Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody

Department of Antibody Engineering, Center of Molecular Immunology, Havana, Cuba.
The Journal of Immunology (Impact Factor: 4.92). 12/2008; 181(9):6625-34. DOI: 10.4049/jimmunol.181.9.6625
Source: PubMed


1E10 mAb is an anti-Id murine mAb (Ab2 mAb) specific for an Ab1 mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In preclinical studies, this Ab2 Ab was able to mimic NeuGc-containing gangliosides only in animals lacking expression of these Ags in normal tissues. In this study, we report on the immune responses elicited in 20 non-small cell lung cancer patients treated with 1 mg of aluminum hydroxide-precipitated 1E10 mAb. In the hyperimmune sera from 16 of 20 patients, a strong specific Ab response of both IgM and IgG isotypes against NeuGcGM3 ganglioside was observed. Patient immune sera were able to induce complement-independent cell death of NeuGcGM3-expressing X63 murine myeloma target cells. Significant immunoreactivity to NeuGcGM3 was still detected after the complete abrogation of the reactivity against 1E10 mAb by the adsorption of patient sera with this Ab. We hypothesize that Id(-)Ag(+) Abs could reflect the activation of an autologous idiotypic cascade into the patients. Both Id(+)Ag(+) and Id(-)Ag(+) fractions were separated by affinity chromatography and characterized. Although IgG isotype Abs were found in both fractions, IgM isotype Abs were found only in the Id(-)Ag(+) fraction. Both Id(+)Ag(+) and Id(-)Ag(+) Abs were able to specifically recognize and induce cell death in NeuGcGM3-expressing X63 myeloma target cells. Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times.

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    • "In the case of the anti-idiotype that mimics NGc gangliosides it generates a humoral response that triggers cell death but differently than typical apoptosis (113). Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times (114). Immunizations with the GD2/GD3 surrogates are less mechanism based. "
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    • "Many of these glycolipid compounds are abundantly expressed in tumor cells, being regarded as promising targets for immunotherapy, as is the case of the NeuGcGM3 monosialoganglioside. Clinical trials have been carried out with murine monoclonal anti-idiotype racotumomab to treat adult tumors such as melanoma, breast, and lung cancer, which express surface NeuGc gangliosides. These studies showed a correlation between development of antibodies against NeuGcGM3 and increased survival time (Guthmann et al., 2006; Oliva et al., 2006; Hernandez et al., 2008; Fernandez et al., 2010). Our group reported the expression of these gangliosides in 85% of the cases of neuroblastoma studied (Scursoni et al., 2011). "
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    • "This role has been confirmed by the finding that “auto-anti-idiotypic” antibodies against the induced antibody (Ab1) arise during the immune response in mice (Kluskens and Kohler, 1974; Cosenza, 1976) and in humans (Stefanescu et al., 1993). The second, fundamentally proposes that antibodies can themselves function as surrogates of antigens and immunogens (McNamara et al., 1984; Hernandez et al., 2008, 2011) that redefines anti-Ids as network antigens (Kohler et al., 1989). In short, a promise that has wide sweeping implications is that anti-Ids can function as mimics of ligands and antigens, functioning as surrogates binding competitively to antigen-specific cell receptors. "
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