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Galectin inhibitors: A new generation of single-domain antibodies to target both intracellular and extracellular galectins for cancer treatment

Nehmé, Rita; Fortier, Marlène; Létourneau, Myriam; Granger Joly de Boissel, Philippine; Dumoulin, Alyssa; Fuselier, Camille; Chatenet, David ORCID logoORCID: https://orcid.org/0000-0002-7270-4328; Doucet, Nicolas ORCID logoORCID: https://orcid.org/0000-0002-1952-9380 et St-Pierre, Yves ORCID logoORCID: https://orcid.org/0000-0002-1948-2041 (2023). Galectin inhibitors: A new generation of single-domain antibodies to target both intracellular and extracellular galectins for cancer treatment In: Annual Meeting of the Society for Glycobiology (SFG), November 05-08, 2023, Hawaii.

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Galectins are a family of evolutionarily conserved lectins known for their preference for β-galactoside-containing glycoconju- gates. Based on their carbohydrate-recognition domains (CRDs), the 12 members of the human galectin family are classified as prototypic, tandem-repeat type and chimeric-type. Galectins perform various homeostatic functions both inside and outside the cells. However, abnormally high levels of galectins can be expressed by cancer cells. The conventional wisdom has been that galectins play a central role in cancer by creating local and systemic immunosuppression, enabling cancer cells to escape the host’s immune defense. While significant attention has been directed towards extracellular galectins and their glycan-binding activity, galectins are also well-known for their ability to promote cancer progression intracellularly. Due to these factors, there has been an increased interest in using galectins as therapeutic targets. Despite considerable efforts toward the development of specific galectin inhibitors, limited success has been met until now. This is due primarily to the lack of highly specific, high- affinity galectin inhibitors and the limited understanding of each galectin’s role in cancer progression. Here, we present the results of several years of research that led to the development of a diverse panel of functional galectin-specific nanobodies (Nbs) and their genetically engineered minibody forms. GAL-7-specific Nbs were generated by screening a synthetic camelid library with biotinylated full-length recombinant galectins. Following three rounds of selection, VHH clones were randomly selected and tested in a non-absorbed phage ELISA assay using avidin plates and biotinylated galectins. Positive clones were selected based on their amino acid sequences, and their cDNA was cloned into the pHEN2 expression vector. In certain cases, the cDNA encoding the Nbs was inserted into pFUSE vectors to generate minibodies with a human IgG1-Fc fragment or was used to generate galectin-specific intrabodies, including PROTACs.Overall, we successfully generated more than 40 Nbs and minibodies targeting galectin-1, -2, -7, -9, and -13-16. We have also generated vectors encoding ALFA-tagged intrabodies to target intracellular pools of galectins and intrabodies fused to the von Hippel–Lindau (VHL) protein to redirect intracellular galectins to the ubiquitination machinery. Hit-to-lead phases led to the identification of high-affinity, highly specific and functional Nbs capable of inhibiting galectin-induced apoptosis. Lead Nbs for galectin-1 and galectin-7 were also tested in vivo for their ability to target galectin-positive mammary tumors using PET/CT imaging. In addition to providing a novel set of research tools to study galectins, our work opens the way to new treatments for different types of cancer, especially for hard-to-treat cancers where galectins have been shown to play an important role in tumor progression.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique P189 Glycobiology (2023) 33(11):1043-1044
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 08 avr. 2024 14:58
Dernière modification: 08 avr. 2024 14:58
URI: https://espace.inrs.ca/id/eprint/15591

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