Suppressive Immune Response of Poly(sarcosine) Conjugated Proteins: PSARylation.

Polymer conjugation is a widely used strategy to improve the pharmacokinetics of protein therapeutics by extending their half-life and protecting them from degradation. Poly(ethylene glycol) (PEG) is the most commonly used polymer for this purpose. However, its use can trigger unwanted immune responses, leading to the production of anti-PEG antibodies that compromise efficacy. This issue has driven the search for alternative polymers, with poly(sarcosine) (PSAR), derived from an endogenous amino acid, emerging as a promising candidate. Despite this potential, the immunogenicity of PSAR-protein conjugates (PSARylation) has not been systematically compared with that of PEGylated counterparts. In this report, we show that conjugating a model protein antigen to high-molecular-weight PSAR more effectively suppresses immune responses against both the protein and the polymer than PEG. Although polymer conjugation has traditionally been viewed as a means of steric "masking" of a protein, our results demonstrate that the chemical nature of the polymer is a critical, independent factor, as PSAR conjugates elicited lower antibody production than PEG conjugates of identical hydrodynamic size. This study highlights polymer selection as an important design parameter for minimizing immunogenicity in next-generation protein therapeutics. Polymers derived from biological building blocks, such as PSAR, offer a promising route to developing safer, more effective biopharmaceuticals with better tolerance and reduced risk of adverse immune reactions.