Nehmé, Rita; Fortier, Marlène; Létourneau, Myriam; Granger Joly de Boissel, Philippine; Dumoulin, Alyssa; Fuselier, Camille; Chatenet, David 
ORCID: https://orcid.org/0000-0002-7270-4328; Doucet, Nicolas ORCID: https://orcid.org/0000-0002-1952-9380 et St-Pierre, Yves ORCID: 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.
Résumé
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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