Modeling effective doses of therapeutic antibodies targeting clustered surface receptors

Abstract

Abstract A longstanding practice for therapeutic dosing of monoclonal antibodies is to identify the maximally tolerated dose. However, this approach has encountered limited success with some antibodies, especially in failed cancer trials. Here we report on an alternative dose-finding approach using antibodies against the promising new oncological target, tumor necrosis factor receptor 2 (TNFR2). TNFR2 expression is largely restricted to cancer cells and to regulatory T cells (Treg) in the tumor microenvironment. TNFR2 inhibition with antibodies reduces immunosuppressive Treg with subsequent activation of effector T cells and can directly kill cancer cells. Drawing on cytotoxicity assays in a human lymphoma cell line (JeKo-1) and pharmacokinetic data from cynomolgus monkeys, we developed a semi-mechanistic pharmacokinetic/receptor occupancy (PK/RO) model for the tumor microenvironment. As shown previously, TNFR2 antagonistic signaling is best when the antibody stabilizes an anti-parallel dimer of two adjacent TNFR2 proteins on the cell surface. Culture studies with a TNFR2 antagonist antibody show a bell-shaped dose-response curve instead of sigmoidal. Thus, we hypothesize that the maximal activity occurs at doses below the maximum tolerated. Dose modeling in monkeys confirmed that the antibody dose-response followed a bell-shaped curve. Due to lower peak-to-trough ratio, a subcutaneous (SC) route was found more effective at reaching the desired cell surface bivalent complexes while staying on the left side of the bell-shaped curve. Our findings address dosing challenges associated with the complex biology of bivalent antibodies and support a mechanistic hypothesis that may help explain clinical observations with antibodies targeting clustered receptors. While this work focuses on a TNFR2-targeting antibody, it highlights the importance of identifying an optimal exposure range rather than maximizing dose. In this context, dosing strategies that maintain drug concentrations within this range, including SC administration, may improve therapeutic performance.