This article was originally published in the August 2018 edition of Matreya’s Newsletter for Glyco/Sphingolipid Research (PDF).

Cellular glycosylation profiles can affect cell recognition, inter- and intracellular signaling, cell adhesion, and cell-cell interactions. Changes in the expression of cell surface carbohydrates have been associated with oncogenesis. The pattern of expression can be disease-type specific, and levels of anti-carbohydrate antibodies can be elevated with the onset of disease. Thus, these glycans can be useful biomarkers of disease.

Fucosylated Ganglioside G_M1

The sphingolipid monosialoganglioside fucosylated ganglioside G_M1 (fucosyl G_M1) has been identified as a tumor-associated antigen. It has high prevalence in certain cancers, including small cell lung cancer (SCLC) tumors, but is absent in most normal tissues except for a subset of peripheral sensory neurons and dorsal root ganglia. These features make it a promising target in immune-targeted cancer therapy. Fucosyl G_M1 antibodies have shown complement activation and cytotoxic effects in fucosyl G_M1-expressing cell lines as well as xenograft and syngeneic models.¹ Combination therapy of anti-fucosyl G_M1 with standard of care chemotherapy has been shown to enhance antitumor activity compared to monotherapy alone.¹ Therapies combining anti-fucosyl G_M1 with antibodies directed against CD137 or PD-1 checkpoint proteins involved in innate and adaptive immunity also significantly enhance SCLC cytotoxicity.¹ Fucosyl G_M1, along with disialosyl galactosyl globoside and G_b2 antibodies, have been shown to be critically high in hepatocellular carcinoma (HCC) patients.² These cancer-associated carbohydrate antigens seem to show better predictive sensitivity than the current gold standard clinical biomarker serum α-fetoprotein.²

O-Acetylated Gangliosides

Sialic acid-containing glycosphingolipids (gangliosides) also play important roles in cell adhesion, cell recognition, and signal transduction. O-Acetylation of hydroxyl groups on the sialic acid is a common modification of gangliosides and can occur at the C4, 7, 8, and 9 positions. This causes major changes in their physiological and biochemical properties, including resistance to sialidase hydrolysis and lectin binding. Acetylated gangliosides have especially been correlated with various cancers.

Ganglioside G_D2 was the first ganglioside shown to be an effective target antigen for cancer immunotherapy with the regulatory approval of the chimeric anti-G_D2 therapeutic antibody dinutuximab. However, this therapeutic antibody’s dose-limiting side effect of causing neuropathic pain has limited its application. The O-acetylated derivative of G_D2 has also received attention as a novel antigen to target G_D2-positive cancers. With an absence of O-acetyl G_D2 expression on nerve fibers, anti- O-acetyl G_D2 lacks allodynic properties and has been tested in preclinical applications on O-acetyl G_D2-expressing tumors that may eventually be applied to CAR T cell therapy.³

Accumulation of the ganglioside G_D3 is known to induce apoptosis. However, acetylation at the 9-OH position, forming 9-O-acetyl G_D3, thwarts this important function. While a critical imbalance of the ratio of G_D3 to 9-O-acetyl G_D3 has been shown to promote tumor survival in glioblastoma cell cultures, cleavage of the acetyl group of 9-O-acetyl G_D3 restores normal G_D3 and reduces tumor cell viability.⁴

Explore ganglioside products from Cayman

Because O-acetyl gangliosides readily revert to their non-acetylated form, they have a limited shelf life of approximately three months when stored at -20°C. Longer term storage of these compounds will result in a mixture of the acetylated and non-acetylated gangliosides. To ensure the highest purity of the acetylated product, we produce and purify O-acetylated gangliosides on a custom basis.

Let Cayman’s experts provide a competitive quote. Contact us to send your specifications.

References

1. Ponath, P., Menezes, D., Pan, C., et al. A novel, fully human anti-fucosyl-GM1 antibody demonstrates potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer. Clin. Cancer Res. 24(20), 5178-5189 (2018).

2. Wu, C.-S., Yen, C.-J., Chou, R.-H., et al. Cancer-associated carbohydrate antigens as potential biomarkers for hepatocellular carcinoma. PLoS One 7(7), e39466 (2012).

3. Fleurence, J., Fougeray, S., Bahri, M., et al. Targeting O-acetyl-GD2 ganglioside for cancer immunotherapy. J. Immunol. Res. 5604891 (2017).

4. Birks, S.M., Danquah, J.O., King, L., et al. Targeting the GD3 acetylation pathway selectively induces apoptosis in glioblastoma. Neuro. Oncol. 13(9), 950-960 (2011).