Director, Immunobiology/Associate Professor, Medicine Massachusetts General Hospital/Harvard Medical School Boston, Massachusetts, United States
Disclosure(s):
Denise Faustman, MD, PhD: No financial relationships to disclose
Introduction/Rationale: A longstanding practice for therapeutic dosing of monoclonal antibodies is to identify the maximally tolerated dose (MTD). However, this approach has had limited success with some antibodies, especially in cancer trials. Here we report on an alternative approach using novel antibodies against tumor necrosis factor receptor 2 (TNFR2), an oncology target. TNFR2 expression is largely restricted to cancer cells and to regulatory T cells (Treg) in the tumor microenvironment; TNFR2 inhibition with antibodies reduces immunosuppressive Tregs with subsequent activation of effector T cells and can directly kill cancer cells.
Methods: Using data from cytotoxicity assays in a human lymphoma cell line (JeKo-1) and a pharmacokinetic (PK) study in cynomolgus monkeys, we developed a semi-mechanistic PK/receptor occupancy model for the tumor microenvironment and simulated effective doses of novel anti-TNFR2 antagonist antibodies for humans.
Results: TNFR2 antagonistic signaling was best when the antibody stabilized an anti-parallel dimer of two adjacent TNFR2 proteins on the cell surface. Studies in culture showed a bell-shaped, rather than sigmoidal, dose-response curve. Thus, maximal activity occurred at doses far below the MTD. 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 than an intravenous (IV) route at reaching the desired cell surface bicomplexes.
Conclusion: These findings define the complex biology of bivalent antibodies and help explain a vast literature on failed cancer antibody clinical trials. For such antibodies, modeling of cell surface clustering antibodies predicts potency with low doses and SC administration. A low dose of antibodies, delivered subcutaneously, allows for consistent, optimal concentration of drug with a low peak-to-trough ratio that maximizes bicomplex formation, and is therefore recommended over higher-dose IV administration.
