Modeling effective doses of therapeutic antibodies targeting clustered surface receptors

Standard monoclonal antibody dosing aims for the maximally tolerated dose (MTD) — an approach that has repeatedly failed in oncology. Using antibodies against TNFR2 (a target largely restricted to cancer cells and immunosuppressive regulatory T cells in the tumor microenvironment), the authors developed a semi-mechanistic pharmacokinetic/receptor-occupancy (PK/RO) model built on JeKo-1 lymphoma cytotoxicity assays and cynomolgus monkey PK data. Because a TNFR2 antagonist antibody must stabilize an anti-parallel dimer of two adjacent receptors, its dose–response is bell-shaped rather than sigmoidal — meaning maximal activity occurs below the MTD. Modeling in monkeys confirmed the bell-shaped curve and showed that subcutaneous (SC) dosing, with its lower peak-to-trough ratio, more reliably maintains the exposure window that maximizes bivalent surface complexes. The work argues for identifying an optimal exposure range rather than maximizing dose for antibodies targeting clustered receptors.