Abstract B029: Forging strong bidirectional preclinical and translational research for optimized drug development of Sym023 (S095018), a novel anti-TIM3 antibody

Abstract Immune checkpoint inhibitors targeting TIM3, a molecule frequently co-expressed with PD1 on exhausted T cells and myeloid cells, represent a promising approach in cancer immunotherapy. Inhibition of TIM3 in myeloid cells promotes their activation and has been shown to enhance anti-tumor responses in both monotherapy and combination with immunotherapy or chemotherapy in mouse models (PMID: 34108686). Sym023 (S095018) offers a novel strategy for targeting TIM3 with distinct properties. Beyond blocking the binding of galectin 9 and phosphatidylserine to TIM3, our preclinical studies demonstrate that Sym023 has a direct effect on dendritic cells, inducing their maturation and triggering downstream activation of T cells. In mouse models, the combination of Sym023 (S095018) with an anti-PD1 antibody significantly improved survival and tumor control. Based on these findings and existing literature, the safety and efficacy of the combination of Sym023 with anti-PD1 (sym021) was evaluated in a phase Ib/II expansion study (Sym021-02; NCT04641871) in biliary tract cancer (BTC) patients. An in-depth biomarker plan was implemented to analyze biopsies at screening and the end of cycle 1 (EOC1). On 19 tumor biopsies, 7-plex immunohistochemistry (IHC) and transcriptomic profiling (Nanostring) were performed to study the changes in immune infiltrates during the treatment course. The combination of Sym023 and Sym021 led to increased levels of IFNg and myeloid chemokines (e.g., CXCL9, CXCL10). Treatment resulted in a higher density of activated T cells within the tumor islets, along with the upregulation of cytotoxicity-related genes. Transcriptomic profiling further revealed an upregulation of antigen processing pathways, supporting the translatability of Sym023’s mechanism of action on both T cells and myeloid cells in patients. Drawing from preclinical and biomarker data from the Sym021-02 trial, a biomarker-driven analysis was conducted to identify patients most likely to respond to the Sym023 and anti-PD1 combination. Through this translational analysis, non-small cell lung cancer (NSCLC) was identified as having significant infiltration by myeloid cells and CD8+ T cells, along with high intra-tumoral TIM3 expression, positioning NSCLC as a relevant and promising indication for this combination therapy. A platform trial (NCT06162572) featuring an arm combining cemiplimab (anti-PD1) with Sym023 (S095018) was launched for first-line treatment of patients with advanced/metastatic NSCLC with high PDL1 expression. Citation Format: Julia Geronimi, Aditi Varthaman, Trine Lindsted, Franziska Uhlenbrock, Camilla Frölich, Vincent Lombardi, Christelle Cousin, Mathieu Boucher, Audrey Delmas, Pauline Darcel, Xenophon Ianopulos, Hélène Kaplon. Forging strong bidirectional preclinical and translational research for optimized drug development of Sym023 (S095018), a novel anti-TIM3 antibody [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B029.