A guide to maximizing the therapeutic potential of protein-polymer conjugates by rational design

Abstract

Proteins are an important class of therapeutics that have advantages including high target specificity, but challenges to their use include rapid clearance and low physical stability. Conjugation of synthetic polymers is an effective approach to address the drawbacks and enhance other properties such as solubility. In this review, we present various considerations in synthesizing protein-polymer conjugates for therapeutic applications with a focus on the choice of polymer, protein, and conjugation method, as well as characterization and evaluation of the resulting conjugate in order to maximize the therapeutic potential of the protein drug.

Fig. 1

A summary of the polymer selection process.

Fig. 2

Commonly used conjugation chemistries for different protein residues (PDB ID: 4INS).

Fig. 3

A summary of the conjugation chemistry selection process. Adapted with permission from ref. . Copyright 2011 Springer Nature.

Fig. 4

Insulin-trehalose polymer conjugate. The conjugate synthesized by non-selective route was used for (a) in vivo pharmacokinetics (n = 5) and (b) bioactivity in mice after heating (90 °C, 30 min) (n = 5). (c) Synthesis of LysB29 selective conjugate by the grafting-from approach. Adapted with permission from ref. and . Copyright 2017–2018 American Chemical Society.

Fig. 5

Imaging biodistribution of PEGylated diabody using PET. (a) Conjugation of PEG and metal chelator to diabody (Dia). (b) Structures of maleimide PEG, linear (Mal-PEG-L) and branched (Mal-PEG-B), and metal chelator used (isothiocyanate desferrioxamine, NCS-DFO). (c) PET-CT images obtained from a mouse injected with ⁸⁹Zr-DFO-Dia-PEG20k-B, ⁸⁹Zr-DFO-Dia-PEG20k-L, or ⁸⁹Zr-DFO-Dia-PEG40k-B, with a white arrow indicating the location of the tumor. Adapted with permission from ref. . Copyright 2018 Elsevier.