This Small Business Innovation Research (SBIR) Phase I project will begin to address some of the current challenges in peptide drug delivery and chemical protein conjugation. Using Redwood Bioscience's patented technology platform, a protein engineering technique, it is possible to insert a non-canonical amino acid containing a unique handle into any protein of interest. This unique handle, an "aldehyde tag", can be specifically elaborated chemically with a synthetic therapeutic peptide, for example. At Redwood Bioscience, this protein engineering technology is used to generate universal protein scaffolds, IgG Fc domains, that are easy to chemically elaborate, result in a homogenous product and can be used as long lasting protein-peptide therapies. Importantly, using this technology it is possible to elaborate the protein scaffolds with multiple tags for small molecule attachment, increasing the potential payload capacity of the carrier scaffold.
The broader/commercial impact of this research is the development of best in class therapeutics with increased payload capacity and the resulting delivery of sufficiently high concentrations of a desired drug. This is a significant and substantial improvement over the current technologies available. Moreover, through ?expanding the chemical space of protein drugs?, Redwood?s technology has application in developing novel hybrid drugs with unique protein-chemical architectures, including multivalent constructs with enhanced payload capacity. The company plans to expand its pipeline of best in class therapeutic compounds, loading Fc scaffold carrier proteins with peptide or small molecule candidates, identified as potential therapeutics currently suffering from poor PK profiles.
Low molecular weight peptides have historically had limited therapeutic utility due to rapid clearance. There has been significant effort focused on developing drug delivery systems, including systems incorporating large biomolecules as carrier proteins, to improve the half-life profile of these compounds. Protein carriers offer several advantages over other delivery methods including a good safety profile. Many of these carrier proteins are recombinant genetic fusions with the peptide of interest. With fusion, the carrier’s attachment to the peptide is limited to the termini, and that placement can impact peptide function and thus potency. Additionally, the optimal benefit of protein chemical modification is achieved when the modification is site-specific. However, none of the existing methods for site-specific protein modification are simple, non-toxic, and applicable to proteins expressed in mammalian cells. As a consequence, many therapeutic proteins that could be improved by chemical modification have yet to be optimized in this manner and there is a great need for technologies that will afford precise chemical modification of protein therapeutics. We developed a technology platform that can modify proteins in a controlled, site-specific manner, maintaining the natural, biologically active form of the protein, while enhancing the protein's medicinal utility. We are using our protein engineering technology to generate universal protein scaffolds that are easy to chemically elaborate, resulting in homogenous products that can be used as long lasting protein-peptide therapies to treat unmet medical needs. Importantly, using our technology we can elaborate proteins of interest with multiple points for small molecule attachment, increasing the potential payload capacity of a carrier scaffold. Increased payload capacity and the resulting delivery of sufficiently high concentrations of a desired drug is a significant and substantial improvement over the current technologies available and results in significantly lower cost of goods. In the first phase of this project we expanded our library of scaffolds to include aldehyde-tagged Fc fragments that contain multiple aldehyde tags in the protein backbone. Chemically conjugating a therapeutic peptide to the protein resulted in a higher drug payload. Work for the phase I of the grant included generating Fc-therapeutic conjugates and testing them for in vitro activity. We observed sufficiently enhanced efficacy with the highly conjugated small molecule-Fc conjugates. This initial in vitro data is an initial proof of principle, highlighting the therapeutic potential of site-specifically modified carrier biologics and the opportunity to generate best in class therapeutics or to generate novel small molecule-protein hybrids.
