Immunotherapy has gained great breakthroughs since the 21st century, which however has limitations of relatively low objective response rate, short progression-free survival and drug resistance. The exclusion, desertification and exhaustion of immune cells in the tumor microenvironment (TME) have been found and confirmed in many tumor cases, accounting for the major problems of current PD1/L1-oriented immunotherapy. Cytokines, on the other hand, have been demonstrated efficacious in activating immune cells in TME and achieved great progress in certain diseases, but it is generally accompanied by severe systematic toxicities. The field of antibody-cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the TME to expand the therapeutic window of cytokine therapy. Therefore, we have developed IAP0971 as a novel immunocytokine that binds specifically to PD1 and fuses IL15/IL15Rα complex for cancer immunotherapy. In IAP0971, IL15/IL15Rα complex specifically binds to the IL2/15Rβγ and promotes the proliferation and activation of T cells and NK cells, without activation of Treg cells or inducing apoptosis of activated T cells which are common side effects of IL2-based therapies. Anti-PD1 antibody in IAP0971 can specifically target IL15 into the TME due to the high expression of PD1 in the TME. Both of the components act in the same location and on the same cells at the same time showing great cis-synergy, which will further improve the effectiveness and therapeutic window of IAP0971. We report here the preclinical characterization of IAP0971 including pharmacology, pharmacodynamics, pharmacokinetics and toxicology, and discuss its potential as a novel agent for treating patients with advanced malignant tumors. IAP0971 bound to human IL2/15Rβ specifically and blocked PD1/PDL1 signaling. IAP0971 promoted the proliferation of CD8+T cells and NKT cells, and further activated NK cells to kill tumor cells validated by in vitro assays. In a 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. In summary, IAP0971 has demonstrated a favorable safety profile and potent anti-tumor activities in vivo, which has the potential to address both primary non-responsiveness and acquired resistance of current immunotherapy. IAP0971 is the first armed PD1/IL15 immunocytokine with IND approval from both FDA and NMPA. The indications of IAP0971 include lung cancer, cervical cancer, head and neck squamous cell carcinoma, liver cancer, lymphoma, and other malignant tumors. A Phase I/IIa clinical trial to evaluate the safety, tolerability and preliminary efficacy of IAP0971 in patients with locally advanced or metastatic malignant tumors is currently on-going (NCT05396391).

Citation Format: Liusong Yin, Xiaoling Jiang, Chongbing Wu, Zi Chen. IAP0971, A novel PD1/IL15 immunocytokine that binds specifically to PD1 and fuses IL15/IL15Rα complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1889.