Ganglioside GD3 synthase (GD3S), a novel cancer drug target

Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups (GD3) and disialoganglioside with two glycosyl groups (GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion, angiogenesis and in preventing immunosuppression of tumors. GD3 synthase (GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers. The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S, and its potential as a drug target in cancers.

Anti-GD2 Monoclonal Antibody (dinutuximab) with GM-CSF, Interleukin 2, and Cis-retinoic Acid for the Treatment of High-risk Neuroblastoma / 임상소아혈액종양

Neuroblastoma, one of the most common solid tumors in early childhood, exhibits aberrant cell-surface glycosylation patterns. In neuroblastoma, disialoganglioside (GD2) is expressed homogeneously and abundantly on 100% of neuroblastoma cells. GD2 is a good tumor marker for developing an anti-tumor-monoclonal antibody (mAb) to neuroblastoma. Immunotherapy, using anti-GD2-mAb, has been tried since last 20 years to improve the prognosis of high risk neuroblastoma patients who show a 5-year survival rate of less than 30% regardless of an intense multimodal therapy. Since the first clinical trial of murine anti-GD2-mAb 3F8 had been performed, multiple clinical studies showed that anti-GD2-mAb might improve the prognosis of high risk neuroblastoma patients. Anti-GD2-mAb removes the neuroblastoma cells via apoptosis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. To elicit a stronger ADCC response to antibody therapy, cytokines such as, GM-CSF and interleukin-2 are concomitantly administered, which stimulate the natural anti-tumor activity of the immune system. Children's Oncology Group performed a study of chimeric anti-GD2-mAb (ch14.18) administration with GM-CSF, IL-2 for high risk neuroblastoma patients and showed the improvement of overall survival rate. Based on this study US FDA approved the chimeric anti-GD2-mAb (commercially manufactured dinutuximab) for the treatment of high risk neuroblastoma. Dinutuximab is the the first mAb for use in combination of cytokines for the maintenance treatment of pediatric patients with high risk neuroblastoma who achieve at least a partial response to intensified multimodal therapy. The first anti-tumor-mAb used for children, dinutuximab, could be the base of further development of mAb against the cancers in childhood.

Anti-GD2 Monoclonal Antibody (dinutuximab) with GM-CSF, Interleukin 2, and Cis-retinoic Acid for the Treatment of High-risk Neuroblastoma / 임상소아혈액종양

Neuroblastoma, one of the most common solid tumors in early childhood, exhibits aberrant cell-surface glycosylation patterns. In neuroblastoma, disialoganglioside (GD2) is expressed homogeneously and abundantly on 100% of neuroblastoma cells. GD2 is a good tumor marker for developing an anti-tumor-monoclonal antibody (mAb) to neuroblastoma. Immunotherapy, using anti-GD2-mAb, has been tried since last 20 years to improve the prognosis of high risk neuroblastoma patients who show a 5-year survival rate of less than 30% regardless of an intense multimodal therapy. Since the first clinical trial of murine anti-GD2-mAb 3F8 had been performed, multiple clinical studies showed that anti-GD2-mAb might improve the prognosis of high risk neuroblastoma patients. Anti-GD2-mAb removes the neuroblastoma cells via apoptosis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. To elicit a stronger ADCC response to antibody therapy, cytokines such as, GM-CSF and interleukin-2 are concomitantly administered, which stimulate the natural anti-tumor activity of the immune system. Children's Oncology Group performed a study of chimeric anti-GD2-mAb (ch14.18) administration with GM-CSF, IL-2 for high risk neuroblastoma patients and showed the improvement of overall survival rate. Based on this study US FDA approved the chimeric anti-GD2-mAb (commercially manufactured dinutuximab) for the treatment of high risk neuroblastoma. Dinutuximab is the the first mAb for use in combination of cytokines for the maintenance treatment of pediatric patients with high risk neuroblastoma who achieve at least a partial response to intensified multimodal therapy. The first anti-tumor-mAb used for children, dinutuximab, could be the base of further development of mAb against the cancers in childhood.

Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness / 대한해부학회지

Glioblastoma multiforme (GBM) is the most malignant World Health Organization grade IV brain tumor. GBM patients have a poor prognosis because of its resistance to standard therapies, such as chemotherapy and radiation. Since stem-like cells have been associated with the treatment resistance of GBM, novel therapies targeting the cancer stem cell (CSC) population is critically required. However, GBM CSCs share molecular and functional characteristics with normal neural stem cells (NSCs). To elucidate differential therapeutic targets of GBM CSCs, we compared surface markers of GBM CSCs with adult human NSCs and found that GD2 and CD90 were specifically overexpressed in GBM CSCs. We further tested whether the GBM CSC specific markers are associated with the cancer stemness using primarily cultured patient-derived GBM cells. However, results consistently indicated that GBM cells with or without GD2 and CD90 had similar in vitro sphere formation capacity, a functional characteristics of CSCs. Therefore, GD2 and CD90, GBM specific surface markers, might not be used as specific therapeutic targets for GBM CSCs, although they could have other clinical utilities.

Potentiality of Anti-idiotypic Antibodies Mimicking GD2 to Induce Cellular Immunity

BACKGROUND: Disialoganglioside GD2 is a tumor-associated antigen that is overexpressed on tumor cells of neuroectodermal origin, such as melanoma, small cell lung carcinoma and neuroblastoma. Immunity against GD2 has anti-tumor activities, but GD2 is poorly immunogenic. Anti-idiotypic antibodies that mimic GD2 may induce more effective immune responses than GD2 antigen itself, because they are protein antigens and are known to be able to break immune tolerance. In our previous study, we produced anti-idiotypic antibodies mimicking GD2 (3A4 and 3H9), which induced humoral immunity. However, cellular immunity is essential to eradicate tumor cells in vivo as well as humoral immunity. In the present study, we investigated whether these anti-idiotypic antibodies 3A4 and 3H9 could induce cellular immunes responses. METHODS: BALB/C mice were immunized with anti-idiotypic antibody 3A4 or 3H9, or normal mouse IgG as a negative control. Lymphoproliferative responses, cytokine production responses, and delayed-type hypersensitivity reactions were measured in mice immunized with the anti-idiotypic antibodies. RESULTS: Both the anti-idiotypic antibody 3A4 and 3H9 induced GD2-specific lymphoproliferative responses and IFN-gamma production of lymph node lymphocytes in BALB/C mice. Only anti-idiotypic antibody 3H9 induced significant GD2-specific delayed-type hypersensitivity in the mice. CONCLUSION: These results show that anti-idiotypic antibodies 3A4 and 3H9 have the potentiality of inducing GD2-specific cellular immune responses that cannot be induced by the native antigen GD2 itself.

Characterization of Anti-anti-idiotypic Antibodies (Ab3) Induced by Immunization of Anti-idiotypic Antibodies (Ab2) Mimicking Disialoganglioside GD2

BACKGROUND: Disialoganglioside GD2 is a tumor-associated antigen that is overexpressed on tumor cells of neuroectodermal origin, such as melanoma and neuroblastoma. Anti-idiotypic antibodies that mimic GD2 may induce more effective immune responses than GD2 antigen itself, because they are protein antigens and are known to be able to break immune tolerance. In this study, to explore the potential of anti-idiotypic antibodies as tumor vaccines, the ability of anti-idiotypic antibodies (Ab2) to induce anti-anti-idiotypic antibodies (Ab3) that bind to the original antigen GD2 was investigated. METHODS: Six monoclonal anti-idiotypic antibodies (1A8, 1G5, 2B6, 3A4, 3D6, 3H9) to monoclonal antibody M2058, which is a monoclonal antibody to GD2, were produced in mice. Three (1A8, 3A4, 3H9) of them were selected based on their ability to inhibit the binding of Ab1 to D142.34 (murine melanoma cell expressing GD2). These 3 different Ab2 were injected into rabbits, and rabbit Ab3 induced by each of them were characterized. RESULTS: Ab3-containing sera from two rabbits immunized with 1A8, 3A4, or 3H9 bound significantly (P<0.05) to D142.34 but not to B78.96 (GD2-negative cell), and bound significantly (P<0.05) to isolated GD2 but not to GD1a. Ab3-containing sera from two rabbits immunized with 3A4 or 3H9 inhibited significantly (P<0.05) the binding of Ab1 M2058 to D142.34, and inhibited significantly (P<0.05) the binding of Ab1 M2058 to the Ab2. CONCLUSION: These results suggest that anti-idiotypic antibodies 3A4 and 3H9 have a potential to be used as vaccines against tumors expressing GD2 by inducing GD2-specific antibodies (Ab3).