Abstract 2234: SOF10, a novel selective anti-latent TGF-β1 antibody, augments the efficacy of anti-PD-L1 antibody via modulation of the tumor microenvironment

Abstract Background: TGF-β is a highly pleiotropic cytokine, consisting of three isoforms: TGF-β1, TGF-β2, and TGF-β3. The TGF-β signaling is known to be associated with a poor response to immune checkpoint inhibitors. Multiple agents targeting TGF-β have been developed with focus on the physiological effects of TGF-β in the tumor microenvironment; however, inhibition of multiple TGF-β isoforms have exhibited serious cardiac toxicity and bleeding in nonclinical studies. TGF-β1 is expressed as inactive latent complex and reported to be most highly expressed among all the isoforms in tumors. Selective inhibition of latent TGF-β1 activation may address the potential safety risk and provide an effective approach for targeting the TGF-β pathway in tumors. Methods: We generated SOF10, a novel anti-latent TGF-β1 antibody, which selectively inhibits latent TGF-β1 activation. To assess the inhibitory mechanism of SOF10 for latent TGF-β1 activation, we evaluated multiple proteases-mediated TGF-β1 activation, integrin-mediated TGF-β1 activation, and determined the structure of the SOF10 Fab and latent TGF-β1 complex. We then tested combinational efficacy of SOF10 with anti-PD-L1 antibody in EMT6 murine breast cancer model, and CT26 murine colon cancer model. To analyze the effects on tumor microenvironment, we evaluated CD8 T cells and cancer-associated fibroblasts (CAFs). Finally, we conducted 3-month repeat-dose toxicity studies (GLP) in mice and cynomolgus monkey. Results: SOF10 inhibited multiple proteases- and αvβ8-mediated latent TGF-β1 activation. Structural analysis of SOF10 showed the unique binding mode in which SOF10 inserted into the dimer surface of the LAP domain of TGF-β1. In vivo studies demonstrated combinatorial effect of SOF10 and anti-PD-L1 antibody in tumor growth inhibition for the treatment of EMT-6 and CT26 murine cancer models. Evaluation of CD8 T cells showed increased influx and enhanced activation of CD8 T cells in the combination group. RNA analysis of CAFs also revealed downregulation of ECM synthesis by SOF10 treatment. Lastly, no toxicologically relevant changes were observed in 3-month repeat-dose toxicity studies (GLP). Conclusions: Our data suggest that SOF10, a selective anti-latent TGF-β1 antibody, can exert antitumor efficacy in combination with anti-PD-L1 antibody by modulating CAF dynamics and overcomes immune exclusion with preferable safety profile. Clinical studies of SOF10 are currently on-going for patients with solid cancer (NCT05867121) Citation Format: Kenji Nakagawa, Izumi Sato, Masakazu Kanamori, Silvia Sun, Kentaro Asanuma, Hiroki Kawauchi, Chisako Kanamaru, Yoko Kayukawa, Saori Matsuo, Meiri Shida-Kawazoe, Takehisa Kitazawa, Tomoyuki Igawa, Hideaki Shimada. SOF10, a novel selective anti-latent TGF-β1 antibody, augments the efficacy of anti-PD-L1 antibody via modulation of the tumor microenvironment [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 2234.