Defining Structure-Function Relationships of Amphiphilic Excipients Enables Rational Design of Ultra-Stable Biopharmaceuticals

Abstract

Biopharmaceuticals are the fastest growing class of drugs in the healthcare industry, but their global reach is severely limited by their propensity for rapid aggregation. Currently, surfactant excipients such as polysorbates and poloxamers are used to prevent protein aggregation, which significantly extends shelf-life. Unfortunately, these excipients are themselves unstable, oxidizing rapidly into 100s of distinct compounds, some of which cause severe adverse events in patients. Here, we leverage the highly stable, well-defined, and modular nature of amphiphilic polyacrylamide-derived excipients to isolate the key mechanisms responsible for excipient-mediated protein stabilization. With a library of compositionally identical but structurally distinct amphiphilic copolymers, we quantify multiple relationships between polymer properties and fundamental phenomena to rationally design new ultra-stable surfactant excipients, increasing the stability of a notoriously unstable biopharmaceutical, monomeric insulin, by an order of magnitude. This comprehensive and generalizable understanding of excipient structure-function relationships represents a paradigm shift for the formulation of biopharmaceuticals, moving away from trial-and-error screening approaches towards rational design. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/599313v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1d3a557org.highwire.dtl.DTLVardef@c1277org.highwire.dtl.DTLVardef@904be2org.highwire.dtl.DTLVardef@1660ed4_HPS_FORMAT_FIGEXP M_FIG C_FIG