Monoclonal antibodies to a glycolipid antigen on neuroblastoma cells

Cancer Research (Impact Factor: 9.33). 07/1985; 45(6):2642-9.
Source: PubMed


Using a somatic cell hybridization technique, four murine monoclonal antibodies (three immunoglobulin M and one immunoglobulin G3) were produced against a human neuroblastoma cell surface glycolipid antigen. They reacted strongly with all human neuroblastoma tumor-containing specimens and six of eight human neuroblastoma cell lines. More than 98% of each neuroblastoma cell population possessed this surface antigen, and in the presence of complement, 100% of them were killed. While melanoma and osteogenic sarcoma carried this antigen, leukemia and most Ewing's and Wilms' tumors did not. There was no cross-reaction with 30 normal or remission bone marrow samples and none with normal human tissues other than neurons in vitro. This antigen was neuraminidase sensitive, separable on thin-layer chromatogram, and did not modulate after combining with the monoclonal antibodies. These antibodies could detect less than 0.1% tumor cells deliberately seeded in the bone marrow samples. Because of their unique properties, these monoclonal antibodies may have diagnostic and therapeutic potentials.

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Available from: Peter F Coccia, Jul 07, 2014
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    • "GD2 is a member of the b-series gangliosides, which are normally expressed during fetal development and are highly restricted to the central nervous system in healthy adults, with low levels of expression on peripheral nerves and skin melanocytes (2). GD2 has been found to be expressed in neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small-cell lung cancer, brain tumors, and sarcomas (3–5). Recent evidence has also shown that GD2 can be found on breast cancer stem cells (6, 7), as well as on neuroectodermal (8) and mesenchymal stem cells (9, 10). "
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    ABSTRACT: Disialoganglioside GD2 is an important target on several pediatric and adult cancer types including neuroblastoma, retinoblastoma, melanoma, small-cell lung cancer, brain tumors, sarcomas, and cancer stem cells. We have utilized structural and computational methods to refine the framework of humanized monoclonal antibody 3F8, the highest affinity anti-GD2 antibody in clinical development. Two constructs (V3 and V5) were designed to enhance stability and minimize potential immunogenicity. Construct V3 contained 12 point mutations and had higher thermal stability and comparable affinity and in vitro tumor cells killing as the parental hu3F8. Construct V5 had nine point mutations to minimize potential immunogenicity, but resulted in weaker thermal stability, weaker antigen binding, and reduced tumor killing potency. When construct V3 was combined with the single point mutation HC:G54I, the resulting V3-Ile construct had enhanced stability, antigen binding, and a nearly sixfold increase in tumor cell killing. The resulting product is a lead candidate for clinical development for the treatment of GD2-positive tumors.
    Frontiers in Immunology 08/2014; 5:372. DOI:10.3389/fimmu.2014.00372
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    • "have been extensively tested in clinics (157). The murine IgG3 monoclonal antibody (MAb) 3F8 was the first well-characterized anti-GD2 antibody (158). Its efficacy in treating NB was initially described in 1987 in the report of a Phase 1 trial which included patients with refractory high-risk NB (159). "
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    ABSTRACT: Neuroblastoma (NB), accounting for 10% of childhood cancers, exhibits aberrant cell-surface glycosylation patterns. There is evidence that changes in glycolipids and protein glycosylation pathways are associated to NB biological behavior. Polysialic acid (PSA) interferes with cellular adhesion, and correlates with NB progression and poor prognosis, as well as the expression of sialyltransferase STX, the key enzyme responsible for PSA synthesis. Galectin-1 and gangliosides, overexpressed and actively shedded by tumor cells, can modulate normal cells present in the tumor microenvironment, favoring angiogenesis and immunological escape. Different glycosyltransferases are emerging as tumor markers and potential molecular targets. Immunotherapy targeting disialoganglioside GD2 rises as an important treatment option. One anti-GD2 antibody (ch14.18), combined with IL-2 and GM-CSF, significantly improves survival for high-risk NB patients. This review summarizes our current knowledge on NB glycobiology, highlighting the molecular basis by which carbohydrates and protein-carbohydrate interactions impact on biological behavior and patient clinical outcome.
    Frontiers in Oncology 07/2014; 4:114. DOI:10.3389/fonc.2014.00114
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    • "Gangliosides are glycosphingolipids containing a lipid component and a carbohydrate chain that are found on the cell surface that are believed to play a role in cell attachment and cell-cell interactions. Several of these gangliosides, including GM2, disialoganglioside (GD2), and GD3, are expressed by tumors such as melanoma [97–100], sarcomas, and neuroblastoma [101–103]. "
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    ABSTRACT: Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. Corrigendum to “Sarcoma Immunotherapy: Past Approaches and Future Directions”
    Sarcoma 03/2014; 2014(10):391967. DOI:10.1155/2014/391967
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