title: Generation and preclinical characterization of a Fc-optimized GITR-Ig fusion protein for induction of NK cell reactivity against leukemia.
abstract: Natural killer (NK) cells are cytotoxic lymphocytes that largely contribute to the efficacy of therapeutic strategies like allogenic stem cell transplantation in acute myeloid leukemia (AML) and application of Rituximab in chronic lymphocytic leukemia (CLL). The tumor necrosis factor (TNF) family member GITR ligand (GITRL) is frequently expressed on leukemia cells in AML and CLL and impairs the reactivity of NK cells which express GITR and upregulate its expression following activation. We developed a strategy to reinforce NK anti-leukemia reactivity by combining disruption of GITR-GITRL interaction with targeting leukemia cells for NK antibody-dependent cellular cytotoxicity (ADCC) using GITR-Ig fusion proteins with modified Fc moieties. Neutralization of leukemia-expressed GITRL by the GITR domain enhanced cytotoxicity and cytokine production of NK cells depending on activation state with NK reactivity being further largely dependent on the engineered affinity of the fusion proteins to the Fc receptor. Compared with wild-type GITR-Ig, treatment of primary AML and CLL cells with mutants containing a S239D/I332E modification potently increased cytotoxicity, degranulation, and cytokine production of NK cells in a target-antigen-dependent manner with additive effects being observed with CLL cells upon parallel exposure to Rituximab. Fc-optimized GITR-Ig may thus constitute an attractive means for immunotherapy of leukemia that warrants clinical evaluation.
authors: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors: Benjamin Joachim
authors: BJ
authors: Schmiedel
authors: Antje
authors: A
authors: Werner
authors: Julia
authors: J
authors: Steinbacher
authors: Tina
authors: T
authors: Nuebling
authors: Corina
authors: C
authors: Buechele
authors: Ludger
authors: L
authors: Grosse-Hovest
authors: Helmut Rainer
authors: HR
authors: Salih
mesh_terms: D002478:Cells, Cultured; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins
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