Author(s): Julia Coronella, Lingna Li, Kimberly Johnson, Steven PirieShepherd, Robert Murphy
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CVX-22 is a CovX-BodyTM , produced by covalently attaching a Thrombospondin-1 (TSP1) type 1 repeat peptide mimetic to the Fab binding site of a humanized IgG1 molecule. CVX-22 has markedly increased serum stability in comparison with the native TSP1 type 1 repeat peptide mimetic. CVX-22 significantly decreased tumor growth and microvessel density in the syngeneic B16 and xenograft C32 mouse models of melanoma, consistent with its previously described antiangiogenic activity. To further dissect the mechanism of this effect, the numbers and proliferation status of defined tumor endothelial cell (TEC) subsets from the B16 model were examined by flow cytometry and immunohistochemistry. Overall proliferation of TEC was reduced by treatment with CVX-22, as measured by an 82% decrease in BrdU labeling. This reduced proliferation resulted from the selective reduction in numbers of a specific subset of cells, the actively proliferating VEGFR2-positive subpopulation. In contrast, the numbers of VEGFR2-negative TEC remained unchanged. Because the VEGFR2-positive subset of TEC actively propagates, while the VEGFR2-negative subset is quiescent, a reduction in numbers of the active compartment significantly reduces the overall number of labeled TEC. However, while the numbers of active VEGFR2-positive TEC were reduced, the VEGFR2-positive subset remained qualitatively unchanged. The proliferation rate and VEGFR2 receptor density of this VEGFR2-positive subpopulation was unaffected, indicating that the selective reduction in numbers of activated TEC occurred by attrition rather than induction of quiescence. Increased caspase staining of TEC in CVX-22-treated tumors suggested induction of apoptosis in vivo. These data indicate that CVX-22 acts as an antiangiogenic by selective removal of only the most mitotically active, VEGFR2-positive TEC. The overrepresentation of this subpopulation of cells in sites of tumor angiogenesis may confer a unique specificity for tumor vasculature by CVX-22.
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This article was published in Anticancer Research
and referenced in Immunotherapy: Open Access