Mannose-6-phosphate (M6P) is recognized by the mannose-6-phosphate receptor and plays an important role in the transport of cargo to the endosomes, making it an attractive tool to improve endosomal... Show moreMannose-6-phosphate (M6P) is recognized by the mannose-6-phosphate receptor and plays an important role in the transport of cargo to the endosomes, making it an attractive tool to improve endosomal trafficking of vaccines. We describe herein the assembly of peptide antigen conjugates carrying clusters of mannose-6-C-phosphonates (M6Po). The M6Po's are stable M6P mimics that are resistant to cleavage of the phosphate group by endogenous phosphatases. Two different strategies for the incorporation of the M6Po clusters in the conjugate have been developed: the first relies on a "post-assembly" click approach employing an M6Po bearing an alkyne functionality; the second hinges on an M6PoC-glycoside amino acid building block that can be used in solid-phase peptide synthesis. The generated conjugates were further equipped with a TLR7 ligand to stimulate dendritic cell (DC) maturation. While antigen presentation is hindered by the presence of the M6Po clusters, the incorporation of the M6Po clusters leads to increased activation of DCs, thus demonstrating their potential in improving vaccine adjuvanticity by intraendosomally active TLR ligands. Show less
One of the main challenges in the development of an effective anti-cancer vaccine is the generation of an adequate and directed cellular immune response. Antigen presenting cells play an important... Show moreOne of the main challenges in the development of an effective anti-cancer vaccine is the generation of an adequate and directed cellular immune response. Antigen presenting cells play an important role in obtaining such immune responses as they express pathogen recognition receptors (PRRs), for example Toll-like receptors (TLRs) and Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), and Fc receptors. This enables them to recognize pathogen associated molecular patterns (PAMPs). A promising strategy in immunotherapy is the use of PRR ligands or antibody-recruiting molecules (ARMs) that are covalently bound to an antigenic peptide. The research in this Thesis describes the design and synthesis of new carbohydrate ligands and conjugates for TLR4, NOD2 and mannose-6-phosphate receptor (MPR) in which these ligands are covalently bound to antigenic peptides. In the second part of this Thesis, Fc receptors are exploited as they bind to an immune complex, which is formed by binding of an antibody to an ARM. Therefore several C-glycosyl lysine building blocks are designed and synthesized of which C-rhamnose was conjugated several times to an antigenic peptide. Show less
