficacy mainly by activating intratumoral CD8(+) T cells but fails to re-activate terminally exhausted CD8(+) T cells. Interleukin-10 (IL-10) has been shown to directly expand and activate these cells and to exert a synergistic effect when combined with ICB. Nevertheless, the clinical application of IL-10 for cancer immunotherapy is restricted by severe hematological toxicity. Here, we design FP008 (anti-PD-1×IL-10M), a clinical-stage fusion protein composed of an anti-PD-1 antibody and an attenuated IL-10 monomer (IL-10M). Mechanistically, the activity and toxicity of IL-10M are significantly reduced, while its therapeutic benefits are enhanced through anti-PD-1-targeted enrichment and cis-activation. Anti-PD-1×IL-10M therapy displays robust anti-tumor activity in various mouse models, including those resistant to anti-PD-1 therapy, and exhibits promising safety in GLP toxicology studies in cynomolgus monkeys. Altogether, reinvigorating exhausted CD8(+) T cells in the tumor microenvironment through anti-PD-1×IL-10M represents a promising therapeutic strategy for overcoming anti-PD-1/L1-refractory solid tumors.