Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Abstract

The covalent attachment of protein-resistant polymers to therapeutic proteins is a widely used method for extending their in vivo half-lives; however, the effect of molecular weight of polymer on the in vitro and in vivo functions of protein-polymer conjugates has not been well elucidated. Herein we report the effect of molecular weight of poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) on the in vitro and in vivo properties of C-terminal interferon-alpha (IFN)-POEGMA conjugates. Increasing the molecular weight of POEGMA decreased the in vitro activity of IFN-α but increased its thermal stability and in vivo pharmacokinetics. Intriguingly, the in vivo antitumor efficacy of IFN-α was increased by increasing the POEGMA molecular weight from ca. 20 to 60 kDa, but was not further increased by increasing the molecular weight of POEGMA from ca. 60 to 100 kDa due to the neutralization of the improved pharmacokinetics and the reduced in vitro activity. This finding offers a new viewpoint on the molecular size rationale for designing next-generation protein-polymer conjugates, which may benefit patients by reducing administration frequency and adverse reactions, and improving therapeutic efficacy.