Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma

Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies.

A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma.

To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC₅₀ and EC₉₀ values from an ex vivo cytotoxicity assay).

The doses predicted to have average serum concentrations between the EC₅₀ and EC₉₀ range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC₉₀. The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC₉₀. All patients who responded to the RP2D of teclistamab had exposure above the maximum EC₉₀ in both serum and bone marrow on cycle 3, Day 1 of treatment.

Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range.

NCT03145181, date of registration: May 9, 2017.