Clinical Validation of a QSP Model for ISB 2001, a Trispecific T Cell Engager to Support Optimal FIH Study Design in...

ISB 2001 is a trispecific antibody that binds to two tumor-associated antigens (TAA), CD38 and BCMA, and crosslinks to CD3 on T cells resulting in T cell-mediated cytotoxicity of tumor cells expressing these TAAs. ISB 2001 is currently being tested in relapsed and/or refractory multiple myeloma (RRMM) patients in the first-in-human (FIH) TRIgnite-1 study (NCT05862012). The CD3ε-binding domain of ISB 2001 does not cross-react with CD3 in cynomolgus monkeys. Therefore, no pharmacokinetic, efficacy, or toxicology data could be generated in a fully cross-reactive preclinical species to facilitate prediction of optimal FIH dose or the clinical efficacy dose range. For T cell engagers (TCEs), the minimum anticipated biological effect level (MABEL) approach is widely used to derive FIH doses. While this method is considered safe, this standard approach may result in starting doses that are sometimes too low to elicit meaningful clinical activity, potentially leading to several dose escalation cohorts at subtherapeutic levels in seriously ill patients. We used a novel quantitative systems pharmacology (QSP) model to inform FIH dose selection and predict the clinical efficacy dose range for ISB 2001. This modeling strategy enabled an efficient dose escalation design for the TRIgnite-1. This approach is consistent with the emerging FDA roadmap to reduce animal testing by utilizing computational modeling methodologies for FIH dose selection. Finally, we demonstrate the validation of the QSP model and approach by comparing its predictions with evolving preliminary safety, PK, and antimyeloma activity data from the ongoing TRIgnite-1 clinical trial.