Abstract 2365: Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo

Abstract Background: IL-11 is known as an inflammation-related factor, and it has been proved to be a key driver in fibrotic diseases. Besides, the roles of IL-11 in tumor immunopathology were recognized more in-depth and comprehensively in recent years. IL-11 expression is highly and positively correlated with overall survival in various cancer types, including colorectal cancer, hepatocellular carcinoma and lung cancer. It was reported that IL-11 promoted tumor cell growth and metastasis, mediated partly through its direct effects on macrophages, T cells and cancer-associated fibroblasts. All these studies indicated that blocking IL-11 signaling may be a promising therapeutic approach for the treatment of solid tumors. In this report, 9MW3811, a high-affinity IL-11 blocking antibody was developed to test its anti-tumor activity and synergistic effects with anti-PD-1 antibody in mouse tumor models. Methods: 9MW3811 was generated by mouse hybridoma technology followed by antibody humanization and affinity maturation. Affinity of 9MW3811 was measured by Octet system. Its blocking activity of IL-11/IL11Ra/gp130 protein interaction was detected by ELISA, and the inhibiting effect of IL-11-mediated signaling was assessed with a luciferase reporter cell-based assay. In vivo efficacy of 9MW3811 was tested on A549 xenograft and LUSC PDX models. ScRNA-seq data collection and computational analysis were used to investigate immune cell tumor infiltration and differentiation. The synergistic tumor-suppressing effect of 9MW3811 with anti-PD-1 antibody was evaluated in MC38, CT26 and Hepa1-6 syngeneic models. Results: 9MW3811 showed sub-nanomolar binding affinity to recombinant and membrane bound IL-11 derived from human, mouse, rat and dog. 9MW3811 effectively blocked the formation of IL-11/IL-11R/gp130 protein complex, and inhibited the downstream cell signaling transduction. In the NSCLC A549 xenograft model, as compared with isotype control hIgG, 9MW3811 (2mpk) showed significant tumor growth inhibition (TGI 62%). In two LUSC PDX models, the TGIs for 9MW3811 (10 mpk) were 50% and 28%, respectively. Further, in MC38 and Hepa1-6 syngeneic models, 9MW3811 addition increased the TGI of anti-PD-1 antibody from 45% to 83%, and 34% to 75%, respectively. Interestingly, in an anti-PD-1 non-responsive CT26 model, the combo of 9MW3811/anti-PD-1 antibody exhibited an impressive antitumor activity (TGI 67%). Mechanistic study showed that treatment with 9MW3811 could significantly ameliorate T cell exhaustion, increase CD8+ T cells tumor infiltration and enhance the cytotoxic function of these infiltrated T cells by modulating the expression of a variety of cytokines/chemokines Conclusion: Our results demonstrated profound antitumor activity of 9MW3811 in different tumor models. 9MW3811 is currently in phase I clinical trials in AU, CN and US. Citation Format: Shuang Wang, Chang Zhang, Shasha Jiao, Dadi Zeng, Rongjuan Wang, Min Wang, Weining Lu, Bin Zheng, Xun Gui, Jinchao Zhang. Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2365.