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

ISB 2001 is a trispecific T cell engager (TCE) that binds the tumor-associated antigens CD38 and BCMA and crosslinks CD3 on T cells to trigger T cell–mediated killing of myeloma cells. Because its CD3-binding domain is not cross-reactive in cynomolgus monkeys, no conventional preclinical PK, efficacy, or toxicology data were available to guide first-in-human (FIH) dosing. Rather than rely on the conventional, conservative MABEL approach (which tends to start far below therapeutic levels and exposes seriously ill patients to multiple subtherapeutic escalation cohorts), the team built a quantitative systems pharmacology (QSP) model integrating in-vitro, in-vivo, and clinical benchmark data (including teclistamab) to select an efficacy-proximal FIH dose and predict the clinical efficacy dose range. The strategy enabled an efficient phase 1 dose-escalation design for the TRIgnite-1 study (NCT05862012) and aligns with the emerging FDA roadmap to reduce animal testing through computational methods. The model’s predictions were then validated against evolving preliminary safety, PK, and antimyeloma activity data from the ongoing trial.