Development of Novel VEGF Analogs
Department of Health and Human Services
Agency Tracking Number:
Solicitation Topic Code:
Small Business Information
Trophogen, 6 Taft Ct, Ste 150, Rockville, MD, 20850
Socially and Economically Disadvantaged:
AbstractDESCRIPTION (provided by applicant): Our previous structure-function studies resulted in the development of the first analogs of glycoprotein hormones with major increases in receptor binding and bioactivity ("super-active analogs"). The majority of cancers are highly dependent on vascular endothelial growth factor A (VEGF-A) interaction with its KDR (kinase domain receptor) receptor to support tumor angiogenesis. Complete inhibition of synthesis and action of all the multiple forms of VEGF is difficult to achieve, and the use of more general receptor antagonists appears vital as an adjunct in any anti-angiogenic therapy. Previous attempts to develop high affinity VEGF agonists and antagonists were not successful, but we have developed several novel high affinity analogs of glycoprotein hormones that are structurally related to VEGF. We hypothesize that our novel approach of growth factor modifications would be entirely applicable to VEGF. New VEGF analogs will consist of linked monomers of VEGF with two types of modifications within the same molecule. First, "gain-of-function" amino acid substitutions will be introduced to enhance binding to the KDR receptor at one pole of the VEGF dimer (Site 1). We will apply charge scanning mutagenesis of amino acid residues within the peripheral loops of VEGF (Site 1) as well as other rational design methods previously proven successful for glycoprotein hormones. Our preliminary data indicate that it is possible to increase binding affinity of VEGF to the KDR receptor up to ten fold. This could be enhanced considerably in future studies by determining optimal combinations of selected amino acid substitutions. The second type of modifications will include "loss-of-function" mutations with or without mutations introducing additional glycosylation site or pegylation at the second pole of VEGF dimer (Site 2). Such an asymmetrical VEGF molecule with enhanced KDR receptor binding at one pole and elimination of binding at the second pole is expected not only to antagonize the action of VEGF but also to limit the pool of monomeric KDR receptors capable of heterodimerizing with other related receptors. In vitro receptor binding assays and bioactivity studies with human endothelial cells will be used to characterize these novel agonists and antagonists. In the subsequent Phase II studies we will assess the therapeutic potential of VEGF analogs using animal models of angiogenesis and tumorigenesis.
* information listed above is at the time of submission.