Chemistry:Globo H

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Short description: Globo-series glycosphingolipid antigen
Globo H
Globo H - structure.png
Names
IUPAC name
N-((2S,3R,E)-1-(((2R,3R,4R,5S,6R)-5-(((2S,3R,4R,5R,6R)-5-(((2R,3R,4S,5S,6R)-4-(((2S,3R,4R,5R,6R)-3-acetamido-4-(((2R,3R,4S,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-hydroxyoctadec-4-en-2-yl)palmitamide
Other names
  • globohexaosylceramide
  • α-L-Fuc-(1→2)-β-D-Gal-(1→3)-β-D-GalNAc-(1→3)-α-D-Gal-(1→4)-β-D-Gal-(1→4)-α-D-GlcOCeramide
Identifiers
3D model (JSmol)
ChEBI
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Globo H (globohexaosylceramide) is a globo-series glycosphingolipid antigen that is present on the outer membrane of some cancer cells.[1][2] Globo H is not expressed in normal tissue cells, but is expressed in a number of types of cancers, including cancers of the breast, prostate, and pancreas.[1][3] Globo H's exclusivity for cancer cells makes it a target of interest for cancer therapies.[1][2]

Structure

Chemical Structure of Globo H[4]

Defined by the monoclonal antibody MBr1, Globo H has been isolated from breast cancer cell line MCF-7, and its structure has been determined through several analyses, including NMR spectroscopy and methylation analysis.[5] Globo H consists of a hexasaccharide of the structure Fucα(1-2)Galβ(1-3)GalNAcβ(1-3)Galα(1-4)Galβ(1-4)Glcβ(1) with a ceramide attached to its terminal glucose ring at the 1 position in a beta linkage.[6]

Synthesis

Biosynthesis

Biosynthesis of Globo H[1][7]

Globo H's biosynthetic pathway is involved in the synthesis pathways of other globo-series glycosphingolipid antigens that are also specific to cancer cells, including stage-specific embryonic antigen-3 (SSEA3) and stage-specific embryonic antigen-4 (SSEA4).[1] The biosynthetic pathway of these antigens includes the enzyme β 1,3-galactosyltransferase V (β3GalT5).[1] β3GalT5 catalyzes the galactosylation of globoside-4 (Gb4) to SSEA3.[1] SSEA3 can then be converted to SSEA4 by sialyltransferase adding a sialic acid group to its end, or it can be converted to Globo H by fucosyltransferase adding a fucose ring to its end.[1] Playing a part in the formation of three different cancer-specific antigens, β3GalT5 is of particular interest in its relevance to cancer treatment, and it has been shown to be critical for cancer cell survival.[8]

Chemical Synthesis

In order to study its potential as a cancer therapy target, Globo H has been synthesized in the laboratory.[9] One synthesis is achieved by first building two trisaccharides from their component sugars, and then linking them.[9] The trisaccharides, with most of their functional groups protected to prevent side reactions, are linked by creating the GalNAcβ(1-3)Gal bond.[9] A thioethyl group is added to the 1 position on one of the protected galactose rings, and in the presence of methyl triflate, this reacts with the hydroxyl group on the 3 position of the other galactose to link the trisaccharides and form the hexasaccharide.[9] The ceramide is added to the 1 position of the terminal glucose ring after hexasaccharide formation.[9]

Globo H as a Therapeutic Target

As a Tumor Associated Carbohydrate Antigen (TACA), Globo-H is a promising clinical target for immunotherapy. While absent in normal tissues, the glycosphingolipid is overexpressed in a variety of epithelial cancer cell types including human pancreatic, gastric, lung, colorectal, esophageal, and breast tumors.[10][11]

Globo H Anticancer Vaccines

Globo-H's TACA character allows for its utilization as an anticancer vaccine, inducing antibody response against the epitope. The resulting humoral immunity could enable the selective eradication of Globo H-presenting tumors.[12] The Taiwanese biopharma company OBI Pharma, Inc., was first to develop Adagloxad Simolenin (OBI-822), a Globo H hexasaccharide conjugated with the immunostimulatory carrier protein KLH.[12] The Phase III GLORIA study is underway evaluating the carbohydrate-based immunogen's effects in high risk triple-negative breast cancer (TNBC) patients with an estimated completion date in 2027.[13]

