Translational Approach of Using Ex Vivo Cytotoxicity and Early Clinical Data to Predict Teclistamab Efficacious Therapeutic Range in Multiple Myeloma Patients
Authors: Girgis Suzette , Wang Lin Shun Xin , Pillarisetti Kodandaram , Banerjee Arnob , Goldberg Jenna D. , Shetty Shoba , Stephenson Tara , Hilder Brandi W. , Hanna Brett , Smit Jennifer , Adams III Homer , Sun Yu-Nien (Tom) , Infante Jeffrey R. , Elsayed Yusri A , Sharma Amarnath 
Published: February 2021

B cell maturation antigen (BCMA; CD269; TNFRSF17) is a surface receptor, expressed on benign and malignant plasma cells. The restricted expression of BCMA on B-cell lineage makes it an ideal target for multiple myeloma (MM) immunotherapy. BCMAxCD3 bispecific antibody (Teclistamab; JNJ-64007957) has been developed to recruit CD3+ T-cells to BCMA+ MM cells. Teclistamab demonstrated potent cytotoxicity in a murine xenograft model and against ex vivo primary MM cells.
Teclistamab clinical starting dose in the first in human (FIH) study in relapsed refractory MM patients began at the minimal anticipated biological effect level (MABEL) of 0.3 µg/kg using the EC20 of the in vitro cytotoxicity assay in the purified T cells model with MM.1R cell line. Since the MABEL dose is usually low, it is important to have guidance on the expected therapeutic range in patients.
The therapeutic concentrations of teclistamab were estimated from an ex vivo cytotoxicity assay in which samples from MM patients (frozen purified mononuclear cells from bone marrow) were treated with healthy human purified T cells (1:1 ratio) spiked with teclistamab and incubated for 48 hours. The mean and range of EC50 and EC90 values of the cytotoxicity endpoint were estimated. The pharmacokinetic (PK) data following the first cycle doses in the low dose cohorts in the FIH study in MM patients were modeled using 2-compartment model and simulated to predict the doses that will have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC50 and EC90).
The predicted doses with average serum concentrations between the mean EC50 (372 ng/mL) and mean EC90 (2287 ng/mL) range were validated with the observed clinical data showing positive response in 2 out of 4 patients at the 38.4 µg/kg intravenous treatment dose level and their average serum teclistamab concentration overlaid within the estimated therapeutic range. This was also confirmed with the teclistamab concentrations in bone marrow samples (measured in a subset of MM patients in the study) where they were found to superimpose in the estimated therapeutic range. In addition, simulations predicted the dose that will have trough levels above the maximum EC90 (6070 ng/mL), to account for patients with high tumor burden, at which the observed clinical data have shown promising response rate and has been selected to be the recommended subcutaneous phase 2 dose of 1500 µg/kg.
In conclusion, ex vivo cytotoxicity assay with MM patients bone marrow samples is an informative tool to predict the efficacious serum concentration of immuno-oncology drugs in MM patients. PK modeling and simulations of MM patients' data in FIH study coupled with the ex vivo cytotoxicity estimates provided guidance on the expected recommended phase 2 dose during the escalation phase of the FIH study.

Disclosures
Girgis: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Wang Lin:Johnson & Johnson: Current Employment. Pillarisetti:Johnson & Johnson: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Shetty:Johnson & Johnson: Current Employment. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hanna:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Smit:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Adams III:Genmab: Current Employment. Sun:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Infante:Janssen: Current Employment. Elsayed:Johnson & Johnson: Current Employment. Sharma:Johnson & Johnson: Current Employment.