Development of a Versatile Cancer Vaccine Format Targeting Antigen-Presenting Cells Using Proximity-Based Sortase A-Mediated Ligation of T‑Cell Epitopes

Cancer vaccines are a promising strategy to increase tumor-specific immune responses in patients who do not adequately respond to checkpoint inhibitors. Cancer vaccines that contain patient-specific tumor antigens are most effective but also necessitate the production of patient-specific vaccines. T...

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Published in:	Bioconjugate chemistry Vol. 35; no. 11; pp. 1805 - 1814
Main Authors:	Wang, Aru Z., Brink, Hendrik J., Bouma, Rianne G., Affandi, Alsya J., Nijen Twilhaar, Maarten K., Heijnen, Dijmphna A. M., van Elk, Joelle, Maaskant, Janneke J., Konijn, Veronique A. L., Stolwijk, Joeke G. C., Kalay, Hakan, Olesek, Katarina, van Kooyk, Yvette, van der Schoot, Johan M. S., Bentlage, Arthur E. H., Scheeren, Ferenc A., Verdoes, Martijn, Vidarsson, Gestur, Kuijl, Coenraad P., den Haan, Joke M. M.
Format:	Journal Article
Language:	English
Published:	American Chemical Society 20-11-2024
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Summary:	Cancer vaccines are a promising strategy to increase tumor-specific immune responses in patients who do not adequately respond to checkpoint inhibitors. Cancer vaccines that contain patient-specific tumor antigens are most effective but also necessitate the production of patient-specific vaccines. This study aims to develop a versatile cancer vaccine format in which patient-specific tumor antigens can be site-specifically conjugated by a proximity-based Sortase A (SrtA)-mediated ligation (PBSL) approach to antibodies that specifically bind to antigen-presenting cells to stimulate immune responses. DEC205 and CD169 are both receptors expressed on antigen-presenting cells that can be targeted to deliver antigens and stimulate T-cell responses. We used the CRISPR/HDR platform to produce mouse heavy chain IgG2a antibodies with DEC205 or CD169 specificity containing an SrtA recognition motif followed by a SpyTag at the C-terminus. Using a recombinant protein of SrtA linked to SpyCatcher, we applied proximity-based SrtA-mediated ligation to ligate fluorescein isothiocyanate (FITC)-labeled or antigenic peptides to the antibodies. Ligated antibodies bound to DEC205-expressing dendritic cells or CD169-expressing macrophages both in vitro and in vivo. More importantly, immunization with DEC205- or CD169-specific Abs linked to T-cell epitopes efficiently stimulated T-cell responses in vivo. To conclude, we have developed a cancer vaccine format using PBSL that enables the rapid incorporation of tumor antigens and could potentially be implemented for the synthesis of personalized cancer vaccines.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1043-1802 1520-4812 1520-4812
DOI:	10.1021/acs.bioconjchem.4c00403