Novel Trispecific Antibody Offers New Path Forward for Patients With Multiple Myeloma

A quantitative systems pharmacology (QSP) model of ISB 2001, a novel trispecific antibody, offers an effective pathway for designing phase 1 studies of future T-cell engagers (TCEs) for patients with relapsed or refractory multiple myeloma (MM).¹

Previous literature revealed very low first-in-human (FIH) dose selection in the TCE space through minimum anticipated biological effect level (MABEL). Due to the lack of pharmacokinetic (PK) monkey and preclinical toxicology data on FIH dose calculation, the researchers developed a human QSP model to determine an efficient phase 1 dose escalation design for patients with relapsed or refractory MM. To enable efficacy predictions, the model was calibrated with in vitro and in vivo experiments.¹

The in vitro pharmacology model for ISB 2001 and teclistamab for T-cell activation and tumor cytotoxicity was developed using in-house and experimental data, while the in vivo preclinical efficacy model was built around murine PK and physiologically based PK (PBPK) data of ISB 2001 and teclistamab with and without tumors present.²

To calculate the minimal pharmacologically active dose (MPAD) of ISB 2001, the researchers benchmarked the QSP model with clinical data of teclistamab. Objective tumor responses occurred at dose levels starting from 50 µg/kg.¹

This research was measured alongside part one of an ISB 2001-101 study focused on dose escalation and PK bioanalysis. Through clinical validation of the ISB 2001 QSP model, anti-tumor activity of dose range matching was observed within model predictions.¹

“Despite the absence of monkey PK and toxicology data, this QSP-guided approach successfully predicted an optimal FIH dose, clinical PK, safety, and anti-myeloma activity, while minimizing patient exposure to sub-therapeutic doses,” the researchers concluded.¹

References

1. 2025 American Association for Cancer Research Annual Meeting. Abstract No. 3694.
2. Carretero-Iglesia L, et al. Nat Cancer. 2024; 5:1494–1514. doi:10.1038/s43018-024-00821-1