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Non-Natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity.

Non-Natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity.

Authors :
Guerreiro A
Compañón I
Lazaris FS
Labão-Almeida C
Oroz P
Ghirardello M
Marques MC
Corzana F
Bernardes GJL
Source :
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Dec 02; Vol. 63 (49), pp. e202411009. Date of Electronic Publication: 2024 Nov 02.
Publication Year :
2024

Abstract

Glycopeptides derived from the glycoprotein mucin-1 (MUC1) have shown potential as tumor-associated antigens for cancer vaccine development. However, their low immunogenicity and non-selective conjugation to carriers present significant challenges for the clinical efficacy of MUC1-based vaccines. Here, we introduce a novel vaccine candidate based on a structure-guided design of an artificial antigen derived from MUC1 glycopeptide. This engineered antigen contains two non-natural amino acids and has an α-S-glycosidic bond, where sulfur replaces the conventional oxygen atom linking the peptide backbone to the sugar N-acetylgalactosamine. The glycopeptide is then specifically conjugated to the immunogenic protein carrier CRM <subscript>197</subscript> (Cross-Reactive Material 197), a protein approved for human use. Conjugation involves selective reduction and re-bridging of a disulfide in CRM <subscript>197</subscript> , allowing the attachment of a single copy of MUC1. This strategy results in a chemically defined vaccine while maintaining both the structural integrity and immunogenicity of the protein carrier. The vaccine elicits a robust Th1-like immune response in mice and generates antibodies capable of recognizing human cancer cells expressing tumor-associated MUC1. When tested in mouse models of colon adenocarcinoma and pancreatic cancer, the vaccine is effective both as a prophylactic and therapeutic use, significantly delaying tumor growth. In therapeutic applications, improved outcomes were observed when the vaccine was combined with an anti-programmed cell death protein 1 (anti-PD-1) checkpoint inhibitor. Our strategy reduces batch-to-batch variability and enhances both immunogenicity and therapeutic potential. This site-specific approach disputes a prevailing dogma where glycoconjugate vaccines require multivalent display of antigens.<br /> (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Details

Language :
English
ISSN :
1521-3773
Volume :
63
Issue :
49
Database :
MEDLINE
Journal :
Angewandte Chemie (International ed. in English)
Publication Type :
Academic Journal
Accession number :
39275921
Full Text :
https://doi.org/10.1002/anie.202411009