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

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.

Effects of Pre-Sleep Whey vs. Plant-Based Protein Consumption on Muscle Recovery Following Damaging Morning Exercise.

Pre-sleep whey protein intake has been shown to improve overnight muscle protein synthesis, muscle size and strength, and muscle recovery. Despite a growing interest in alternative protein sources, such as plant-based protein, there is no evidence regarding the efficacy of plant-based proteins consumed pre-sleep. Therefore, we aimed to compare whey vs. plant-based pre-sleep protein dietary supplementation on muscle recovery in middle-aged men. Twenty-seven recreationally active, middle-aged men performed 5 sets of 15 repetitions of maximal eccentric voluntary contractions (ECC) for the knee extensors (ext) and flexors (flex), respectively, in the morning. Participants consumed 40 g of either whey hydrolysate (WH, n = 9), whey isolate (WI, n = 6), rice and pea combination (RP, n = 6), or placebo (PL, n = 6) 30 min pre-sleep on the day of ECC and the following two nights. Catered meals (15% PRO, 55% CHO, 30% Fat) were provided to participants for 5 days to standardize nutrition. Plasma creatine kinase (CK), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured at pre, immediately post (+0), +4, +6, +24, +48, and +72 h post-ECC. Isometric (ISOM) and isokinetic (ISOK) maximal voluntary contraction force were measured at pre, immediately post (+0), +24, +48, and +72 h post-ECC. Muscle soreness, thigh circumference, and HOMA-IR were measured at pre, +24, +48, and +72 h post-ECC. CK was increased at +4 h post-ECC, remained elevated at all time points compared to baseline (p < 0.001), and was significantly greater at +72 h compared to all other time points (p < 0.001). IL-6 was increased at +6 h (p = 0.002) with no other time differing from baseline. ISOMext was reduced after ECC (p = 0.001) and remained reduced until returning to baseline at +72 h. ISOMflex, ISOKext, and ISOKflex were reduced after ECC and remained reduced at +72 h (p < 0.001). Muscle soreness increased post-ECC (p < 0.001) and did not return to baseline. Thigh circumference (p = 0.456) and HOMA-IR (p = 0.396) did not change post-ECC. There were no significant differences between groups for any outcome measure. These data suggest that middle-aged men consuming 1.08 ± 0.02 g/kg/day PRO did not recover from damaging eccentric exercise at +72 h and that pre-sleep protein ingestion, regardless of protein source, did not aid in muscle recovery when damaging eccentric exercise was performed in the morning.