Abstract Selective activation of T cells expressing specific TCR Vβ components presents a promising clinically validated strategy for the treatment of advanced metastatic cancers. IPN01203 is a bi-specific antibody designed to activate and expand T cells expressing Vβ6/Vβ10 TCRs, that are enriched in tumor infiltrating lymphocytes (TILs) relative to other Vβ subsets, while also providing unique co-stimulation to IL-2/IL-15βγ cytokine receptors. IPN01203 pharmacology was characterized across human, cynomolgus, and murine immune cells for target engagement, signaling, and functional responses. Efficacy and PK-PD relationships were evaluated in murine tumor models, with immune profiling via scRNAseq/TCRseq. In vivo pharmacology and toxicology were further assessed in cynomolgus monkeys (NHPs). Collectively, these studies established a robust translational framework to support FIH study design. IPN01203 demonstrated potent and selective binding to Vβ6/Vβ10 T CD8+ and CD4+ T cell subsets (EC50 ∼1. 2-1. 3 nM), with minimal activity on B cells and monocytes. IPN01203 induced CD25 expression and expansion of Vβ6/Vβ10 T cells, activating both TCR (pERK, pSLP76) and IL-15R (pSTAT5) signaling pathways. TCR sequencing confirmed enrichment of TRBV6-5, 6-1, 6-2, and 10-3 clonotypes. T cells acquired a TCM phenotype. In NHP PBMCs, similar potency and selectivity were observed, with EC50 values around 0. 3 nM. Murine surrogate mIPN01203 selectively expanded TRBV13+ CD8+ T cells, with comparable activity as IPN01203. Surface plasmon resonance studies revealed high-affinity (Kd) binding to human Vβ6-5 (1. 9 nM), cynomolgus Vβ6-2 (5. 6 nM), and IL-15Rβγ (0. 4-0. 5 nM), supporting clonotype specificity. In NHPs, IPN01203 led to a dose-dependent and sustained expansion of peripheral Vβ6/Vβ10 T cells, with expression of markers CD25 and pSTAT5, as well as limited cytokine release or expansion of Treg, aligned with the expected MoA. Despite anti-drug antibody responses, pharmacodynamic effects were maintained. In several syngeneic murine tumor models, mIPN01203 achieved robust tumor growth inhibition, and complete regressions and immune memory were observed in CT26 and B16F10 models. Tumor efficacy was dependent on expansion and activation of both CD8+ and Vβ13+-specific T cells and similar Vβ13+ T-cells peripheral expansion. scRNAseq and TCRseq demonstrated the expansion of TCM and TEM of Vb13+ TILs and an increase in the CD8: Treg ratio as well as increased clonal diversity. Nonclinical toxicology findings support an acceptable safety profile for IPN01203 aligned with its MoA. These findings position IPN01203 as a promising next gen immuno-oncology bi-specific antibody for selective in vivo T cell modulation with durable antitumor efficacy, clonotype-specific engagement and memory T cell formation, supporting its advancement in clinical development. A Phase I FIH study received IND approval and is recruiting patients (NCT07213830). Citation Format: Enguerran Mouly, Karen Bunting, Andrew Bayliffe, Benjamin Beaufils, Marion Dehez, Dorinne Desposito, Gurkan Guntas, Thierry Guyon, Mary Jane Hinrichs, Jonathan Hsu, Wei Huang, Madan Katragadda, Dihia Labat-Meghnem, Guillaume Lang, Jacques Moisan, Aaron Navartil, Kent Nybakken, Karunya Srinivasan, Zhen Su, Jian Tang, Stephan G. Klinz, Elisabetta Leo. Development of IPN01203, a dual T cell agonist activating Vβ6/Vβ10 TCR-expressing T cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND12.
Mouly et al. (Fri,) studied this question.