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Rapid Access of Antibodies to ₅ß₁ Integrin Overexpressed on the Luminal Surface of Tumor Blood Vessels

¹ Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, California and ² Protein Design Labs, Inc., Fremont, California

Requests for reprints: Donald M. McDonald, Cardiovascular Research Institute, S1363, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0130. Phone: 415-476-2118; Fax: 415-476-4845; E-mail: dmcd{at}itsa.ucsf.edu.

Integrin ₅ß₁ is overexpressed on endothelial cells of tumor vessels and is uniformly and rapidly accessible to antibodies in the bloodstream. Here, we determined whether antibodies rapidly gain access to integrin overexpressed on the abluminal (basolateral) surface of endothelial cells through vascular leakiness or whether the rapid accessibility results instead because the integrin is overexpressed on the luminal (apical) surface of endothelial cells due to loss of cell polarity. Using tumors in RIP-Tag2 transgenic mice as a model, we first compared the binding pattern of intravascular anti-₅ß₁ integrin antibody with the leakage pattern of nonspecific IgG. The distributions did not match: anti-₅ß₁ integrin antibody uniformly labeled the tumor vasculature, but IgG was located in patchy sites of leakage. We next injected an antibody to fibrinogen/fibrin, which resulted in patchy labeling of tumors that matched the leakage of IgG and the overall distribution of fibrin in tumors. Similarly, injected antibodies to the basement membrane protein fibronectin, a ligand of ₅ß₁ integrin, or type IV collagen produced patchy sites of leakage instead of uniform labeling of vascular basement membrane. Differences in the kinetics of labeling, which for ₅ß₁ integrin antibody was near maximal by 10 minutes but for the other antibodies gradually increased over 6 hours, indicated differences in accessibility of their respective targets. Isosurface rendering of confocal microscopic images was consistent with antibody binding to ₅ß₁ integrin on the luminal surface of endothelial cells. Together, these findings indicate that the rapid accessibility of ₅ß₁ integrin in RIP-Tag2 tumors results from overexpression of the integrin on the luminal surface of tumor vessels.

Key Words: angiogenesis • immunohistochemistry • pancreas • RIP-Tag2 mice • vascular targeting

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