ABSTRACT Covalent conjugation of therapeutic peptides and proteins with the “stealth” polymer poly(ethylene glycol) (PEG), termed PEGylation, is a widely used approach to increase the circulation half-life and stability of “biologics” —peptide, protein and oligonucleotide drugs— and to reduce their immunogenicity. However, recent studies show that PEG is itself immunogenic, as anti-PEG antibodies have been induced in patients treated with some PEGylated drugs, and circulating anti-PEG antibodies have also been found in individuals naïve to PEGylated therapeutics, possibly induced by chronic exposure to PEGs present in consumer products. Motivated by this compelling clinical need and commercial opportunity, the overall objective of this STTR proposal is to develop biologic conjugates of a novel PEG-like polymer — poly(oligoethyene glycol methyl methacrylate) (POEGMA), wherein the PEG chain is distributed as short oligoethylene glycol (OEG) oligomers along a polymer backbone (Fig. 1) — to eliminate PEG's immunogenicity while preserving its ability to prolong plasma half life. The outcome of this project, if successful, will be the identification of a POEGMA conjugate with the same or better activity as the linear PEG conjugate, but with minimal PEG antigenicity and reduced overall immunogenicity, thereby providing a next-generation technology that is superior to PEGylation.