TARGETING ANGIOGENESIS WITH TOXIN VEGF FUSION PROTEINS
DESCRIPTION: (Applicant's Description)
The overall goal of this project is to develop a commercially viable bacterial
toxin-VEGF (vascular endothelial growth factor) fusion protein for selective
targeting of endothelial cells at sites of angiogenesis, primarily in solid
tumors and growing metastases. VEGF interacts with the endothelial cell
specific KDR/flk-1 receptor that is overexpressed in endothelial cells at the
sites of angiogenesis relative to its expression on quiescent endothelium.
In Phase I of this project we have constructed, expressed and purified two
novel fusion proteins, SLT-VEGF/L and SLT-VEGF/S which contain, respectively,
The A subunit of Shiga-like toxin I (SLT) and a functionally active fragment
of the A subunit. SLT causes hemorrhagic
colitis and hemolytic uremic syndrome by damaging endothelial cells suggesting
that endothelial cells are particularly sensitive to SLT .
SLT-VEGF/L and SLT-VEGF/S proteins selectively inhibit growth of endothelial
cells overexpressing KDR/flk-1 receptors with IC-50 of 0.15 nM. At low
nanomolar concentrations SLT-VEGF/L is cytotoxic for endothelial cells
overexpressing KDR/flk-l receptors. However, these proteins do not affect
growing endothelial cells with low numbers of KDR/flk-l receptors, quiescent
endothelial cells, and growing non-endothelial cells. These results provide a
rationale for Phase II in vivo testing of SLT-VEGF fusion proteins as highly
selective inhibitors of angiogenesis. We will also test whether SLT-VEGF
proteins may synergize with other antitumor drugs by enhancing delivery
through damaged tumor endothelium or by creating hypoxic conditions for
bioreductive therapeutics. Finally, we will optimize SLT-VEGF fusion proteins
to achieve high levels of expression, activity, and stability that are
necessary for preclinical and clinical trials.
PROPOSED COMMERCIAL APPLICATION:
A brief summary of the potential commercial applications of the research: VEGF-toxin fusion proteins that inhibit angiogenesis but do not affect normal endothelium or normal cells will be commercial products for therapy of angioaenesis-dependent pathologies.
Small Business Information at Submission:
Principal Investigator:Joseph M. Backer
705 N MOUTAIN RD NEWINGTON, CT 06111
Number of Employees: