Characterization of a Proapoptotic Antiganglioside GM2 Monoclonal Antibody and Evaluation of Its Therapeutic Effect on Melanoma and Small Cell Lung Carcinoma Xenografts

Antigen Discovery and Preclinical Biology, Corixa Corporation, Seattle, Washington, USA.
Cancer Research (Impact Factor: 9.33). 08/2005; 65(14):6425-34. DOI: 10.1158/0008-5472.CAN-05-0300
Source: PubMed

ABSTRACT Monoclonal antibodies have begun to show great clinical promise for the treatment of cancer. Antibodies that can directly affect a tumor cell's growth and/or survival are of particular interest for immunotherapy. Previously, we described monoclonal antibody DMF10.62.3 that had antiproliferative and proapoptotic effects when it bound an antigen of unknown identity on tumor cells in vitro. In this report, we determined that DMF10.62.3 and a clonally related antibody DMF10.167.4 recognize the ganglioside GM2. These antibodies react with a GM2 epitope that is expressed on a large number of tumor cell lines, including human melanoma and small cell lung carcinoma, but not on normal primary lines or most normal tissues. Interestingly, this pattern of cellular reactivity is distinct from that reported for other previously described GM2 antibodies, a difference that is presumably due to DMF10.167.4's binding to a unique GM2-associated epitope. Additional characterization of DMF10.167.4 revealed that this antibody was able to induce apoptosis and/or block cellular proliferation when cultured in vitro with the human Jurkat T lymphoma, CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines. In vivo, DMF10.167.4 antibody was well tolerated in mice and did not detectably bind to or damage normal tissues. However, this antibody was able to prevent murine E710.2.3 lymphoma, human CHL-1 melanoma, and SBC-3 small cell lung carcinoma lines from establishing tumors in vivo and blocked progression of established CHL-1 and SBC-3 tumors in vivo. Therefore, monoclonal antibody DMF10.167.4 has immunotherapeutic potential.

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    • "Anti-ganglioside antibodies have shown to have anti-tumor cytotoxic capacities. It has been reported the ability of a murine anti-GM2 to induce apoptosis through caspase activation in lymphoma, melanoma, and lung cancer cells expressing the antigen (Retter et al., 2005). The binding of an anti-GD2 antibody to the ganglioside expressed in lung cancer cells induced apoptosis by the reduction in the levels of phosphorylation of FAK and activation of mitogen-activated kinase p38. "
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    ABSTRACT: Surgery, chemotherapy, and radiation therapy are standard modalities for cancer treatment, but the effectiveness of these treatments has reached a plateau. Thus, other strategies are being explored to combine with the current treatment paradigms in order to reach better clinical results. One of these approaches is the active immunotherapy based on the induction of anti-tumor responses by anti-idiotypic vaccination. This approach arose from Jerne's idiotypic network theory, which postulates that B lymphocytes forms a functional network, with a role in the establishment of the immune repertoires, in the regulation of natural antibody production and even in the establishment of natural tolerance. Due to the large potential diversity of the immunoglobulin variable regions, the idiotypes repertoire can mimic the universe of self and foreign epitopes, even those of non-protein nature, like gangliosides. Gangliosides are sialic acid-containing glycolipids that have been considered attractive targets for cancer immunotherapy, based on the qualitative and quantitative changes they suffer during malignant transformation and due to their importance for tumor biology. Although any idiotype could be able to mimic any antigen, only those related to antigens involved in functions relevant for organism homeostasis, and that in consequence has been fixed by evolution, would be able not only to mimic, but also to activate the idiotypic cascades related with the nominal antigen. The present review updates the results, failures and hopes, obtained with ganglioside mimicking anti-idiotypic antibodies and presents evidences of the existence of a natural response against gangliosides, suggesting that these glycolipids could be idiotypically relevant antigens.
    Frontiers in Oncology 11/2012; 2:170. DOI:10.3389/fonc.2012.00170
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    • "Their mechanisms of action include both direct tumor cell destruction as indirect targeting of growth and pro-angiogenic mediators [17]. Various studies have described mAbs against known melanoma antigens that could be used as markers for diagnosis and prognosis or as targets for immunotherapeutic approaches [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]. However, no antitumor antibody is currently available for clinical use in melanoma [28] and markers defining different phenotypes typical of unique populations of melanoma are also not available. "
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    ABSTRACT: Because melanoma incidence has increased at a dramatic rate, it is relevant to identify novel melanoma antigens for diagnosis and develop monoclonal antibodies recognizing such molecules. Some monoclonal antibodies (mAbs), raised against murine melanoma, identify molecules correlated with carcinogenesis. Herein, we describe a murine melanoma-associated 230 kDa molecule, expressed only in tumorigenic cell lines. Moreover, its expression is higher in more metastatic than less metastatic cells. G12F2 mAb, produced against this antigen, inhibited in vitro proliferation of both murine and human melanoma cells and enhanced in vitro complement activity. It also affected in vivo tumor growth and lung metastases formation. This 230kDa molecule represents an important target for experimental melanoma studies and may become a potential diagnostic marker for malignancy as well as a useful tool for immunotherapeutic approaches.
    Cancer Letters 05/2008; 262(2):276-85. DOI:10.1016/j.canlet.2007.12.017 · 5.62 Impact Factor
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    ABSTRACT: Multiple mechanisms have been proposed to account for immune escape by tumors. Although gangliosides have long been known to suppress T-cell immunity, few studies have examined the effect of human tumor-derived gangliosides on immune responses. Here, we show that gangliosides isolated from renal cell carcinoma (RCC) cell lines and clear cell tumor tissue can induce apoptosis in peripheral blood T cells. The RCC tissue-derived gangliosides also suppressed IFN-gamma and, in many cases, interleukin-4 production by CD4+ T cells at concentrations (1 ng/mL-100 pg/mL) well below those that induce any detectable T-cell death (4-20 microg/mL). Additional findings show that GM2 expressed by RCC plays a significant role in promoting T-cell dysfunction. This is supported by the demonstration that all RCC cell lines examined (n = 5) expressed GM2 as did the majority of tumors (15 of 18) derived from patients with clear cell RCC. Furthermore, an antibody specific for GM2 (DMF10.167.4) partially blocked (50-60%) T-cell apoptosis induced by coculturing lymphocytes with RCC cell lines or with RCC tissue-derived gangliosides. DMF10.167.4 also partially blocked the suppression of IFN-gamma production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4+ T cells.
    Cancer Research 08/2006; 66(13):6816-25. DOI:10.1158/0008-5472.CAN-06-0250 · 9.33 Impact Factor
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