Alternative vaccine conjugates have been developed which avoid issues associated with the protein carrier KLH by substituting it with a lipid or carbohydrate-based carrier. Examples include the use of lipid A derivatives[14] or entirely carbohydrate vaccine conjugates such as Globo H-PS A1[15]

Anti-Globo H Antibodies

Globo H-targeting antibodies are another strategy currently being evaluated in the cancer therapeutic space. OBI Pharma's OBI-888 is a humanized IgG1 antibody that selectively binds to the Globo H antigen among other Globo series glycosphingolipids such as SSEA-3 and SSEA-4.[16] Additionally, in vivo studies of OBI-888 in various Globo H-positive (GH+) xenografts models showed promising tumor growth inhibition results.[17] OBI-888's human Phase I/II study for the treatment of metastatic and locally advanced solid tumors is estimated to finish in December 2022.[18]

Based on OBI-888, the first-in-class antibody-drug conjugate (ADC) 0BI-999 was additionally developed, linking OBI-888 to monomethyl auristatin E, a synthetic antineoplastic agent.[19] The ADC is currently undergoing phase II trial in patients with advanced solid tumors, with an estimated completion date in Dec 2023.[20] In Dec 2019 & Jan 2020, OBI-999 was granted two Orphan Drug Designations by the FDA for the treatment of pancreatic and gastric cancer.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Chuang, Po-Kai; Hsiao, Michael; Hsu, Tsui-Ling; Chang, Chuan-Fa; Wu, Chung-Yi; Chen, Bo-Rui; Huang, Han-Wen; Liao, Kuo-Shiang et al. (2019-02-26). "Signaling pathway of globo-series glycosphingolipids and β1,3-galactosyltransferase V (β3GalT5) in breast cancer" (in en). Proceedings of the National Academy of Sciences 116 (9): 3518–3523. doi:10.1073/pnas.1816946116. ISSN 0027-8424. PMID 30808745. 
  2. ↑ 2.0 2.1 Hung, Jung-Tung; Cheng, Jing-Yan; Wu, Chia-Cheng; Yu, Alice L. (2012-04-15). "Abstract 2529: A monoclonal anti-Globo H antibody, VK9 can mediate CDC/ADCC and inhibit adhesion of Globo H+cancer cells to extracellular matrix" (in en). Abstract 2529: A monoclonal anti-Globo H antibody, VK9 can mediate CDC/ADCC and inhibit adhesion of Globo H+ cancer cells to extracellular matrix. 72. 2529. doi:10.1158/1538-7445.AM2012-2529. https://cancerres.aacrjournals.org/content/72/8_Supplement/2529. 
  3. ↑ Yang, Ching-Yao; Lin, Mong-Wei; Chang, Yih-Leong; Wu, Chen-Tu (2017-12-12). "Globo H expression is associated with driver mutations and PD-L1 expressions in stage I non-small cell lung cancer". Cancer Biomarkers 21 (1): 211–220. doi:10.3233/CBM-170660. ISSN 1875-8592. PMID 29036791. https://pubmed.ncbi.nlm.nih.gov/29036791/. 
  4. ↑ Park, Tae Kyo; Kim, In Jong; Hu, Shuanghua; Bilodeau, Mark T.; Randolph, John T.; Kwon, Ohyun; Danishefsky, Samuel J. (1996-11-20). "Total Synthesis and Proof of Structure of a Human Breast Tumor (Globo-H) Antigen" (in en). Journal of the American Chemical Society 118 (46): 11488–11500. doi:10.1021/ja962048b. ISSN 0002-7863. https://pubs.acs.org/doi/10.1021/ja962048b. 
