Potent Cytolytic Activity and Specific IL15 Delivery in a Second-Generation Trispecific Killer Engager.

Autor:	Felices M; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Lenvik TR; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Kodal B; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Lenvik AJ; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Hinderlie P; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Bendzick LE; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Schirm DK; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Kaminski MF; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., McElmurry RT; Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota., Geller MA; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Eckfeldt CE; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota., Vallera DA; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota., Miller JS; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota. mille011@umn.edu.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2020 Sep; Vol. 8 (9), pp. 1139-1149. Date of Electronic Publication: 2020 Jul 13.
DOI:	10.1158/2326-6066.CIR-19-0837
Abstrakt:	Natural killer (NK) cells are potent immune modulators that can quickly lyse tumor cells and elicit inflammatory responses. These characteristics make them ideal candidates for immunotherapy. However, unlike T cells, NK cells do not possess clonotypic receptors capable of specific antigen recognition and cannot expand via activating receptor signals alone. To enable NK cells with these capabilities, we created and have previously described a tri-specific killer engager (TriKE) platform capable of inducing antigen specificity and cytokine-mediated NK-cell expansion. TriKE molecules have three arms: (i) a single-chain variable fragment (scFv) against the activating receptor CD16 on NK cells to trigger NK-cell activation, (ii) an scFv against a tumor-associated antigen (CD33 here) to induce specific tumor target recognition, and (iii) an IL15 moiety to trigger NK-cell expansion and priming. Here, we demonstrate that by modifying the anti-CD16 scFv with a humanized single-domain antibody against CD16, we improved TriKE functionality. A CD33-targeting second-generation TriKE induced stronger and more specific NK-cell proliferation without T-cell stimulation, enhanced in vitro NK-cell activation and killing of CD33-expressing targets, and improved tumor control in preclinical mouse models. Given these improved functional characteristics, we propose rapid translation of second-generation TriKEs into the clinic. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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