Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance

Anne Louise Sørensen, Celso A. Reis, Mads A. Tarp, Ulla Mandel, Kavitha Ramachandran, Vasanthi Sankaranarayanan, Tilo Schwientek, Ros Graham, Joyce Taylor-Papadimitriou, Michael A Hollingsworth, Joy Burchell, Henrik Clausen

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.

Original languageEnglish (US)
Pages (from-to)96-107
Number of pages12
JournalGlycobiology
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2006

Fingerprint

Glycopeptides
Antibody Formation
Anti-Idiotypic Antibodies
Antibodies
Neoplasms
Humoral Immunity
Carbohydrate Sequence
Cells
Immunization
Glycosylation
Antigens
Glycosyltransferases
Peptides
Cancer Vaccines
Mucins
Immunotherapy
Polysaccharides
Epitopes
Vaccines
Carbohydrates

Keywords

  • Cancer vaccine
  • Glycopeptides
  • MUC1
  • O-glucosylation
  • STn

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sørensen, A. L., Reis, C. A., Tarp, M. A., Mandel, U., Ramachandran, K., Sankaranarayanan, V., ... Clausen, H. (2006). Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. Glycobiology, 16(2), 96-107. https://doi.org/10.1093/glycob/cwj044

Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. / Sørensen, Anne Louise; Reis, Celso A.; Tarp, Mads A.; Mandel, Ulla; Ramachandran, Kavitha; Sankaranarayanan, Vasanthi; Schwientek, Tilo; Graham, Ros; Taylor-Papadimitriou, Joyce; Hollingsworth, Michael A; Burchell, Joy; Clausen, Henrik.

In: Glycobiology, Vol. 16, No. 2, 01.02.2006, p. 96-107.

Research output: Contribution to journalArticle

Sørensen, AL, Reis, CA, Tarp, MA, Mandel, U, Ramachandran, K, Sankaranarayanan, V, Schwientek, T, Graham, R, Taylor-Papadimitriou, J, Hollingsworth, MA, Burchell, J & Clausen, H 2006, 'Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance', Glycobiology, vol. 16, no. 2, pp. 96-107. https://doi.org/10.1093/glycob/cwj044
Sørensen, Anne Louise ; Reis, Celso A. ; Tarp, Mads A. ; Mandel, Ulla ; Ramachandran, Kavitha ; Sankaranarayanan, Vasanthi ; Schwientek, Tilo ; Graham, Ros ; Taylor-Papadimitriou, Joyce ; Hollingsworth, Michael A ; Burchell, Joy ; Clausen, Henrik. / Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. In: Glycobiology. 2006 ; Vol. 16, No. 2. pp. 96-107.
@article{78566d37a9084b6d96dc20c416d09e76,
title = "Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance",
abstract = "The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.",
keywords = "Cancer vaccine, Glycopeptides, MUC1, O-glucosylation, STn",
author = "S{\o}rensen, {Anne Louise} and Reis, {Celso A.} and Tarp, {Mads A.} and Ulla Mandel and Kavitha Ramachandran and Vasanthi Sankaranarayanan and Tilo Schwientek and Ros Graham and Joyce Taylor-Papadimitriou and Hollingsworth, {Michael A} and Joy Burchell and Henrik Clausen",
year = "2006",
month = "2",
day = "1",
doi = "10.1093/glycob/cwj044",
language = "English (US)",
volume = "16",
pages = "96--107",
journal = "Glycobiology",
issn = "0959-6658",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance

AU - Sørensen, Anne Louise

AU - Reis, Celso A.

AU - Tarp, Mads A.

AU - Mandel, Ulla

AU - Ramachandran, Kavitha

AU - Sankaranarayanan, Vasanthi

AU - Schwientek, Tilo

AU - Graham, Ros

AU - Taylor-Papadimitriou, Joyce

AU - Hollingsworth, Michael A

AU - Burchell, Joy

AU - Clausen, Henrik

PY - 2006/2/1

Y1 - 2006/2/1

N2 - The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.

AB - The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.

KW - Cancer vaccine

KW - Glycopeptides

KW - MUC1

KW - O-glucosylation

KW - STn

UR - http://www.scopus.com/inward/record.url?scp=31144451097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=31144451097&partnerID=8YFLogxK

U2 - 10.1093/glycob/cwj044

DO - 10.1093/glycob/cwj044

M3 - Article

VL - 16

SP - 96

EP - 107

JO - Glycobiology

JF - Glycobiology

SN - 0959-6658

IS - 2

ER -