Cobra conjugates and cancer

Cobra venom factor (CVF) is a glycoprotein that kills mammalian cells by inducing their lysis via complement-assisted activation from the host organism. By conjugating this protein to antibodies that are specific to the surface of cancerous cells, CVF has potential for use in the selective elimination of tumors.

CVF–antibody conjugates offer several advantages for the directed killing of tumor cells as compared with similar immunoconjugates of toxins or drugs. First, CVF is nontoxic because cell killing is mediated by the host. Second, unlike toxins or drugs, CVF does not require internalization by targeted cells. And third, CVF does not cause severe complications such as induction of secondary malignancies or cytotoxicity resistance.

If CVF–antibody conjugates are to be used as therapeutics, it is necessary to ensure that their antigen-binding capacity and CVF cytocidal activity are not blocked, and that CVF immunoreactivity, which arises from its oligosaccharide chains, is eliminated.Researchers have made several attempts to conjugate tumor-specific antibodies to CVF via their side-chain amino acid residues. In most cases, the activity of CVF was significantly impaired, presumably because of damage to the essential amino acids in the complement-binding domain.

Now, Q. Fu and D. C. Gowda from Georgetown University Medical Center (Washington, DC) have developed a different coupling approach. Using galactose oxidase treatment of CVF and subsequent in situ derivatization with hydrazides, these researchers bound the amino acids of ovarian-cancer-specific IgG to CVF oligosaccharides, which are distal to the CVF complement-binding domain (Bioconjugate Chem. 2001, 12, 271–279). The results were promising. The obtained protein tandem preserved significant antigen-binding capacity and retained up to 75% of CVF hemolytic activity, while becoming nonimmunogenic.

This is the first study that demonstrates the robust potential of CVF oligosaccharides for the design of tumor-active immunoconjugates.