Phosphorylcholine Polymer Conjugation Improves the Pharmaceutical Performance of Protein Therapeutics

Proteins hold significant potential for the treatment of various diseases. However, challenges such as immunogenicity and limited <i>in vivo</i> resident time hinder their clinical translation. This study introduces thiol-maleimide click chemistry to achieve controlled polymer-protein conjugation. Poly(2-methacryloyloxyethyl phosphorylcholine)-uricase (PMPC-UOX) conjugates with three distinct polymer chain lengths were prepared, and their <i>in vitro</i> and <i>in vivo</i> performances were compared. Owing to the antifouling properties of PMPC polymers, the conjugates exhibited chain length-dependent performance. A longer PMPC polymer chain in the conjugate resulted in a greater reduction in immunological phagocytosis, a prolonged plasma half-life, lower immunogenicity, and improved therapeutic outcomes compared to both the native protein and conjugates with shorter polymer chains. This study elucidates the interplay between the zwitterionic polymer chain length and the <i>in vivo</i> pharmaceutical performance of protein therapeutics, enabling precise control of zwitterionic polymer modification to achieve optimal outcomes. Furthermore, we envision that this protein modification platform can be retooled to deliver a plethora of protein therapeutics.