Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Abstract

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. Thirty-two animals received multiple escalating doses (100-300-600-1,000 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 trimolecular 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 eight monkeys receiving continuous 7-day infusions. 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. A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacologic activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies. .

Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: a retrospective study by the I-BFM Study Group

“…Although we unfortunately have no data on surface marker expression in these specific cases, more experimental therapy such as flotetuzumab or CAR T cells may offer opportunities to circumvent chemotherapy drug resistance and need to be explored in these high-risk FUS-ERG patients, certainly after relapse. [57][58][59][60] supervised the study; and all coauthors performed critical review of the manuscript and gave their final approval.…”

Mechanistic Quantitative Pharmacology Strategies for the Early Clinical Development of Bispecific Antibodies in Oncology

“…Some examples of the use of QSP models to translate preclinical data to the clinic are emerging in the literature for the CD3 bsAbs. For example, Campagne et al 61 . developed a PK/PD model for a bispecific CD123/CD3 DART molecule in non‐human primates.…”

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Recently, three mechanistic PK/PD modeling analyses for bispecific biotherapeutics have been published to guide rational translational research and clinical study design for T-cell redirecting bsAbs. 16–18 All three of these model analyses explored strategies to predict and translate in vivo pharmacodynamic and toxic effects (i.e., cytokine release) using in vitro data for T-cell redirecting bsAbs and physiological system measurements, and accounted for the concentration of the tri-molecular synapse between bsAb, T cell, and target tumor cell. These analyses pioneered the use of mechanism-based PK/PD modeling to characterize the critical steps that govern the pharmacological effects mediated by T-cell redirecting bsAbs.…”