Abstract 3425: A novel anti-EGFR × IL-10M (FP010) fusion protein for solid tumor therapy

Abstract CD8+ T cell exhaustion has been recognized as an important factor contributing to the resistance to PD-1/PD-L1 inhibitors. Recently, IL-10 was found to reinvigorate tumor-infiltrating terminally exhausted CD8+ T cells via metabolic reprogramming, and enhance their proliferation, cytotoxicity and cytokine secretion. Notably, combining IL-10 with anti-PD-1 or CAR-T therapies markedly enhanced their antitumor efficacy. In a Phase 1b clinical trial, PEGylated IL-10 showed promising therapeutic potential in NSCLC and RCC. However, severe hematologic toxicities limited its clinical applications. To overcome this challenge, we engineered the dimeric IL-10 into a monomeric form (IL-10M) to reduce its downstream activity, thus minimizing its toxicity. We then developed FP010, an anti-EGFR × IL-10M fusion protein of which IL-10M was fused to the C-terminus of the heavy chain of an engineered anti-EGFR antibody (panitumumab Fab combined with IgG1 Fc). This design allowed FP010 to preferentially accumulate in EGFR-expressing tumors, thereby enhancing its therapeutic effect. In this study, we evaluated FP010’s antitumor activity in vitro and in vivo, as well as its safety profile in cynomolgus monkeys. FP010 showed binding and blocking activity similar to that of panitumumab on A431 cells, and could significantly inhibit their proliferation. Additionally, FP010 exhibited strong ADCC activity. FP010 exhibited much lower downstream signal activity than wild type IL-10 in a STAT3 reporter assay. However, FP010 still kept its ability in promoting IFN-γ secretion and inhibiting apoptosis in exhausted CD8+ T cells, indicating its ability to reinvigorate these cells. In vivo studies demonstrated potent antitumor activity of FP010 in both MC38-cEGFR and B16-cEGFR models, better than IL-10M or anti-EGFR antibody alone. We further assessed the hematologic toxicities of FP010 in cynomolgus monkeys. No evident hematologic toxicity was observed with FP010 at a dose of 10 mg/kg IV QW. In contrast, Panitumumab × wt IL-10 caused a remarkable decrease of erythrocytes at the same dose, consistent with the adverse effects of PEGylated IL-10 observed in clinical trials. FP010 has demonstrated significant antitumor activity in vitro and in vivo, with acceptable adverse effects observed in cynomolgus monkeys. These data indicate that FP010 has great potential for cancer immunotherapy, especially for tumors with resistance to PD-1/PD-L1 inhibitors due to T cell exhaustion. Citation Format: Jian Guo, Jiaojiao Ding, Ce Gu, Linhui Ye, Dujuan Zhu, Yingye Ou, Zhe Zhang, Baiguang Ren, Chang Zhou, Bingquan Shen, Xiaodong Wu, Ke Chen, Di Lu, Yongting Huo. A novel anti-EGFR × IL-10M (FP010) fusion protein for solid tumor 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 3425.