Targeting glycosylated motifs on cancer cells using innovative lectins fragments for theranostic applications

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Targeting glycosylated motifs on cancer cells using innovative lectins fragments for theranostic applications

François Bulteau 1,2,3 , Michel Thepaut 1 , Maxime Henry 2 , David Goyard 3 , Olivier Renaudet 3 , Jean-Luc Coll 2 , Franck Fieschi 1

1 Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, France, 2 Univ. Grenoble Alpes, INSERM, Institut of Advenced Bioscience, Grenoble, France, 3 Univ. Grenoble Alpes, CNRS, Department of molecular chemestry, Grenoble, France

We estimate about 3.91 million new cases of cancer in Europe in 2018. And 1.93 million cancer deaths. Half of these are breast, colorectal, prostate and lung cancers.

Currently, several ligands such as RGD peptides, folic acid and recombinant antibodies are used to target cancer cells based on the fact that they recognize receptors overexpressed on the surface of cancer cells. In the present work, our strategy consists in the generation of new tools that target the glycosylation profile of cell surface epitopes.

Many cellular features are altered during the process of carcinogenesis and in particular the glycosylation profile of the membrane of the cancer cells. Notably, it has been observed in many cancers (colon, breast and uterus) appearance of new specific glycosylations patterns (not present on healthy cells)[1][2]. Among them, of particular importance is the Thomsen-nouveau (Tn) antigen, it’s a N-acetylgalactosamine link to the serine or a threonine[3]. Tn antigen is an O glycosylation types.

In the other side, they are proteins, named lectins, which bind specifically and reversibly with sugars. The MGL (macrophage galactose type C-type lectin) can bind with N-acetylgalactosamine).

The innovative goal of my project is to use MGL to target and to deliver molecules of interest such as fluorescent contrast agents and/or therapeutic agents. However, the antigen is not considered as a biomarker yet.

In preliminary experiments, recombinant extracellular domain of MGL constructs have been produced (trimeric) and validated for their functionality. They have been then tested by flow cytometry and confocal microscopy for their specificity toward cancer cell lines positive or negative for the Tn antigen.

The first results show a strong and specific labelling of the Tn-positive cell lines by the MGL.

This strategy is very promising for various applications in oncology. Next steps will be to test our new MGL constructs on 3D spheroid cell cultures and in tumor bearing animals. Later, we will clone the carbohydrate recognition domain (CRD) of this lectin, produce it in E. coli, and load 4 or 6 copies of this CRD on artificial chemical platforms (RAFT) in order to generate multivalent recognition motifs and regioselectivity.

I. Brockhausen, “Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions,” EMBO Rep., vol. 7, no. 6, pp. 599–604, 2006.

E. Lisowska, “Tn antigens and their significance in oncology.,” Acta Biochimica Polonica, vol. 42, no. 1. pp. 11–17, 1995.

L. R. Loureiro et al., “Challenges in antibody development against Tn and sialyl-Tn antigens,” Biomolecules, vol. 5, no. 3, pp. 1783–1809, 2015.

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European Carbohydrate Organisation

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