Tumor cell reactivity mediated by IgM antibodies in sera from melanoma patients vaccinated with GM2 ganglioside covalently linked to KLH is increased by IgG antibodies |
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Authors: | P Livingston Shengle Zhang Sucharita Adluri Tzy-Jynn Yao Linda Graeber Govindaswami Ragupathi F Helling Martin Fleisher |
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Institution: | (1) Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Fax: (212) 794 4352, US;(2) Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA, US;(3) Department of Clinical Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA, US |
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Abstract: | Natural IgM antibodies against the melanoma cell-surface ganglioside GM2, and IgM antibodies induced by vaccination with
GM2 adherent to bacillus Calmette-Guerin, have been correlated with increased disease-free and overall survival in melanoma
patients in previous phase I and II clinical trials. A vaccine containing GM2 covalently attached to keyhole limpet hemocyanin
(KLH) plus the immunological adjuvant QS-21 now induces higher-titer, longer-lasting IgM antibodies against GM2 and has recently
entered phase III clinical trials. For the first time this new vaccine also induces IgG antibodies against GM2 in the majority
of immunized patients. With regard to immunity against bacteria, IgM antibodies have been described to be 1000-fold more effective
than IgG antibodies at opsonification, complement-mediated cytotoxicity and protection from bacterial challenge. Though IgG
antibodies have the theoretical advantage of being able to mediate antibody-directed cell-mediated cytotoxicity (ADCC), they
may inhibit complement mediated IgM effector mechanisms against melanoma cells. Our goal was to confirm the functional characteristics
of the anti-GM2 IgM and IgG antibodies induced by vaccination and to determine the impact that IgG antibodies might have on
IgM antibody reactivity with GM2-positive tumor cells. Post-immunization sera from seven immunized patients were separated
by size-exclusion chromatography into IgM and IgG fractions and a variety of serological assays were performed with the individual
fractions and their combinations. Assays identifying specific IgM or IgG reactivity demonstrated partial inhibition by the
opposite fraction. However, when the endpoint was complement-mediated lysis or overall antibody binding, which may more faithfully
predict in vivo complement-mediated opsonification and lysis, the combinations of IgM and IgG fractions consistently demonstrated
higher reactivity than either fraction alone. In addition, ADCC was induced in all seven patients. The results were the same
whether the sera were obtained after 2 months or 2 years of immunizations. These findings suggest that IgG antibodies induced
by the GM2-KLH plus QS-21 vaccine will not inhibit and should further augment the clinical impact of induced IgM antibodies.
Received: 25 April 1996 / Accepted: 21 October 1996 |
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Keywords: | Complement Vaccine Conjugate vaccine GM2 ganglioside Melanoma Fractionation |
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