GD2

Last updated
GD2
GD2 ganglioside.png
Names
IUPAC name
(2R,4R,5S,6S)-2-[3-[(2S,3S,4R,6S)-6-[(2S,3R,4R,5S,6R)-5-[(2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(E)-3-hydroxy-2-(octadecanoylamino)octadec-4-enoxy]oxan-3-yl]oxy-3-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3-amino-6-carboxy-4-hydroxyoxan-2-yl]-2,3-dihydroxypropoxy]-5-amino-4-hydroxy-6-(1,2,3-trihydroxypropyl)oxane-2-carboxylic acid
Other names
Ganglioside G2
Identifiers
3D model (JSmol)
PubChem CID
UNII
  • CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O[C@H]2[C@@H]([C@H]([C@H]([C@H](O2)CO)O[C@H]3[C@@H]([C@H]([C@H]([C@H](O3)CO)O)O)NC(=O)C)O[C@@]4(C[C@H]([C@@H]([C@H](O4)C(C(CO[C@@]5(C[C@H]([C@@H]([C@H](O5)C(C(CO)O)O)N)O)C(=O)O)O)O)N)O)C(=O)O)O)O)O)C(/C=C/CCCCCCCCCCCCC)O
Properties
C74H134N4O32
Molar mass 1591.882 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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GD2 is a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans.

Contents

The relatively tumor-specific expression of GD2 makes it a suitable target for immunotherapy with monoclonal antibodies or with artificial T cell receptors. [1] An example of such antibodies is hu14.18K322A, a monoclonal antibody. This anti-GD2 antibody is currently undergoing a phase II clinical trial in the treatment of previously untreated high risk neuroblastoma given alongside combination chemotherapy prior to stem cell transplant and radiation therapy. [2] A prior phase I clinical trial for patients with refractory or recurrent neuroblastoma designed to decrease toxicity found safe dosage amounts and determined that common toxicities, particularly pain, could be well managed. [3] The chimeric (murine-human) anti-GD2 monoclonal antibody ch14.18 is FDA-approved for the treatment of pediatric patients with high-risk neuroblastoma and has been studied in patients with other GD2-expressing tumors. [4]

See also

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

Chimeric antigen receptor T cells are T cells that have been genetically engineered to produce an artificial T cell receptor for use in immunotherapy.

<span class="mw-page-title-main">Neuroblastoma</span> Medical condition

Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the abdomen, neck, or chest, or a painless bluish lump under the skin.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

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<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. Antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

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Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Bi-specific T-cell engager</span>

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies that are investigated for use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.

<span class="mw-page-title-main">Trifunctional antibody</span>

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.

Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.

Racotumomab is a therapeutic cancer vaccine for the treatment of solid tumors that is currently under clinical development by Recombio, an international public-private consortium with the participation of the Center of Molecular Immunology at Havana, Cuba (CIM) and researchers from Buenos Aires University and National University of Quilmes in Argentina. It induces the patient's immune system to generate a response against a cancer-specific molecular target with the purpose of blocking tumor growth, slowing disease progression and ultimately increasing patient survival.

Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.

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Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is given by slow injection into a vein.

Dinutuximab and dinutuximab beta are monoclonal antibodies used as a second-line treatment for children with high-risk neuroblastoma. Each antibody is made of both mouse and human components and targets glycolipid GD2, expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. They differ in that dinutuximab is manufactured using mouse cells, and dinutuximab beta is manufactured using hamster cells. The dosing regime differs, and dinutuximab is given in combination with granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), while dinutuximab beta can be given alone.

<span class="mw-page-title-main">Isatuximab</span>

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<span class="mw-page-title-main">PD-1 and PD-L1 inhibitors</span>

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<span class="mw-page-title-main">Holger Lode</span> German specialist for pediatrics (born 1967)

Holger Lode is a German specialist for pediatrics. He is Professor and Chair of the Department of General Pediatrics and Pediatric Hematology and Oncology at the University Medicine Greifswald. He is also the director of the Center of Pediatrics and Adolescent Medicine in Greifswald. Lode is well known for his clinical and scientific work on immunotherapy of neuroblastoma.

David G. Maloney is an oncologist and researcher at Fred Hutchinson Cancer Research Center and the University of Washington who specializes in developing targeted immunotherapies for the treatment of blood cancers.

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as a medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.

Roy S. Herbst is an American oncologist who is the Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, and Associate Director for Translational Research at Yale Cancer Center and Yale School of Medicine in New Haven, Connecticut.

References

  1. Wierzbicki, Andrzej; Gil, Margaret; Ciesielski, Michael; Fenstermaker, Robert A.; Kaneko, Yutaro; Rokita, Hanna; Lau, Joseph T.; Kozbor, Danuta (2008). "Immunization with a Mimotope of GD2 Ganglioside Induces CD8+ T Cells That Recognize Cell Adhesion Molecules on Tumor Cells". Journal of Immunology. 181 (9): 6644–6653. doi:10.4049/jimmunol.181.9.6644. PMC   2730120 . PMID   18941255.
  2. "Clinical trials using anti-GD2 monoclonal antibody hu14.18K322A". National Cancer Institute. Retrieved April 20, 2018.
  3. Navid F, et al. (May 2014). "Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma". Journal of Clinical Oncology. 32 (14): 1445–52. doi:10.1200/JCO.2013.50.4423. PMC   4017710 . PMID   24711551.
  4. Bassel N, Cengiz I, Owonikoko TK (July 2020). "Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy". Frontiers in Oncology. 10: 1000. doi: 10.3389/fonc.2020.01000 . ISSN   2234-943X. PMC   7358363 . PMID   32733795.

Further Reading