Globo H

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Globo H
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
  • InChI=1S/C72H130N2O32/c1-5-7-9-11-13-15-17-19-21-23-25-27-29-31-42(81)41(74-48(82)32-30-28-26-24-22-20-18-16-14-12-10-8-6-2)38-95-68-59(92)56(89)62(46(36-78)100-68)102-70-60(93)57(90)63(47(37-79)101-70)103-71-61(94)65(53(86)45(35-77)98-71)105-67-49(73-40(4)80)64(52(85)44(34-76)97-67)104-72-66(55(88)51(84)43(33-75)99-72)106-69-58(91)54(87)50(83)39(3)96-69/h29,31,39,41-47,49-72,75-79,81,83-94H,5-28,30,32-38H2,1-4H3,(H,73,80)(H,74,82)/b31-29+/t39-,41-,42+,43+,44+,45+,46+,47+,49+,50+,51-,52+,53-,54+,55-,56+,57+,58-,59+,60+,61+,62+,63-,64+,65-,66+,67-,68+,69-,70-,71+,72-/m0/s1
    Key: NQUSQNBGWFMOFP-PBNVMRQJSA-N
  • CCCCCCCCCCCCC\C=C\[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O[C@@H]5O[C@H](CO)[C@H](O)[C@H](O)[C@H]5O[C@@H]5O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]5O)[C@H]4NC(C)=O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)NC(CCCCCCCCCCCCCCC)=O
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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

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

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

Orphan Drug Designations by the FDA for the treatment of pancreatic and gastric cancer.[21]

References

  1. ^
    PMID 30808745
    .
  2. ^
    ISSN 0008-5472. {{cite book}}: |journal= ignored (help
    )
  3. PMID 29036791
    .
  4. ISSN 0002-7863
    .
  5. PMID 6501317
    .
  6. PMID 18689688
    .
  7. PMID 32512916
    .
  8. PMID 26677875
    .
  9. ^
    ISSN 0002-7863
    .
  10. S2CID 22303340
    .
  11. S2CID 225447790. {{cite book}}: |journal= ignored (help
    )
  12. ^
    PMID 25665650
    .
  13. S2CID 219778189
    .
  14. PMID 26918109
    .
  15. PMID 34123241
    .
  16. S2CID 242693378. {{cite book}}: |journal= ignored (help
    )
  17. S2CID 241616016. {{cite book}}: |journal= ignored (help
    )
  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". {{cite journal}}: Cite journal requires |journal= (help)
  19. S2CID 219265652. {{cite book}}: |journal= ignored (help
    )
  20. S2CID 219773934
    .
  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. {{cite press release}}: |last= has generic name (help)
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