Abstract
Purpose: Certolizumab pegol is a novel PEGylated Fc-free anti-tumour necrosis factor alpha (TNF α) biopharmaceutical. We have determined the structure of certolizumab pegol using a variety of techniques. Methods: Crystals of Fab' were grown and analysed by X-ray crystallography. The structures of Fab' and Fab'-PEG conjugate in solution were investigated by a variety of spectroscopic, analytical ultracentrifugation, small-angle X-ray scattering and viscometric techniques. Results: The structure of the Fab' moiety of certolizumab pegol was determined by crystallography at 2.25 Å resolution, and was confirmed by orthogonal, in-solution spectroscopic techniques (circular dichroism, Fourier transform infrared and Raman spectroscopies) for the Fab', both without and with the attached PEG moiety. The Fab' was found to have typical Fab'-like structure. Small-angle X-ray scattering and analytical ultracentrifugation studies showed that certolizumab pegol is a highly flexible, asymmetrical molecule, with solution properties dictated by the PEG. The PEG moiety is tethered to the Fab' at a specific point near the Fab' C-terminus, but it does not adhere to or wrap around the surface of the Fab'. The PEG is flexible and (when time averaged) effectively covers part or all of the Fab' moiety. The Fab' was unaffected by any interaction, rearrangement or modification by the PEG moiety. The PEG-like properties of certolizumab pegol were reflected in the viscosity of its aqueous solution, which is significantly greater than that of molar-equivalent solutions of Fab' without PEG. However, even at 150 mg/mL (at 20 < SUPER > o < the of a or interface. Conclusion: The PEG moiety of the novel biopharmaceutical certolizumab pegol provides prolonged circulating half-life to Fab' in vivo, while not affecting the Fab' structure, but acting as a protectant under some circumstances. The behaviour of certolizumab pegol in solution is dominated by the PEG moiety.
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