Chemical Glycosylation in the Synthesis of Glycoconjugate Antitumor Vaccines

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 05/2007; 446(7139):1000-7. DOI: 10.1038/nature05813
Source: PubMed


Therapeutic vaccines derived from carbohydrate antigen-adjuvant combinations are a promising approach for cancer immunotherapy. One of the critical limitations in this area is access to sufficient quantities of tumour-associated carbohydrate antigens and glycoconjugate adjuvants. At present, availability of the complex oligosaccharide constructs that are needed for the systematic design and evaluation of novel vaccine formulations relies on de novo chemical synthesis. The use of both state-of-the-art and emerging glycosylation technologies has led to significant advances in this field, allowing the clinical exploration of carbohydrate-based antigens in the treatment of cancer.

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    • "Protein glycosylation provides the functional diversity needed to generate extensive phenotypes from a limited genotype [1] [2]. There is increasing evidence for the role of glycoproteins and glycans in a wide range of cell–cell and cell–matrix recognition, development and morphogenesis, evasion of immune responses, and other important biological functions [3] [4] [5]. Changes in glycosylation are also a hallmark of disease. "
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    ABSTRACT: As one of the most important post-translational modifications, the discovery, isolation and identification of glycoproteins are becoming increasingly important. In this study, a Con A-magnetic particle conjugate-based method was utilized to selectively isolate the glycoproteins and their glycomes from the healthy donor and hepatocellular carcinoma (HCC) case sera. Followed the isolated glycoproteins and their N-linked glycans were identified by LC-ESI-MS/MS and MALDI-TOF/TOF-MS, respectively. 93 glycoproteins from the healthy donors and 85 glycoproteins from the HCC cases were identified. There were 34 different glycoproteins shown between the healthy donors (21/34) and the HCC cases (13/34). 28 glycans from the healthy donors and 30 glycans from the HCC cases were detected and there were 22 different glycans shown between the healthy donors (10/22) and HCC cases (12/22). Among these glycoproteins, 50 were known to be N-linked glycoproteins and 3 novel glycopeptides from 2 predicted potential glycoproteins were discovered. Moreover, the lectin blotting, western blotting and lectin/glyco-antibody microarrays were applied to definitely elucidate the change of selective protein expressions and their glycosylation levels, the results indicated that the differences of the identified glycoproteins between the healthy donors and HCC cases were caused by the change of both protein expression and their glycosylation levels.
    Proteomics 05/2013; 13(9). DOI:10.1002/pmic.201200259 · 3.81 Impact Factor
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    • "Tn antigen has gained attention in antitumor vaccine applications as it is known to generate immune response in cancer patients. [32] [33]. From a study of Konska et al. [34], Tn antigen is expressed in 60%–80% of cancer cells in ductal carcinomas in situ (DCIS) and 20%– 50% of cancer cells in lobular carcinoma in situ. "
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    ABSTRACT: Positive margins have been a critical issue that hinders the success of breast- conserving surgery. The incidence of positive margins is estimated to range from 20% to as high as 60%. Currently, there is no effective intraoperative method for margin assessment. It would be desirable if there is a rapid and reliable breast cancer margin assessment tool in the operating room so that further surgery can be continued if necessary to reduce re-excision rate. In this study, we seek to develop a sensitive and specific molecular probe to help surgeons assess if the surgical margin is clean. The molecular probe consists of the unique aqueous quantum dots developed in our laboratory conjugated with antibodies specific to breast cancer markers such as Tn-antigen. Excised tumors from tumor-bearing nude mice were used to demonstrate the method. AQD-Tn mAb probe proved to be sensitive and specific to identify cancer area quantitatively without being affected by the heterogeneity of the tissue. The integrity of the surgical specimen was not affected by the AQD treatment. Furthermore, AQD-Tn mAb method could determine margin status within 30 minutes of tumor excision, indicating its potential as an accurate intraoperative margin assessment method.
    International Journal of Surgical Oncology 12/2012; 2012(1):861257. DOI:10.1155/2012/861257
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    • "Cell membrane glycoproteins are in the interface with the surrounding environment and constitute an important class of biomolecules in living cells [1]. They play a decisive role in cell–cell and cell–matrix recognition, cell fate, signal transduction, and other important biological functions [2] [3] [4]. Many diseases leading to cellular dysfunction are associated with either an alteration in plasma membrane glycoprotein expression or the glycan profile of plasma membrane proteins [5]. "
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    ABSTRACT: The discovery, isolation, and subsequent identification of cell membrane glycoproteins involved in the structure and function of the cell surface are becoming more and more important. Here, concanavalin A-magnetic particle conjugates were employed to isolate the special membrane glycoproteins from living HepG-2 cells. The isolated glycoproteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and liquid chromatography-tandem mass spectrometry as well as annotated. A total of 37 membrane glycoproteins were identified, and 25 of them were ascertained to locate in the extracellular region.
    Analytical Biochemistry 10/2011; 421(1):339-41. DOI:10.1016/j.ab.2011.10.033 · 2.22 Impact Factor
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