{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:34:41Z","timestamp":1790271281703,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T00:00:00Z","timestamp":1679616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cytovia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Glypican-3 (GPC3) is an oncofetal antigen that is highly expressed in multiple solid tumors, including hepatocellular carcinoma, and is barely expressed in adult normal tissues except the placenta. NKp46 activation receptor is expressed in all-natural killer (NK) cells, including tumor-infiltrating NK cells. FLEX-NKTM is a platform for the production of tetravalent multifunctional antibody NK cell engagers (NKE). CYT-303 was designed using the FLEX-NK scaffold, incorporating a novel humanized NKp46 binder that does not induce NKp46 internalization and a humanized GPC3 binder that targets the membrane-proximal lobe to mediate NK cell-redirected killing of HCC tumors. CYT-303 shows sub-nanomolar binding affinities to both GPC3 and NKp46. CYT-303 was highly potent and effective in mediating NK cell-redirected cytotoxicity against multiple HCC tumor cell lines and tumor spheroids. More interestingly, it can reverse the dysfunction induced in NK cells following repeated rounds of serial killing of tumors. It also mediated antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity against GPC3-expressing HCC tumors. In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg\/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC.<\/jats:p>","DOI":"10.3390\/cells12070996","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T06:34:07Z","timestamp":1679639647000},"page":"996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Derivation and Preclinical Characterization of CYT-303, a Novel NKp46-NK Cell Engager Targeting GPC3"],"prefix":"10.3390","volume":"12","author":[{"given":"Antonio","family":"Arulanandam","sequence":"first","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Ming","family":"Chang","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8888-2639","authenticated-orcid":false,"given":"Martine","family":"Cerutti","sequence":"additional","affiliation":[{"name":"Baculovirus and Therapy, UAR3426 Biocampus, Centre National De La Recherche Scientifique (CNRS), 34293 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Choblet","sequence":"additional","affiliation":[{"name":"Baculovirus and Therapy, UAR3426 Biocampus, Centre National De La Recherche Scientifique (CNRS), 34293 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Gao","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Rath","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0409-2497","authenticated-orcid":false,"given":"Armand","family":"Bensussan","sequence":"additional","affiliation":[{"name":"CLCC de Reims, U976 and Institut Godinot, The Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm), 1 Rue Du General Koenig, 51726 Reims CEDEX, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Kadouche","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Teper","sequence":"additional","affiliation":[{"name":"Cytovia Therapeutics, Inc., Natick, MA 01760, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofer","family":"Mandelboim","sequence":"additional","affiliation":[{"name":"The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem, P.O. 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