Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T-cells undergoing trafficking, whereas the formation of the tri-molecular complex results in T-cell activation and clonal expansion. Activated T-cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in 8 monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T-cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions:A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacological activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CCf5zi
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