Abstract 4881: A PD1-IFNα fusion protein, with an attenuated IFNα fused to a clinically validated PD1 mAb, elicited PD1-dependent IFNα signaling and superior anti-tumor efficacy
Authors: Jinyang Li, Yi Wang, Mengqiang Di, Min Wu, Xueying Feng, Yiyi Li, Weiwei Wu, Xiguang Zhang, Shuaixiang Zhou, Huizhong Xiong
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade (ICB) therapies blocking PD1/PDL1 signaling have shown unprecedented clinical efficacy in multiple indications. However, the overall response rate for ICB-sensitive tumors are only 10-50%. Moreover, many types of cancer, e.g. pancreatic, ovarian, and MSS colorectal cancer, remain highly refractory to ICB therapies. Thus, it remains a significant unmet medical need to improve the responsiveness and durability of current ICB therapies. Based on emerging clinical evidence, it is possible to address this challenge by combining PD1 or PDL1 mAbs with drugs targeting complementary mechanisms. Indeed, next-generation ICB therapies, e.g. PD1 x IL2 fusion protein, PD1 x CTLA4 BsAb, and PD1 x VEGF BsAb, have shown promising clinical signals and improved efficacy compared to PD1 mAb. This underlines the potential of incorporating two clinically validated anti-cancer mechanism-of-action into one drug. IFNα has shown clinical efficacy and potential synergistic anti-cancer effect with PD1 mAb. Indeed, soluble IFNα has been approved to treat cancer. Similar to the development of other cytokine-based therapies, it is necessary and challenging to overcome off-tumor activity of IFNα to achieve efficacy-safety balance, limit systemic toxicity, and improve pharmacokinetics profile and drug exposure. Here, we engineered a PD1-IFNα fusion protein composed of a functionally attenuated IFNα and a clinically validated PD1 mAb, Sintilimab, aiming to specifically stimulate PD1-positive immune cells. This PD1-IFNα fusion protein utilized bivalent PD1 binders and induced potent PD1/PDL1 blockade. To minimize systemic toxicity induced by IFNα and improve developability, we engineered human IFNα-2b to decrease the affinity between IFNα and IFNα receptors. The PD1-IFNα fusion protein elicited highly PD1-dependent IFNα signaling, selectively activated in PD1-high cells compared to PD1-low cells. Systemic administration of a mouse surrogate molecule showed superior anti-tumor efficacy compared to PD1 mAb, with undetectable toxicity, in several mouse syngeneic tumor models. This PD1-IFNα fusion protein showed favorable pharmacokinetics profile in mice and drug developability. Together, our pre-clinical data demonstrated that a bifunctional PD1-IFNα fusion protein elicits robust PD1/PDL1 signaling blockade and PD1-dependent IFNα signaling activation to achieve anti-tumor efficacy, with potential to expand the benefits of ICB therapies to more cancer patients. Citation Format: Jinyang Li, Yi Wang, Mengqiang Di, Min Wu, Xueying Feng, Yiyi Li, Weiwei Wu, Xiguang Zhang, Shuaixiang Zhou, Huizhong Xiong. A PD1-IFNα fusion protein, with an attenuated IFNα fused to a clinically validated PD1 mAb, elicited PD1-dependent IFNα signaling and superior anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4881.