Pifferi, C., et al. Design, synthesis and immunological evaluation of CRM197-based immunogens functionalized with synthetic scaffolds displaying a tumor-associated MUC1 glycopeptide. Biomater Sci, 2025 Nov 20.

Pifferi, C., et al. Design, synthesis and immunological evaluation of CRM197-based immunogens functionalized with synthetic scaffolds displaying a tumor-associated MUC1 glycopeptide. Biomater Sci, 2025 Nov 20. PMID: 41263603

• This study aims to address the challenge of developing effective vaccines against tumor-associated MUC1 (taMUC1), a glycoprotein that is overexpressed and aberrantly glycosylated in many cancers but remains poorly immunogenic. The researchers developed a semi-synthetic vaccine platform that displays taMUC1 glycopeptides on synthetic cyclic peptide scaffolds, which are then conjugated to the CRM197 carrier protein. This innovative approach seeks to enhance antigen presentation and immune recognition by preserving antigen accessibility and promoting clustered display, thereby overcoming the limitations associated with weakly immunogenic tumor antigens. The work is grounded in the need to improve cancer vaccine efficacy by optimizing antigen architecture and leveraging adjuvants such as QS-21 to stimulate robust humoral and cellular immune responses, ultimately aiming to generate better targeted immunotherapies against cancer.
• The main results demonstrated that both monovalent and tetravalent CRM197-based conjugates, when formulated with the QS-21 adjuvant, elicited comparable levels of antigen-specific IgGs and activated CD4+ and CD8+ T-cell responses in mice. Importantly, the tetravalent conjugate induced enhanced recognition of native taMUC1 on MCF7 cancer cells, suggesting improved epitope accessibility and immune targeting. These findings highlight that scaffold design and antigen valency significantly influence the immunogenicity and effectiveness of the vaccine platform, with the potential to improve immune responses against weak tumor-associated antigens through optimized antigen presentation and adjuvantation strategies.
• The study reports that all vaccine prototypes, including the CRM197-based conjugates formulated with QS-21, were well tolerated in the animal models. The mice showed no overt signs of distress, illness, abnormal behavior, or significant weight loss throughout the dosing regimen. Therefore, within the scope of this preclinical study, no notable side effects or adverse events were observed.
• The current work is conducted in mouse models, which may not fully recapitulate human immune responses. The safety profile, immunogenic durability over time, and efficacy in humans remain to be established. Additionally, the complex synthesis and conjugation processes, although optimized for preclinical evidence, might pose manufacturing challenges for clinical translation. Proposed next steps include translating this vaccine framework into clinical studies to assess safety, immunogenicity, and efficacy in humans. Further investigation is needed to evaluate long-term immune responses, potential toxicity, and therapeutic efficacy in tumor models, as well as to optimize manufacturing protocols for potential scalability.

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