Anti-PD-1 cis-delivery of low-affinity IL-12 activates intratumoral CD8+T cells for systemic antitumor responses

• Published in: Nature communications 2024-06, Vol.15 (1), p.4701-13
• Main Authors: Zou, Zhuangzhi, Shen, Jiao, Xue, Diyuan, Li, Hongjia, Xu, Longxin, Cao, Weian, Wang, Wenyan, Fu, Yang-Xin, Peng, Hua
• Format: Article
• Language: English
• Subjects: 13; 13/31; 631/250/127/1213; 631/67/1059/153; 631/67/1059/2325; 64; 64/60; 82/1; Affinity; Animals; Antibodies; Anticancer properties; Antitumor activity; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Effectiveness; Female; Fusion protein; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immunosuppression; Interleukin 12; Interleukin-12 - immunology; Interleukin-12 - metabolism; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Metastases; Mice; Mice, Inbred C57BL; multidisciplinary; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Proteins; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - genetics; Robustness; Science; Science (multidisciplinary); Side effects; Toxicity; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49034-1

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. IL-12 has been shown to enhance the efficacy of anti-PD-1 therapy, but this has been hampered by issues with toxicity and poor delivery to the tumour site. In this study, the authors generate an anti-PD-1 antibody/IL-12 fusion protein for specific targeting of IL-12 to tumour sites, resulting in potent anti-tumour immunity with limited toxicity.