  5. ↑ Bremer, E. G.; Levery, S. B.; Sonnino, S.; Ghidoni, R.; Canevari, S.; Kannagi, R.; Hakomori, S. (1984-12-10). "Characterization of a glycosphingolipid antigen defined by the monoclonal antibody MBr1 expressed in normal and neoplastic epithelial cells of human mammary gland". The Journal of Biological Chemistry 259 (23): 14773–14777. doi:10.1016/S0021-9258(17)42669-X. ISSN 0021-9258. PMID 6501317. 
  6. ↑ Wang, Cheng-Chi; Huang, Yen-Lin; Ren, Chien-Tai; Lin, Chin-Wei; Hung, Jung-Tung; Yu, Jyh-Cherng; Yu, Alice L.; Wu, Chung-Yi et al. (2008-08-19). "Glycan microarray of Globo H and related structures for quantitative analysis of breast cancer" (in en). Proceedings of the National Academy of Sciences 105 (33): 11661–11666. doi:10.1073/pnas.0804923105. ISSN 0027-8424. PMID 18689688. Bibcode: 2008PNAS..10511661W. 
  7. ↑ Detzner, Johanna; Pohlentz, Gottfried; Müthing, Johannes (2020-06-04). "Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome" (in en). Toxins 12 (6): 373. doi:10.3390/toxins12060373. ISSN 2072-6651. PMID 32512916. 
  8. ↑ Cheung, Sarah K. C.; Chuang, Po-Kai; Huang, Han-Wen; Hwang-Verslues, Wendy W.; Cho, Candy Hsin-Hua; Yang, Wen-Bin; Shen, Chia-Ning; Hsiao, Michael et al. (2015-12-17). "Stage-specific embryonic antigen-3 (SSEA-3) and β3GalT5 are cancer specific and significant markers for breast cancer stem cells" (in en). Proceedings of the National Academy of Sciences 113 (4): 960–965. doi:10.1073/pnas.1522602113. ISSN 0027-8424. PMID 26677875. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Bilodeau, Mark T.; Park, Tae Kyo; Hu, Shuanghua; Randolph, John T.; Danishefsky, Samuel J.; Livingston, Philip O.; Zhang, Shengli (1995-07-01). "Total Synthesis of a Human Breast Tumor Associated Antigen". Journal of the American Chemical Society 117 (29): 7840–7841. doi:10.1021/ja00134a043. ISSN 0002-7863. https://doi.org/10.1021/ja00134a043. 
  10. ↑ Zhang, Shengle; Cordon-Cardo, Carlos; Zhang, Helen S.; Reuter, Victor E.; Adluri, Sucharita; Hamilton, Wm. Bradley; Lloyd, Kenneth O.; Livingston, Philip O. (1997-09-26). <42::aid-ijc8>3.0.co;2-1 "Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides". International Journal of Cancer 73 (1): 42–49. doi:10.1002/(sici)1097-0215(19970926)73:1<42::aid-ijc8>3.0.co;2-1. ISSN 0020-7136. PMID 9334808. http://dx.doi.org/10.1002/(sici)1097-0215(19970926)73:1<42::aid-ijc8>3.0.co;2-1. 
  11. ↑ Chen, I-Ju; Yang, Ming-Chen; Chen, Yu-Jung (2020-08-13). "Abstract 2946: The prevalence of Globo H in different tumor types: Breast, pancreatic, lung, gastric, colorectal, liver, and esophageal cancers". Experimental and Molecular Therapeutics. 80. American Association for Cancer Research. 2946. doi:10.1158/1538-7445.am2020-2946. http://dx.doi.org/10.1158/1538-7445.am2020-2946. 
  12. ↑ 12.0 12.1 Danishefsky, Samuel J.; Shue, Youe-Kong; Chang, Michael N.; Wong, Chi-Huey (2015-03-17). "Development of Globo-H Cancer Vaccine" (in en). Accounts of Chemical Research 48 (3): 643–652. doi:10.1021/ar5004187. ISSN 0001-4842. PMID 25665650. 
  13. ↑ Rugo, Hope S.; Chow, Louis W. C.; Cortes, Javier; Fasching, Peter A.; Hsu, Pei; Huang, Chiun-Sheng; Kim, Sung-Bae; Lu, Yen-Shen et al. (2020-05-20). "Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence.". Journal of Clinical Oncology 38 (15): TPS599. doi:10.1200/jco.2020.38.15_suppl.tps599. ISSN 0732-183X. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps599. 
  14. ↑ Zhou, Zhifang; Liao, Guochao; Mandal, Satadru S.; Suryawanshi, Sharad; Guo, Zhongwu (2015). "A fully synthetic self-adjuvanting globo H-Based vaccine elicited strong T cell-mediated antitumor immunity". Chemical Science 6 (12): 7112–7121. doi:10.1039/c5sc01402f. ISSN 2041-6520. PMID 26918109. 
  15. ↑ Ghosh, Samir; Trabbic, Kevin R.; Shi, Mengchao; Nishat, Sharmeen; Eradi, Pradheep; Kleski, Kristopher A.; Andreana, Peter R. (2020). "Chemical synthesis and immunological evaluation of entirely carbohydrate conjugate Globo H-PS A1". Chemical Science 11 (48): 13052–13059. doi:10.1039/d0sc04595k. ISSN 2041-6520. PMID 34123241. 
  16. ↑ Chen, Yu-Chi; Yang, Ming-Chen; Shia, Chi-Sheng; Tsao, Chun-Yen; Lai, Jiann-Shiun; Chen, I-Ju (2019-07-01). "Abstract 4814: Specificity, biodistribution, tumor targeting, and pharmacokinetics of a novel humanized anti-Globo H antibody, OBI-888, for cancer immunotherapy". Experimental and Molecular Therapeutics. 79. American Association for Cancer Research. 4814. doi:10.1158/1538-7445.am2019-4814. http://dx.doi.org/10.1158/1538-7445.am2019-4814. 
  17. ↑ Chen, Yu-Chi; Yang, Ming-Chen; Tsai, Yi-Chien; Chang, Hui-Wen; Hsieh, Chang-Lin; Chen, Yu-Jung; Lee, Kuang-Hsiu; Lai, Jiann-Shiun et al. (2019-07-01). "Abstract 544: Anti-tumor efficacy and potential mechanism of action of a novel therapeutic humanized anti-Globo H antibody, OBI-888". Clinical Research (Excluding Clinical Trials). 79. American Association for Cancer Research. 544. doi:10.1158/1538-7445.am2019-544. http://dx.doi.org/10.1158/1538-7445.am2019-544. 
  18. ↑ OBI Pharma, Inc (2020-08-04). A Phase I/II, Open-Label, Dose Escalation and Cohort Expansion Study Evaluating the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Therapeutic Activity of OBI-888 in Patients With Locally Advanced or Metastatic Solid Tumors.. https://clinicaltrials.gov/ct2/show/NCT03573544. 
  19. ↑ Yang, Ming-Chen; Chen, Yu-Jung; Shia, Chi-Sheng; Chang, Hui-Wen; Li, Wan-Fen; Yu, Cheng-Der Tony; Chen, I-Ju (2019-07-01). "Abstract 4815: Novel Globo H targeting antibody-drug conjugate with binding specificity and anti-tumor efficacy in multiple cancer types". Experimental and Molecular Therapeutics. 79. American Association for Cancer Research. 4815. doi:10.1158/1538-7445.am2019-4815. http://dx.doi.org/10.1158/1538-7445.am2019-4815. 
  20. ↑ Tsimberidou, Apostolia Maria; Ajani, Jaffer A.; Hsu, Pei; Chen, I-Ju; Pearce, Tillman E. (2020-05-20). "A phase I/II, open-label, dose-escalation, and cohort-expansion study evaluating the safety, pharmacokinetics, and therapeutic activity of OBI-999 in patients with advanced solid tumors.". Journal of Clinical Oncology 38 (15): TPS3657. doi:10.1200/jco.2020.38.15_suppl.tps3657. ISSN 0732-183X. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3657. 
  21. ↑ Inc, OBI Pharma. "OBI Pharma Granted U.S. FDA Orphan Drug Designation for the Treatment of Gastric Cancer for Its Antibody-Drug Conjugate (ADC) Targeted Cancer Therapy, OBI-999". www.prnewswire.com (Press release). Retrieved 2021-02-27.



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