抗 PD-1 顺式递送低亲和力 IL-12 激活瘤内 CD8(+)T 细胞以产生全身性抗肿瘤反应

Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine.

Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity.

Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1 + CD8 + T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12.

Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.