There is a vital unmet need for improved anti-proliferative therapeutics with high specificity and efficacy and minimal toxicity. Our model proliferative disease is pterygium. In pterygium, corneal cells grow in response to endogenous EGF ligands and obscures vision. The standard treatment is surgical resection with a >45 percent rate of recurrence. Therapeutics designed to inhibit growth-factor mediated cell proliferation have fallen into two general classes: monoclonal antibodies that target the extracellular domain of a receptor, and tyrosine kinase inhibitors designed to inhibit the intracellular domain/downstream signaling pathway. Small peptide therapeutics offer the potential to specifically inhibit protein-protein interactions and modulate intrinsic protein functions. What is missing is a multi-functional therapeutic capable of simultaneously inhibiting extracellular and intracellular targets thereby improving specificity and potency. In this proposal, we outline a strategy to combine rational modular design and phage display to generate a new therapeutic class of biopharmaceuticals that are capable of specifically targeting cell-surface receptors while simultaneously delivering a specific bioactive peptide into cells. We will validate this approach by engineering epidermal growth factor (EGF) to include a peptide chimera that binds an adapter molecule that interrupts a critical cellular function. At the end of Phase 1 we will have identified peptide chimera that can specifically target to, traffic in, and inhibit EGF-dependent proliferation of the corneal cells that form the disfiguration in pterygium. Phase II will improve these drug candidates. If successful the best of these chimera will be used to treat pterygium.
