Anti-αGal-dependent complement-mediated cytotoxicity in metastatic melanoma

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Abstract
Antibodies to the cell surface disaccharide galactose(α1,3)galactose (αGal) are the most prevalent natural antibodies in human serum. The anti-αGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes αGal become sensitive to human serum. A prerequisite for anti-αGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-αGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-αGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-αGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-αGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-αGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of αGal-expressing cells correlated with anti-αGal immunoglobulin M titre (P<0.0001). Anti-αGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-αGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.

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