Safety and Performance
Willem Stemmer, Ph.D., CEO, and Volker Schellenberger, Ph.D., vp drug discovery, cofounders of Amunix, discussed the concept of biosuperiors—recombinant proteins that perform better than the original pharmaceutical.
Amunix has investigated the properties of unstructured amino acid sequences as a substitute for polyethylene glycol (PEG). While both molecules form linear, extended polymers and can be attached to proteins, PEG has a number of unsavory features, including a complex manufacturing process and a heterogeneous make-up. But, perhaps the most significant drawback to PEG is its lack of biodegradability.
Unstructured amino acid polymers, on the other hand, do not display these adverse qualities and can be engineered for the desired length as part of a fusion molecule with the targeted biologic.
With these concepts in mind, Amunix set out to optimize the molecule by a process that went through seven design generations over a three-year period. The optimization included in vivo half-life, expression level, genetic stability, accelerated stability, aggregation, protease resistance, and immunogenicity. Because conventional PEG is not biodegradable and accumulates to form vacuoles in the cells of the kidney, rPEG is designed to be broken down by kidney proteases, and to resist degradation for at least seven days in serum.
Amunix has spun off a company, Versatis, to bring a number of rPEG products to market with a focus on metabolic diseases. It has worked through the manufacturing process and designed a fusion molecule, Exenatide-rPEG, for the treatment of type II diabetes that is not controlled by oral antidiabetic agents. Based on extrapolation from various animal studies, the anticipated dosing is weekly or even biweekly, Dr. Stemmer explained.
Other projects under way use rPEG-coupled antibody fragments, including a single-chain bispecific antibody in which anti-HER-2 and anti-EGF fragments are linked together with rPEG, blocking the unwanted aggregation of the molecules while retaining the original binding ability of the molecules. Another area of investigation comprises RNAse-antibody conjugates linked together by rPEG.
“The rPEG gives antibody fragments long half-life and allows their expression in soluble form in the E. coli cytoplasm,” Dr. Stemmer stated. “We believe the approach holds substantial promise for the development of better therapeutic agents.”