Gangliosides, such as GM2, GD2, GD3, and 9-O-acetyl GD3, are receiving attention as targets for antibody-based and
vaccine-based
therapies of
melanoma. GM2 appears to be a particularly immunogenic
ganglioside in humans, as indicated by the presence of naturally occurring
IgM anti-GM2
antibodies in approximately 5% of humans and the fact that immunization with irradiated GM2-expressing
melanoma cells or purified GM2 adherent to bacillus Calmette-Guérin elicits GM2
antibodies of low to moderate titers in a high proportion of vaccinated patients. To develop
vaccines that consistently induce high titers of
IgM as well as
IgG anti-GM2
antibodies,
vaccines containing GM2 conjugated to
keyhole limpet hemocyanin as the
carrier protein and
QS-21 as the adjuvant have been constructed. The serological response of vaccinated patients was monitored by ELISA using purified
GM2 ganglioside for
IgM and
IgG anti-GM2
antibodies and for GM2 cell surface-reactive
antibodies by immune adherence assays and cytotoxic tests (
IgM antibodies) and mixed hemadsorption assays (
IgG antibodies). The majority of vaccinated patients developed
IgM and
IgG antibodies detectable by ELISA. In most cases, the results of
IgM ELISA correlated with assays for cell surface-reactive
IgM antibodies. This was not true for
IgG anti-GM2
antibodies, where strong discrepancies were seen between high titers in ELISA and little or no reactivity in mixed hemadsorption tests for cell surface-reactive
antibodies. These
IgG antibodies (and the less frequent
IgM antibodies that show similar discrepancies) may be directed against GM2 determinants that are buried, hidden, or not present on GM2-expressing target cells. With regard to a major objective of
ganglioside vaccines--i.e., generation of cytotoxic
antibodies--the GM2-keyhole limpet
hemocyanin/
QS-21 vaccine is clearly superior to the previously tested GM2/bacillus Calmette-Guérin
vaccine. However, variability in patient response and lack of persistence of high-titered
IgM cytotoxic
antibodies in many patients are problems that remain to be solved.