Selective activity against proliferating tumor endothelial cells by CVX-22, a thrombospondin-1 mimetic CovX-Body.
CVX-22 is a CovX-Body, produced by covalently attaching a thrombospondin-1 (TSP-1) type 1 repeat peptide mimetic to a humanized IgG1 molecule. To dissect the antiangiogenic mechanism of CVX-22, the numbers and proliferative status of defined tumor endothelial cell (TEC) subsets from the B16 and C32 melanoma models were examined. CVX-22 treatment reduced the numbers of activated, vascular endothelial growth factor receptor 2 (VEGFR2)-positive TECs. Because the vast majority of mitotically active TECs reside in the VEGFR2 subset, a reduction in numbers of this compartment resulted in an 82% overall decrease in BrdU labeling of TEC. However, the rate of proliferation and VEGFR2 receptor density of this VEGFR2-positive subpopulation were unaffected. Instead, CVX-22 induced endothelial cell apoptosis both in vitro and in vivo, indicating that CVX-22 acts by selective deletion of activated, VEGFR2-positive TEC. The overrepresentation of activated cells in sites of tumor angiogenesis may confer a unique specificity of CVX-22 for tumor vasculature.
Coronella
Julia
J
CovX Research LLC, San Diego, CA 92121, U.S.A. jcoronella@covx.com
Li
Lingna
L
Johnson
Kimberly
K
Pirie-Shepherd
Steven
S
Roxas
Giovanni
G
Levin
Nancy
N
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019700:Thrombospondin 1 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D007074:Immunoglobulin G; D010446:Peptide Fragments; D019700:Thrombospondin 1; D040301:Vascular Endothelial Growth Factor Receptor-2