VEGF-based Targeted Imaging of Tumor Vasculature

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 2R44CA113080-02A2
Agency Tracking Number: CA113080
Amount: $545,177.00
Phase: Phase II
Program: SBIR
Awards Year: 2007
Solicitation Year: 2007
Solicitation Topic Code: N/A
Solicitation Number: N/A
Small Business Information
115A Commerce Drive, Brookfield, CT, 06804
DUNS: 966566465
HUBZone Owned: N
Woman Owned: Y
Socially and Economically Disadvantaged: Y
Principal Investigator
 (203) 775-5677
Business Contact
Phone: (203) 775-5677
Research Institution
DESCRIPTION (provided by applicant): The overall goal of this project is to develop targeted probes for imaging receptors for vascular endothelial growth factor (VEGF) in tumor angiogenesis. Overexpressed VEGF receptors play the crucial role in the onset and progression of tumor angiogenesis and therefore, these receptors are the primary targets of tremendous efforts to develop inhibitors of angiogenesis. However, these receptors are not being used as biomarkers in prescribing or monitoring anti-angiogenic therapy, because there are no non-invasive methods for assessment of their prevalence. Thus, non-invasive imaging of VEGF receptors addresses unmet clinical needs and might lead to evidence-based selection of patient for anti-angiogenic therapy, and design of personalized treatment regiments. In addition, since VEGF receptors are reportedly overexpressed in tumor and contiguous host vasculature at the onset of malignant growth, VEGF receptor imaging might be used for early diagnostics and discrimination between benign and malignant lesions. In Phase I of this project we have developed novel VEGF-based probes for near-infrared fluorescent (NIRF) and single photon emission computed tomography (SPECT) imaging of VEGF receptors that are suitable for clinical development. Site-specific conjugation of contrast agents to appropriately designed VEGF yielded probes that bind to VEGF receptors on endothelial cells as effectively as parental VEGF. We established that our VEGF-based probes undergo receptor-mediated internalization and accumulate in tumor and host endothelial cells overexpressing VEGF receptors. Importantly, using inactivated VEGF-based probes that lost the ability to bind to VEGF receptors, we evaluated a contribution of non-specific mechanisms to probe accumulation in tumor vasculature. Our targeted imaging probes are based on a novel single-chain (sc) VEGF that provides fora significant improvement in expression, refolding, and purification, relative to a conventional VEGF with two subunits linked via disulfide bonds. Site-specific conjugation of contrast agents to scVEGF via our proprietary humanized cysteine containig tag (Cys-tag) ensures homogeneity of the imaging probes. Taking together, our Phase I results open the road to clinical development of VEGF-based probes for selective and specific imaging of VEGF receptors in tumor vasculature. In Phase II, we will establish safety of scVEGF-based probes, develop scalable GLP production of conjugates and characterize utility of these probes for predicting/monitoring responses to a specific inhibitor of VEGF receptors and for early diagnostic of malignant lung lesions. We expect that Phase II results will establish scVEGF-based imaging probes as viable candidates for clinical development. In Phase II of this project we will undertake crucial steps in pre-clinical development of novel targeted probes for molecular imaging of specific receptors that play crucial role in the onset and growth of tumor vasculature and are the primary targets for therapeutic development. Results obtained in the Phase I of this project established 1) feasibility of constructing targeted probes, using a novel proprietary technology, and 2) feasibility of obtaining early and dynamic information about the status of these receptors. Thus, clinical development of these targeted imaging probes open new opportunities for evidence-based selection of patients for specific therapeutic treatments, timely monitoring responses to anti-cancer therapies, for early cancer diagnostics, and discrimination between benign and malignant lesions.

* Information listed above is at the time of submission. *

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