Pharmacokinetics and pharmacodynamics of the cytolytic anti‐<scp>CD</scp>38 human monoclonal antibody <scp>TAK</scp>‐079 in monkey – model assisted preparation for the first in human trial

Abstract

We are studying the fully human, IgG1λ cytolytic monoclonal antibody TAK-079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells. Therefore, safety and function of TAK-079 was evaluated in this species, prior to clinical development, using bioanalytical, and flow cytometry assays. We pooled the data from eight studies in healthy monkeys (dose range 0.03-100 mg/kg) and developed mathematical models that describe the pharmacokinetics and the exposure-effect relationship for NK cells, B cells, and T cells. NK cell depletion was identified as the most sensitive pharmacodynamic effect of TAK-079. It was adequately described with a turnover model (C₅₀ = 27.5 μg/mL on depletion rate) and complete depletion was achieved with an IV dose of 0.3 mg/kg. Intermediate effects on T-cell counts were described with a direct response model (C₅₀ = 11.9 μg/mL) and on B-cell counts with a 4-transit-compartment model (C₅₀ = 19.8 μg/mL on depletion rate). Our analyses substantiate the observation that NK, B and T cells are cleared by TAK-079 at different rates and required different time spans to replete the blood compartment. The models were used to simulate pharmacokinetic and cell depletion profiles in humans after applying a straightforward scaling approach for monoclonal antibodies in preparation for the first-in-human clinical trial.