Controlled release of enhanced cross-hybrid IgGA Fc PD-L1 inhibitors using oncolytic adenoviruses
Hamdan, Firas; Feodoroff, Michaela; Russo, Salvatore; Fusciello, Manlio; Feola, Sara; Chiaro, Jacopo; Antignani, Gabriella; Greco, Francesca; Leusen, Jeanette; Ylösmäki, Erkko; Grönholm, Mikaela; Cerullo, Vincenzo
(2023) Molecular Therapy - Oncolytics, volume 28, pp. 264 - 276
(Article)
Abstract
Immune checkpoint inhibitors have clinical success in prolonging the life of many cancer patients. However, only a minority of patients benefit from such therapy, calling for further improvements. Currently, most PD-L1 checkpoint inhibitors in the clinic do not elicit Fc effector mechanisms that would substantially increase their efficacy. To gain
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potency and circumvent off-target effects, we previously designed an oncolytic adenovirus (Ad-Cab) expressing an Fc fusion peptide against PD-L1 on a cross-hybrid immunoglobulin GA (IgGA) Fc. Ad-Cab elicited antibody effector mechanisms of IgG1 and IgA, which led to higher tumor killing compared with each isotype alone and with clinically approved PD-L1 checkpoint inhibitors. In this study, we further improved the therapy to increase the IgG1 Fc effector mechanisms of the IgGA Fc fusion peptide (Ad-Cab FT) by adding four somatic mutations that increase natural killer (NK) cell activation. Ad-Cab FT was shown to work better at lower concentrations compared with Ad-Cab in vitro and in vivo and to have better tumor- and myeloid-derived suppressor cell killing, likely because of higher NK cell activation. Additionally, the biodistribution of the Fc fusion peptide demonstrated targeted release in the tumor microenvironment with minimal or no leakage to the peripheral blood and organs in mice. These data demonstrate effective and safe use of Ad-Cab FT, bidding for further clinical investigation.
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Keywords: Fc engineering, IgA, IgG, oncolytic adenoviruses, PD-L1 therapy, Molecular Medicine, Oncology, Cancer Research, Pharmacology (medical)
ISSN: 2372-7705
Publisher: Cell Press
Note: Funding Information: F.H. thanks the Research Foundation of the University of Helsinki for funding his doctoral studies at the Faculty of Pharmacy, University of Helsinki. V.C. acknowledges the European Research Council under the Horizon 2020 framework (https://erc.europa.eu), ERC-consolidator grant (agreement 681219), the Jane and Aatos Erkko Foundation (project 4705796), HiLIFE Fellow (project 797011004), the Finnish Cancer Foundation (project 4706116), the Magnus Ehrnrooth Foundation (project 4706235), the Academy of Finland, and Digital Precision Cancer Medicine Flagship iCAN. F.H. J.L. E.Y. and V.C. planned and conceived the experiments. F.H. and M.Feodoroff carried out most of the experiments. S.R. M.Fusciello, S.F. J.C. G.A. F.G. E.Y. and M.G. helped to carry out the experiments and interpret results. J.L. provided significant expertise. F.H. wrote the manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript. V.C. is a co-founder and shareholder of Valo Therapeutics LTD (not related to this study). Funding Information: F.H. thanks the Research Foundation of the University of Helsinki for funding his doctoral studies at the Faculty of Pharmacy, University of Helsinki . V.C. acknowledges the European Research Council under the Horizon 2020 framework ( https://erc.europa.eu ), ERC-consolidator grant (agreement 681219 ), the Jane and Aatos Erkko Foundation (project 4705796 ), HiLIFE Fellow (project 797011004 ), the Finnish Cancer Foundation (project 4706116 ), the Magnus Ehrnrooth Foundation (project 4706235 ), the Academy of Finland , and Digital Precision Cancer Medicine Flagship iCAN . Publisher Copyright: © 2023
(Peer reviewed)