Prossnitz, A.; Nguyen, L. T.; Eckman, N.; Borkar, S.; Tetef, S.; Auzten, A. A. A.; Fuller, G.; Appel, E.

Protein therapeutics, or biopharmaceuticals, are the fastest growing class of drugs in the healthcare industry with products currently licensed for a wide range of diseases including diabetes, cancer, and viral infections. Unfortunately, the highly specific tertiary structure that endows biopharmaceuticals with their remarkable efficacy and safety, also significantly limits shelf-stability and ultimately clinical translation. Recently, we validated that the high-throughput screening of chemically distinct polyacrylamide derivatives could yield libraries of surfactant excipients (biologically inert additives), which dramatically improve the stability of biopharmaceuticals including insulin and monoclonal antibodies by over 50-fold compared to standard commercial surfactants. Here, we explore and isolate the impact of fundamental polymer properties on the stability of clinically relevant ultra-fast acting (monomeric) insulin. A library of compositionally identical polymers was synthesized, and optimization of molecular weight, dispersity, and end-group functionality doubled the stability of monomeric insulin formulations compared to our previous reports, which was ultimately 5-fold more stable than commercial fast acting insulin drug products. Most importantly, with the diverse structure-function relationships present in this new library, we were able to quantify, validate, and predict the fundamental phenomena responsible for the performance of these copolymer excipients. Overall, we present a rigorous investigation into the structure-function relationships of amphiphilic polyacrylamides, validating a framework for the rational design of next-generation excipients and engineering the most stable monomeric insulin formulations reported to-date.