1317 A quantitative systems pharmacology model for first-in-human dosing of MDX2001, a multispecific antibody for the treatment of advanced solid tumors

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Background MDX2001 is a tetravalent T cell engager antibody recognizing CD3 and CD28 on human T cells and cMET and TROP2 on target solid tumor cells. Simultaneous binding of MDX2001 to T cells and targeted tumor cells results in the creation of a multivalent complex bridging the two cells, referred to here as a ‘cross-cell bridging complex’. The formation of this complex underlies the pharmacologic activity for both the efficacy and toxicity of T cell engager (TCE) molecules.1 As with other TCEs, understanding the relationship between drug exposure and the rate of cross-cell bridging complex formation is complicated by its dependence on several variables including local drug concentrations and target binding affinities, local concentration of T cells and target-expressing tumor cells, and the density of target expression. Quantitative systems pharmacology (QSP) modeling was a well-suited tool for integrating MDX2001 data across multiple preclinical study systems to predict pharmacologic activity given its dependency upon multiple interdependent variables. Methods The objective of this study was to develop a QSP model that included PK-PD modeling as well as systems pharmacology to computationally inform dose selections for a Phase 1/2a study evaluating MDX2001. The QSP model was developed and calibrated using inputs from in vitro binding, cytokine release and cytotoxicity assays, along with mouse and cynomolgus monkey pharmacokinetic studies and physiologic target parameters in humans with representation of both cis- and trans- target binding and avidity. The resulting model was used to estimate starting doses based on the minimal anticipated biological effect level as well as pharmacologically active doses using metrics based on the model-predicted cross-cell bridging complexes. Results Model outputs included drug concentration and cross-cell bridging complex levels in the central, peripheral and tumor compartment over time for given dose levels and administration schedules. Based on an EC20 of cytokine release in the central compartment, the model predicts a starting dose of lower than 5.0 μg/kg. The model predicts an efficacious dose in the high μg/kg range based on the EC90 of MDX2001 for cell lysis activity in the tumor compartment. Conclusions The final QSP model supports initiation of first-in-human studies with MDX2001 in patients with advanced solid tumor malignancies. Reference Betts A, van der Graaf PH. Mechanistic quantitative pharmacology strategies for the early clinical development of bispecific antibodies in oncology. 2020;108:528.541. Ethics Approval All animal experiments were performed under protocols approved by the appropriate Institutional Animal Care and Use Committees.

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