PROTEIN SCAFFOLDS FOR DESIGN OF NOVEL ANTICANCER AGENTS

Phylos, Inc., Lexington MA

Investigators

Abstract

Phylos is developing in vitro RNA-protein fusion technology for the rapid identification, selection and engineering of proteins (including antibodies) with unique characteristics. As this technology does not require the use of classical antibodies Or their components, we will investigate the targeting Of small protein scaffolds that may be more suitable for pharmacological use. Further, as we are able to select rare proteins from very large libraries (>10(l4) members), we expect to select binders with a much higher affinity (i.e. KD<l0[-12]) than those obtained using smaller libraries (e.g. phage display or in vivo monoclonal antibody selection). The lower dosing required by such high affinity binders will have clear pharmacological benefits. The additional potential to "evolve" proteins by amplification under error-prone conditions, coupled with positive or negative selection pressure, provides additional flexibility for drug design. As proof-in- principle for this methodology, we will identify high-affinity binders to targets on endothelial cells involved in angiogenesis (i.e. the integrin subunits alpha-v, beta-3, and beta-1 and the VEGF receptor KDR/Flk-l). During Phase I, we will identify at least one novel scaffold to demonstrate the generation of high-affinity binders to at least one of the targets indicated and fully characterize its interaction with the target. During Phase II, we will establish: l) their activity in cell culture; 2) their anti- angiogenic and anti-tumor activities in animal tumor models; and, 3) optimize their pharmacological characteristics to identify a lead compound for use in the clinic. PROPOSED COMMERCIAL APPLICATIONS: This technology will extend and improve the use of monoclonal antibody therapy for cancer. It will provide a means to identify more clinically useful protein targeting scaffolds and simultaneously speed the process of identifying high-affinity antigen binders. The identification of alternate scaffolds of defined and highly constrained structure for selection of antibody mimics will also be useful for small molecule drug design.