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A Single-Step Chemoenzymatic Reaction for the Construction of Antibody–Cell Conjugates

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journal contribution
posted on 06.12.2018, 21:46 by Jie Li, Mingkuan Chen, Zilei Liu, Linda Zhang, Brunie H. Felding, Kelley W. Moremen, Gregoire Lauvau, Michael Abadier, Klaus Ley, Peng Wu
Employing live cells as therapeutics is a direction of future drug discovery. An easy and robust method to modify the surfaces of cells directly to incorporate novel functionalities is highly desirable. However, genetic methods for cell-surface engineering are laborious and limited by low efficiency for primary cell modification. Here we report a chemoenzymatic approach that exploits a fucosyltransferase to transfer bio-macromolecules, such as an IgG antibody (MW∼ 150 KD), to the glycocalyx on the surfaces of live cells when the antibody is conjugated to the enzyme’s natural donor substrate GDP-Fucose. Requiring no genetic modification, this method is fast and biocompatible with little interference to cells’ endogenous functions. We applied this method to construct two antibody–cell conjugates (ACCs) using both cell lines and primary cells, and the modified cells exhibited specific tumor targeting and resistance to inhibitory signals produced by tumor cells, respectively. Remarkably, Herceptin-NK-92MI conjugates, a natural killer cell line modified with Herceptin, exhibit enhanced activities to induce the lysis of HER2+ cancer cells both ex vivo and in a human tumor xenograft model. Given the unprecedented substrate tolerance of the fucosyltransferase, this chemoenzymatic method offers a general approach to engineer cells as research tools and for therapeutic applications.