We have developed a fully synthetic and multifunctional antibody‐recruiting molecule (ARM) to guide natural antibodies already present in the blood stream against cancer cells without pre‐immunization. Our ARM is composed of antibody and tumor binding modules (i.e., ABM and TBM) displaying clustered rhamnose and cyclo‐RGD, respectively. By using a stepwise approach, we have first demonstrated the importance of multivalency for efficient recognition with naturel IgM and αvβ3 integrin expressing M21 tumor cell line. Once covalently conjugated by click chemistry, we confirmed by flow cytometry and confocal microscopy that the recognition properties of both the ABM and TBM are conserved, and more importantly, that the resulting ARM promotes the formation of a ternary complex between natural IgM and cancer cells, which is required for the stimulation of the cytotoxic immune response in vivo. Due to the efficiency of the synthetic process, a larger diversity of heterovalent ligands could be easily explored by using the same multivalent approach and could open new perspectives in this field.
A fully-synthetic anticancer vaccine candidate incorporating an hexadecavalent Tn antigen analogue display via oxime linkages induced tumor-specific IgG antibodies and cellular immune responses in mice coadministered with QS-21 as an adjuvant.
The study of multivalent carbohydrate–protein interactions remains highly complicated and sometimes rendered impossible due to aggregation problems. Bio-Layer Interferometry (BLI) is emerging as a tool to monitor such complex interactions. In this study, various glycoclusters and dendrimers were prepared and evaluated as ligands for lectins produced by pathogenic bacteria Pseudomonas aeruginosa (LecA and Lec B) and Burkholderia ambifaria (BambL). Reliable kinetic and thermodynamic parameters could be measured, and immobilization of either lectin or ligands resulted in high quality data. The methods gave results in full agreement with previous ITC experiments, and presented strong advantages since they require less quantity and purity for the biomolecules.
The recruitment of endogenous antibodies against cancer cells has become a reliable antitumoral immunotherapeutic alternative over the last decade. The covalent attachment of antibody and tumor binding modules (ABM and...
Carbohydrate–protein
interactions play key roles in a wide
variety of biological processes. These interactions are usually weak,
with dissociation constants in the low millimolar to high micromolar
range. Nature uses multivalency to reach high avidities via the glycoside
cluster effect. Capitalizing on this effect, numerous synthetic multivalent
glycoconjugates have been described and used as ligands for carbohydrate-binding
proteins. However, valency is only one of the several parameters governing
the binding mechanisms that are different for every biological receptor,
making it almost impossible to predict. In this context, ligand optimization
requires the screening of a large number of structures with different
valencies, rigidities/flexibilities, and architectures. In this article,
we describe a screening platform based on a glycodendrimer array and
its use to determine the key parameters for high-affinity ligands
of lectin. Several glycoclusters and glycodendrimers displaying varying
numbers of α-N-acetylgalactosamine residues
were covalently attached on glass slides, and their bindings were
studied with the fluorophore-functionalized Helix pomatia agglutinin (HPA) used as a lectin model. This technique requires
minimal quantities of glycoconjugate compared to those for other techniques
and affords useful information on the binding strength. Building of
the glycodendrimer array and quantification of the interactions with
HPA are described.
Invited for the cover of this issue is Olivier Renaudet and co‐workers at the Université Grenoble Alpes and funded by the European Research Council (CoG “LEGO′” no. 647938). The image illustrates a synthetic chemist playing with supramolecular structures to kill cancer cells by using natural antibodies present in the blood stream. Read the full text of the article at 10.1002/chem.201903327.
The utility of synthetic chemistry in cancer immunotherapy has been demonstrated over the past decades with antitumoral vaccines and antibody recruiting molecules (ARM). By using click chemistry, polyfunctional ARMs composed of multivalent antibody and tumoral binding modules to guide natural antibodies to cancer cells without pre‐immunization step have been developed. The resulting ARM was found to promote the formation of a ternary complex that is required for the stimulation of cytotoxic immune response in vivo. More information can be found in the Full Paper by N. Berthet, O. Renaudet, et al. on page 15508.
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