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C‑Mannosyl Lysine for Solid Phase Assembly of Mannosylated Peptide Conjugate Cancer Vaccines
journal contribution
posted on 2020-02-20, 14:43 authored by Tim P. Hogervorst, R. J. Eveline Li, Laura Marino, Sven C. M. Bruijns, Nico J. Meeuwenoord, Dmitri V. Filippov, Herman S. Overkleeft, Gijsbert A. van der Marel, Sandra J. van Vliet, Yvette van Kooyk, Jeroen D. C. CodéeDendritic
cells (DCs) are armed with a multitude of Pattern Recognition
Receptors (PRRs) to recognize pathogens and initiate pathogen-tailored
T cell responses. In these responses, the maturation of DCs is key,
as well as the production of cytokines that help to accomplish T cell
responses. DC-SIGN is a frequently exploited PRR that can effectively
be targeted with mannosylated antigens to enhance the induction of
antigen-specific T cells. The natural O-mannosidic
linkage is susceptible to enzymatic degradation, and its chemical
sensitivity complicates the synthesis of mannosylated antigens. For
this reason, (oligo)mannosides are generally introduced in a late
stage of the antigen synthesis, requiring orthogonal conjugation handles
for their attachment. To increase the stability of the mannosides
and streamline the synthesis of mannosylated peptide antigens, we
here describe the development of an acid-stable C-mannosyl lysine, which allows for the inline introduction of mannosides
during solid-phase peptide synthesis (SPPS). The developed amino acid
has been successfully used for the assembly of both small ligands
and peptide antigen conjugates comprising an epitope of the gp100
melanoma-associated antigen and a TLR7 agonist for DC activation.
The ligands showed similar internalization capacities and binding
affinities as the O-mannosyl analogs. Moreover, the
antigen conjugates were capable of inducing maturation, stimulating
the secretion of pro-inflammatory cytokines, and providing enhanced
gp100 presentation to CD8+ and CD4+ T cells,
similar to their O-mannosyl counterparts. Our results
demonstrate that the C-mannose lysine is a valuable
building block for the generation of anticancer peptide-conjugate
vaccine modalities.
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DC-SIGNTLR 7 agonistPRRpeptide antigen conjugatesmannosylated peptide antigensgp 100 presentationantigen-specific T cellsPattern Recognition ReceptorsSPPSpathogen-tailored T cell responsesMannosylated Peptide Conjugate Cancer Vaccines Dendritic cellsanticancer peptide-conjugate vaccine modalitiesmannosylated antigensSolid Phase AssemblyDCT cell responsessolid-phase peptide synthesisgp 100 melanoma-associated antigen
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