Antibody geometry governs FcRn recycling and clearance, with Fab-at-C-terminus formats lasting longer
- A panel of rationally designed antibody geometries was tested in orthogonal in vitro assays to see how spatial layout affects FcRn-mediated recycling. Placing Fab domains at the C-terminus (invertbodies) improved recycling, while crowding the N-terminus impaired it.
- Architecture and affinity-enhancing Fc mutations acted independently but cooperatively, pointing to a physiological ceiling on recycling. Non-specific endocytosis was affected only modestly.
- In humanized FcRn mice, architecture produced large differences in clearance that disappeared in FcRn-knockout mice. An invertbody variant of golimumab cleared more slowly without losing potency.
💡 Points Based on the abstract
Would I trust a humanized-FcRn mouse to rank half-lives in people? It's a good mechanism check, and the knockout control is reassuring, but cynomolgus data and target-mediated disposal often reshuffle the order. Also, a rearranged format is a new molecule: immunogenicity, aggregation and manufacturability of C-terminal Fabs need to be shown before the longer half-life counts as a win.
Spatial architecture of complex antibody formats dictates pharmacokinetics via FcRn-recycling ↗