Non‐natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity
- Guerreiro, Ana 3
- Compañón, Ismael 1
- Lazaris, Foivos S. 1
- Labão-Almeida, Carlos 3
- Oroz, Paula 1
- Ghirardello, Mattia 1
- Marques, Marta C. 3
- Corzana, Francisco 1
- Bernardes, Gonçalo J. L. 2
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1
Universidad de La Rioja
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2
University of Cambridge
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3
Universidade de Lisboa
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ISSN: 1433-7851, 1521-3773
Año de publicación: 2024
Tipo: Artículo
beta Ver similares en nube de resultadosOtras publicaciones en: Angewandte Chemie International Edition
Resumen
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 CRM197 (Cross-Reactive Material 197), a protein approved for human use. Conjugation involves selective reduction and re-bridging of a disulfide in CRM197, 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….