Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer

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Abstract
Galactose(α1,3)galactose on the surface of cells of non-primate organs is the major xenoantigen responsible for hyperacute rejection in xenotransplantation. The antigen is synthesised by (α1,3)galactosyl transferase. Humans lack this enzyme and their serum contains high levels of pre-existing natural antibody which recognises the structure and activates complement. We have evaluated in vitro the potential for delivery of this enzyme to sensitise human cells to complement attack as a gene therapy approach to cancer. Retrovirus-mediated delivery of (α1,3)galactosyl transferase resulted in high level expression which led to serum-mediated lysis of five human cell targets, including endothelial and primary melanoma cells. Lysis was specific for those cells expressing the antigen in a mixed cell population. The mechanism of cell lysis mimicked that involved in hyperacute rejection: activation of the classical complement pathway by natural antibody specific for galactose(α1,3)galactose. The degree of lysis was determined by both the level of specific antibody and the expression of glycophosphatidylinositol-linked complement regulatory proteins. We conclude that expression of (α1,3)galactosyl transferase is a promising new therapeutic approach for cancer gene therapy, avoiding toxicity problems associated with application of prodrugs and with the potential to elicit further immunological responses.