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

Abstract

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

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

Patients and methods: 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).

Results: 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.

Conclusions: 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.

Clinical trial registration: NCT03145181, date of registration: May 9, 2017.

Conflict of interest statement

B. Hanna, H. Adams, S. Shetty, and Y. Sun were employees of Johnson & Johnson during the completion of this work. All other authors are current employees of Johnson & Johnson and may hold stock in Johnson & Johnson.

© 2022. The Author(s).

Figures

Fig. 1

Teclistamab pharmacokinetic simulation using a non-linear mixed-effect modeling approach. Simulated teclistamab serum concentrations following weekly a intravenous and b subcutaneous dosing. EC50 concentration at 50% of maximum effect, EC90 concentration at 90% of maximum effect, IV intravenous, Max maximum, SC subcutaneous

Fig. 2

Response rates at highly active doses of teclistamab [8]. CR complete response, ORR overall response rate, PR partial response, sCR stringent complete response, VGPR very good PR, ≥ VGPR VGPR or better. aIncludes stringent complete response, complete response, very good partial response, and partial response. Response data are based on a clinical cut-off date of March 29, 2021 [8]

Fig. 3

Teclistamab pharmacokinetic profile following first treatment dose. Teclistamab serum concentrations after a most active intravenous doses and b most active subcutaneous doses. EC50 concentration at 50% of maximum effect, EC90 concentration at 90% of maximum effect, IV intravenous, Max maximum, SC subcutaneous

Fig. 4

Teclistamab concentrations in serum versus bone marrow. a Teclistamab serum concentrations in male cynomolgus monkeys and b teclistamab serum and bone marrow concentrations in patients with multiple myeloma treated with highly active intravenous and subcutaneous doses. Percentage of bone marrow plasma cells at baseline for each patient are shown. BMPC bone marrow plasma cell, EC90 concentration at 90% of maximum effect, IV intravenous, Max maximum, NR nonresponder, SC subcutaneous. aPatients had a partial response or better. bPatients had stable or progressive disease as best response