1186 ASKG193, a novel masked CD19 T-cell engager exhibited potency and expanded safety

Background T-cell engager (TCE) is a potent antibody-based molecule that induced T cell-mediated killing by bridging CD3 and tumor-associated antigen(TAA).However, therapeutic potential has been significantly limited due to its poor pharmacokinetic, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS).Methods To improve the developability of TCEs, a proprietary TCE prodrug platform was established to achieve its overarching objective of modulating immune reactions at a disease site in a selective and controlled manner.Several prodrug-TCE molecules were designed and tested, including binding, cytotoxicity, and cytokine release assays in vitro, as well as safety and efficacy studies in vivo.Results Here, we reported ASKG193, a next generation CD19-CD3 TCE, with a masking strategy to attenuate off-target toxicity, extend half-life and improve systemic exposure.The non-activated ASKG193 showed no activity, while the activated form demonstrated >100 folds attenuation in vitro compared to a CD19 Bi-specific T-cell engager (BiTE).In ex vivo B-cell depletion assay, ASKG193 retained potent cytolytic activity comparable to the CD19 BiTE molecule.In addition, ASKG193 was well tolerated in vivo.Conclusions In summary, the masked CD19 TCE, ASKG193, exhibited superior anti-tumor efficacy, prolonged half-life, and a significantly improved safety profile.Our data demonstrated that the ASKG193 has the potential to substantially broaden the therapeutic window for CD19-targeted immunotherapies.