Immuno-Modulatory Platform for Advanced CLL Therapy

Objectif

This project aims to advance a first-in-class/best-in-disease novel trispecific T cell engager, TRIDENT-19, with improved efficacy as compared to standard CD3-based bispecifics as it overcomes tumor-associated T cell dysfunction. Multispecific antibodies (MA) enable simultaneous engagement of immune effector cells and tumor cells. Crosstalk within the tumor microenvironment frequently impairs T cell function, leading to partial and short-lived responses to CD3-engaging multispecific antibodies in cancers such as in CLL. Based on our ERC-Consolidator funded studies (864815/BOOTCAMP), we made the exciting discovery of an alternative T-cell activating entry point that bypasses tumor-mediated T-cell dysfunction. To exploit this finding, we developed a (ERC PoC funded) trispecific T-cell engager platform to overcome limitations of CD3 engagers. This led to a lead CD19 engaging candidate, TRIDENT-19, that induces potent T cell responses against malignant B cells, outperforming a CD3-based control compound, highlighting its potential as a therapeutic candidate.
IMPACT will address key steps required to move TRIDENT-19 towards clinical readiness:
1) The optimization of the IgG1-based T cell engaging scaffold, by designing backbone variables and identifying the most efficient configuration of the TRIDENT scaffold using cell lines and primary patient-derived tumor- and T cells.
2) Investigation of different binder combinations, comparing clinically validated CD19 binders and assessing whether optimized targeting improves cytotoxic activity.
3) Evaluation of TRIDENT’s applicability to other B-cell malignancies by targeting additional validated antigens. In parallel, the project will develop a comprehensive business plan and engage with CMC, clinical & regulatory experts to define a product development strategy and a clear roadmap that de‑risks the transition into first‑in‑human studies of the lead candidate.