Spatial architecture of complex antibody formats dictates pharmacokinetics via FcRn-recycling

In a panel of rationally designed antibody geometries, spatial architecture drives nearly 15-fold variance in in vivo clearance (CL) in a humanized FcRn mouse model, collapsing in FcRn-knockout mice.

• Why it matters: Non-canonical antibody formats may alter FcRn-mediated recycling, but the strength and direction of this effect across diverse architectures has been unclear, limiting rational pharmacokinetic optimization.
• What they did: The study used orthogonal in vitro assays to quantify FcRn-recycling efficiency and non-specific endocytosis across antibody layouts, then tested clearance in humanized FcRn mice and FcRn-knockout mice.
• The result: Inverting antibody structure by placing Fab domains at the C-terminus (invertbodies) maximized recycling, while N-terminal crowding severely impaired it; architecture and Fc-FcRn affinity mutations acted independently yet cooperatively, enabling a three-fold CL reduction for an invertbody golimumab variant.

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