Basic research efforts focussing on angiogenesis as a target for cancer therapeutics have yet to bear fruit. Of the 58 molecules in development, 46 are still at preclinical stages. One of the most exciting angiogenesis inhibitors is CM101 (also known as GBS toxin). This therapeutic candidate is a polysaccharide isolated from the culture medium of Group B streptococcus, a microbe known to cause respiratory distress in neonates. This is thought to occur through it's binding to a receptor whose expression becomes repressed very shortly after birth. In 1993 it was shown that CM101 can inhibit tumor growth in mice suggesting that receptor expression is reinduced under neoplastic conditions. The mechanism of action was related to a destruction of tumor blood vessels subsequent to local perivascular inflammation. Following successful preclinical studies CM101 was tested in the clinic and out of 15 patients, 5 showed tumor reduction or stabilization. Most recently, Vanderbilt researchers isolated a gene encoding a transmembrane protein that interacts with CM101 from a sheep lung endothelial cell cDNA library. The gene, termed sp55, encodes a 495-amino acid polypeptide. COS-7 cells transfected with a vector containing sp55 express the SP55 protein and bound CM101 in a concentration-dependent manner. Stably transfected CHO cells also bound CM101. The corresponding human gene, hp59, was isolated from a human fetal lung cDNA library and had a predicted identity to SP55 of 86% over 495 amino acids. HP59 protein was shown by immunohistochemistry to be present in the pathological tumor vasculature of the lung, breast, colon, and ovary, but not in the normal vasculature, suggesting that the protein may be critical to pathological angiogenesis. The hp59 gene and/or the HP59 protein was not expressed in a variety of normal tissues. Mice immunized with HP59 and SP55 peptides showed significant attenuation of tumor growth. Immunization effectively inhibited both the tumor angiogenesis and vasculogenesis processes, as evidenced by lack of both HP59- and CD34-positive vessels. Based of this highly convincing data this group is now developing HP59 vaccines towards the clinic and they are looking for potential partners to expedite this development.

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