Preclinical evaluation of IAP0971, a novel immunocytokine that binds specifically to PD1 and fuses IL15/IL15Rα complex

作者：Jihong Chen, Ziyou Shen, Xiaoling Jiang, Zhenzhen Huang, Chongbing Wu, Dongcheng Jiang, Liusong Yin · 发表于：Antibody Therapeutics · 年份：2022 · DOI：10.1093/abt/tbac031 · 被引用次数：10 · 研究领域：Toxin Mechanisms and Immunotoxins、Monoclonal and Polyclonal Antibodies Research、Whipple's Disease and Interleukins

Abstract Background Currently, cytokine therapy for cancer has demonstrated efficacy in certain diseases but is generally accompanied by severe toxicity. The field of antibody-cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the tumor microenvironment to expand the therapeutic window of cytokine therapy. Therefore, we have developed a novel immunocytokine that binds specifically to programmed death 1 (PD1) and fuses IL15/IL15Rα complex (referred to as IAP0971) for cancer immunotherapy. Methods We report here the making of IAP0971, a novel immunocytokine that binds specifically to PD1 and fuses IL15/IL15Rα complex, and preclinical characterization including pharmacology, pharmacodynamics, pharmacokinetics and toxicology, and discuss its potential as a novel agent for treating patients with advanced malignant tumors. Results IAP0971 bound to human IL2/15Rβ proteins specifically and blocked PD1/PDL1 signaling transduction pathway. IAP0971 promoted the proliferation of CD8 + T cells and natural killer T (NKT) cells, and further activated NK cells to kill tumor cells validated by in vitro assays. In an hPD1 knock-in mouse model, IAP0971 showed potent anti-tumor activity. Preclinical studies in non-human primates following single or repeated dosing of IAP0971 showed favorable pharmacokinetics and well-tolerated toxicology profile. Conclusion IAP0971 has demonstrated a favorable safety profile and potent anti-tumor activities in vivo. A Phase I/...