Abstract 3430: FP008, a novel anti-PD-1×IL-10M fusion protein for cancer therapy

Abstract Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have achieved remarkable clinical successes in cancer therapy. However, over 70 % of patients receiving ICI treatments are not responsive or experience disease progression after an initial period of response. Terminal exhaustion of CD8+ T cell was supposed to contribute to this low responsiveness. On the other hand, IL-10 could enhance the anti-tumor activity of ICI by reinvigorating and expanding terminally exhausted CD8+ T cells. Encouraging efficacies have been observed in phase 1 clinical trials of IL-10 therapy, but severe hematologic toxicity and low dosage greatly hindered its efficacy in further clinical trials. We therefore developed FP008, a novel anti-PD-1 × IL-10M (IL-10 monomer) fusion protein, and demonstrated its promising potential for cancer therapy. FP008 exhibited strong anti-PD-1 blocking performance and activity comparable to its parental anti-PD-1 antibody. More importantly, FP008 significantly decreased CD8+ T cells apoptosis and promoted IFN-γ secretion when co-cultured with exhausted CD8+ T cells induced in vitro. This function was mainly caused by the IL-10M moiety, which was modified into a monomer to reduce downstream signaling and the resulting hematologic toxicity. Compared with wild-type (wt) IL-10, IL-10M significantly decreased the phagocytosis of erythrocytes by macrophages in vitro. The result was consistent with the observation in the toxicity study in monkeys. FP008 induced less STAT3 phosphorylation without PD-1 crosslinking in activated CD8+ T cells or reporter cells than wt IL-10. Furthermore, the STAT3 signaling was greatly enhanced after PD-1 crosslinking, indicating FP008 may have strong activity on TILs where PD-1 is highly expressed. In both CT26 and MC38 tumor models in hPD-1 knock-in mice, FP008 dose dependently inhibited tumor growth, with stronger anti-tumor efficacy and longer survival than Keytruda. In a CT26 rechallenge model after FP008 treatment and complete tumor regression, mice were re-challenged with CT26 tumor cells but remained tumor-free without further treatment, indicating that FP008 treatment could induce immunological memory. TILs analysis showed that the number of tumor-infiltrating CD8+ T cells increased, while Treg cells decreased after FP008 treatment. In a GLP toxicology study in cynomolgus monkeys, FP008 was well tolerated at the dose of 10 mg/kg, and produced minimal decrease of erythrocyte and no tissue damage. In conclusion, FP008 showed novel characteristics such as the synergistic function of anti-PD-1 and IL-10M, cis-activation of IL-10M by PD-1 enrichment and improved safety profiles. It demonstrated promising potential for clinical therapy for the anti-PD-1 naïve or resistant patients. Citation Format: Ce Gu, Jiaojiao Ding, Baiguang Ren, Mengying Liang, Linhui Ye, Yingye Ou, Chang Zhou, Bingquan Shen, Jian Guo, Xiaodong Wu, Ke Chen, Yongting Huo, Di Lu. FP008, a novel anti-PD-1×IL-10M fusion protein for cancer therapy [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 3430.