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

• Published in: Angewandte Chemie 2024-12, Vol.136 (49), p.n/a
• Main Authors: Guerreiro, Ana, Compañón, Ismael, Lazaris, Foivos S., Labão‐Almeida, Carlos, Oroz, Paula, Ghirardello, Mattia, Marques, Marta C., Corzana, Francisco, Bernardes, Gonçalo J. L.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Amino acids; Animal models; Antigen; Antigen (tumor-associated); Antigens; Apoptosis; Cancer; Cancer vaccines; Cell culture; Cell death; Colon cancer; Combined vaccines; Conjugation; Effectiveness; Glycoconjugate; Glycopeptides; Glycoproteins; Immune checkpoint inhibitors; Immune response; Immune system; Immunogenicity; Lymphocytes T; Pancreatic cancer; PD-1 protein; Protein modification; Proteins; Structural integrity; Sulfur; Therapeutic applications; Tumors; Vaccine; Vaccine development; Vaccines
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202411009

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 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. A chemically defined vaccine is prepared by combining the structural design of a non‐natural glycopeptide antigen with a site‐specific protein modification. The resulting vaccine, which contains a single copy of the antigen, is both prophylactically and therapeutically effective. Importantly, this approach refutes a prevailing dogma that glycoconjugate vaccines require multivalent presentation of antigens.