Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach

  • Authors:
    • Flavia Pernasetti
    • Jeffrey Nickel
    • Derek Clark
    • Patrick A. Baeuerle
    • Dennis Van Epps
    • Bruce Freimark
  • View Affiliations

  • Published online on: December 1, 2006     https://doi.org/10.3892/ijo.29.6.1371
  • Pages: 1371-1379
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Matrix metalloproteases (MMPs) secreted by both tumor and endothelial cells proteolytically degrade collagen during tumor growth and neo-vascularization. This exposes cryptic binding sites on collagen with functional relevance for angiogenesis. In this report, we characterized a novel humanized monoclonal IgG1 antibody, D93. After humanization, the antibody retained the binding specificity of the parental murine IgM antibody for denatured (dn) collagen. D93 recognized dn-collagen but not native (nat) collagen of different species, including mouse, chicken, and human, indicating that its cryptic binding site(s) is conserved across species. In immunohistochemistry (IHC) studies, D93 stained the basement membrane of blood vessels in several xenograft human tumors or in surgically removed tumor tissues from patients with different types of malignancies. D93 staining was rarely or not present in normal blood vessels of healthy tissues. In in vivo experiments, D93 significantly inhibited basic fibroblast growth factor (bFGF)-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) and the tumor growth of pre-established orthotopic human breast (MDA-MB-435) tumors in mice. D93 i.v. administered in mice was subsequently detected in the subendothelial basement membrane of tumor blood vessels but not blood vessels of normal tissues. Inhibition of growth of pre-established orthotopic human breast MDA-MB-435 tumors was more effective when D93 was combined with Taxol, than either treatment alone. In addition, tumors from animals treated with D93 and/or Taxol showed significantly reduced levels of the endothelial cell-marker CD31. Our data suggest that blockade of cryptic epitopes exposed on collagen IV during angiogenesis and tumor growth by a monoclonal antibody may provide a novel therapeutic modality for treatment of cancer and pathogenic neo-vascularization.

Related Articles

Journal Cover

December 2006
Volume 29 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Pernasetti F, Nickel J, Clark D, Baeuerle PA, Van Epps D and Freimark B: Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach. Int J Oncol 29: 1371-1379, 2006
APA
Pernasetti, F., Nickel, J., Clark, D., Baeuerle, P.A., Van Epps, D., & Freimark, B. (2006). Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach. International Journal of Oncology, 29, 1371-1379. https://doi.org/10.3892/ijo.29.6.1371
MLA
Pernasetti, F., Nickel, J., Clark, D., Baeuerle, P. A., Van Epps, D., Freimark, B."Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach". International Journal of Oncology 29.6 (2006): 1371-1379.
Chicago
Pernasetti, F., Nickel, J., Clark, D., Baeuerle, P. A., Van Epps, D., Freimark, B."Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach". International Journal of Oncology 29, no. 6 (2006): 1371-1379. https://doi.org/10.3892/ijo.29.6.1371