iNKT Activation by Potent Alpha-Galcer Analogues and anti-EGFR-Antibody Glycoconjugates as Useful Tool for Onco-Immunotherapy

CD1d restricted T lymphocytes, a subclass of human lymphocytes, appears to be major players of the immune response. A subpopulation of the CD1d restricted lymphocytes, called iNKT cells, bears a TCR receptor and reacts against -galactosylceramides (-GalCer). Recognition of -GalCer (KRN7000) bound to CD1d molecule of an antigen presenting cell, leads to the fast and strong secretion of a large panel of cytokines. These cytokines can stimulate the maturation of dendritic cells, activate the proliferation of IFN synthesis and stimulate cytotoxic CD8 lymphocytes. These mechanisms contribute to the control of tumor progression.

In view to highlight the potency of deoxy-analogues of -GalCers to modulate the iNKT response, we evaluated the effect of combined alterations of the sphingoid base devoid of both 4-OH¹ and 3-OH groups by substitution with one or two fluorine atoms.^2,3 We shown that, despite suppression of the H-bond donating capacity with CD1d, electron isoelectronic effect of one or two fluorine atoms, vs. oxygen, can modulate the lack of the sphingosine 3-OH on the destabilisation of the CD1d/GalCer/TCR complex by reinstating favourable interactions.

In our continuing efforts to improve iNKT activation, we recently discovered novel a-GalCer analogues proved to be more potent by several orders of magnitude than a-GalCer for IFN- secretion. Intriguingly, unlike a-GalCer, they also proved to be active when loaded on several human cancer cell lines known as not expressing CD1d. This latter result reveals a paramount effect of modified a-GalCer on CD1d/TCR complex stabilization that occurs on cancer cell bed without recruitment of usual APCs. With the aim to mediate a local immune response close to tumour environment, selected a-GalCer derivatives have been associated to the anti-EGFR monoclonal antibody. We found that monoclonal antibody glycoconjugates are able to restore iNKT stimulation at a nM range while keeping antibody cytotoxicity

Author(s): Dubreuil Didier

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