MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response

Autoren

Adele Gabba
Riem Attariya
Sandra Behren
Christian Pett
Joost C van der Horst
Hajime Yurugi
Jin Yu
Moritz Urschbach
Juan Sabin
Gabriel Birrane
Edgar Schmitt
Sandra J van Vliet
Pol Besenius
Ulrika Westerlind
Paul V Murphy

DOI

10.1021/jacs.2c12843

eISSN

1520-5126

ISSN

0002-7863

Ausgabe der Veröffentlichung

24

Zeitschrift

Journal of the American Chemical Society

Sprache

en

Online publication date

2023

Paginierung

13027 - 13037

Datum der Veröffentlichung

2023

Status

Published

Herausgeber

American Chemical Society (ACS)

Herausgeber URL

http://dx.doi.org/10.1021/jacs.2c12843

Datum der Datenerfassung

2023

Titel

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response

Ausgabe der Zeitschrift

145

Datenquelle: Crossref

Abstract

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.

Addresses

School of Biological and Chemical Sciences, University of Galway, University Rd., H91 TK33 Galway, Ireland.

Autoren

Adele Gabba
Riem Attariya
Sandra Behren
Christian Pett
Joost C van der Horst
Hajime Yurugi
Jin Yu
Moritz Urschbach
Juan Sabin
Gabriel Birrane
Edgar Schmitt
Sandra J van Vliet
Pol Besenius
Ulrika Westerlind
Paul V Murphy

DOI

10.1021/jacs.2c12843

eISSN

1520-5126

Externe Identifier

PubMed Identifier: 37279388
PubMed Central ID: PMC10288512

Funding acknowledgements

European Molecular Biology Organization: 7323
Irish Research Council for Science, Engineering and Technology: GOIPG/2016/858
Science Foundation Ireland: 16/IA/4419
European Research Council: 819856
Deutsche Forschungsgemeinschaft: CRC 1066
Kempestiftelserna: JCK-1819.1
Kempestiftelserna: JCK-1819.2

Open access

true

ISSN

0002-7863

Ausgabe der Veröffentlichung

24

Zeitschrift

Journal of the American Chemical Society

Schlüsselwörter

Dendritic Cells
Macrophages
Humans
Glycopeptides
Galactose
Lectins, C-Type
Antigens, Tumor-Associated, Carbohydrate
Vaccines
Mucin-1

Sprache

eng

Medium

Print-Electronic

Online publication date

2023

Open access status

Open Access

Paginierung

13027 - 13037

Datum der Veröffentlichung

2023

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2023

Titel

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

145

Files

https://pubs.acs.org/doi/pdf/10.1021/jacs.2c12843 https://europepmc.org/articles/PMC10288512?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.

Autoren

Adele Gabba
Riem Attariya
Sandra Behren
Christian Pett
Joost C van der Horst
Hajime Yurugi
Jin Yu
Moritz Urschbach
Juan Sabin
Gabriel Birrane
Edgar Schmitt
Sandra J van Vliet
Pol Besenius
Ulrika Westerlind
Paul V Murphy

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/37279388

DOI

10.1021/jacs.2c12843

eISSN

1520-5126

Externe Identifier

PubMed Central ID: PMC10288512

Ausgabe der Veröffentlichung

24

Zeitschrift

J Am Chem Soc

Schlüsselwörter

Humans
Mucin-1
Galactose
Glycopeptides
Antigens, Tumor-Associated, Carbohydrate
Lectins, C-Type
Vaccines
Dendritic Cells
Macrophages

Sprache

eng

Country

United States

Paginierung

13027 - 13037

Datum der Veröffentlichung

2023

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2023

Titel

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

145

Datenquelle: PubMed

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response

Files

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