Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor- associated MUC1 antigen
Ikusi/ Ireki
Data
2023-04Egilea
Pifferi, Carlo
Aguinagalde, Leire
Ruiz de Angulo Dorronsoro, Ane
Sacristán, Nagore
Tonon Baschirotto, Priscila
Poveda, Ana
Anguita Castillo, Juan de Dios
Fernández Tejada, Alberto
Chemical Science 14(13) : 3501-3513 (2023)
Laburpena
The overexpression of aberrantly glycosylated tumor-associated mucin-1 (TA-MUC1) in human cancers
makes it a major target for the development of anticancer vaccines derived from synthetic MUC1-(glyco)
peptide antigens. However, glycopeptide-based subunit vaccines are weakly immunogenic, requiring
adjuvants and/or additional immunopotentiating approaches to generate optimal immune responses.
Among these strategies, unimolecular self-adjuvanting vaccine constructs that do not need
coadministration of adjuvants or conjugation to carrier proteins emerge as a promising but still
underexploited approach. Herein, we report the design, synthesis, immune-evaluation in mice, and NMR
studies of new, self-adjuvanting and self-assembling vaccines based on our QS-21-derived minimal
adjuvant platform covalently linked to TA-MUC1-(glyco)peptide antigens and a peptide helper T-cell
epitope. We have developed a modular, chemoselective strategy that harnesses two distal attachment
points on the saponin adjuvant to conjugate the respective components in unprotected form and high
yields via orthogonal ligations. In mice, only tri-component candidates but not unconjugated or di-
component combinations induced significant TA-MUC1-specific IgG antibodies able to recognize the
TA-MUC1 on cancer cells. NMR studies revealed the formation of self-assembled aggregates, in which
the more hydrophilic TA-MUC1 moiety gets exposed to the solvent, favoring B-cell recognition. While
dilution of the di-component saponin–(Tn)MUC1 constructs resulted in partial aggregate disruption, this
was not observed for the more stably-organized tri-component candidates. This higher structural
stability in solution correlates with their increased immunogenicity and suggests a longer half-life of the
construct in physiological media, which together with the enhanced antigen multivalent presentation
enabled by the particulate self-assembly, points to this self-adjuvanting tri-component vaccine as
a promising synthetic candidate for further development.