Zou et al. developed a fusion protein consisting of anti-PD-1 and a low-affinity murine IL-12 (mut2) with reduced IL-12-mediated NK cell activation, IFNγ release, and associated toxicity. In mice, αPD1-mIL12mut2 showed strong antitumor activity, including an abscopal effect, control of metastases, and protection from rechallenge, with no evidence of toxicity. The high-affinity anti-PD-1 antibody targeted upregulated PD-1 on intratumoral CD8+ T cells, allowing for preferential cis delivery of IL-12mut2 to PD-1+CD8+ T cells, enhancing activation and IFNγ production, even in Tim3+ populations. Similar results were observed in a humanized mouse model.
Contributed by Lauren Hitchings
ABSTRACT: 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.
Author Info: (1) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. University of Chinese Academy of Sciences, 100049, Beiji
Author Info: (1) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. University of Chinese Academy of Sciences, 100049, Beijing, China. (2) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. University of Chinese Academy of Sciences, 100049, Beijing, China. (3) Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China. (4) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. University of Chinese Academy of Sciences, 100049, Beijing, China. (5) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. University of Chinese Academy of Sciences, 100049, Beijing, China. (6) Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China. (7) Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China. (8) Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China. Yangxinfu@tsinghua.edu.cn. (9) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. hpeng@moon.ibp.ac.cn. Guangzhou Laboratory, Guangzhou, 510320, Guangdong, China. hpeng@moon.ibp.ac.cn.
