title: Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell-dependent cytotoxicity.
abstract: In spite of newly emerging therapies and the improved survival of patients with non-Hodgkin lymphoma (NHL), relapses or primary refractory disease are commonly observed and associated with dismal prognosis. Although discovery of the anti-CD20 antibody rituximab has markedly improved outcomes in B-cell NHL, rituximab resistance remains an important obstacle to successful treatment of these tumors. To improve the efficacy of CD20-targeted therapy, we fused interleukin 21 (IL-21), which induces direct lymphoma cytotoxicity and activates immune effector cells, to the anti-CD20 antibody (αCD20-IL-21 fusokine). We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations. Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment. In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments. Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life. In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors. Collectively, the dual functional ability of the αCD20-IL-21 fusokine to induce direct apoptosis and activate immune effector cells may provide benefit over existing treatments for NHL.
authors.affiliation: Department of Molecular and Cellular Pharmacology.|Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Shruti
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.|Sheila and David Fuente Graduate Program in Cancer Biology, and.
authors.forename: Salma
authors.initials: S
authors.lastname: Parvin
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Hyun-Mi
authors.initials: HM
authors.lastname: Cho
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, FL; and.
authors.forename: Kranthi
authors.initials: K
authors.lastname: Kunkalla
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.|Department of Pathology, University of Miami Miller School of Medicine, Miami, FL; and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.affiliation: Molecular Biology Institute, and.|Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, CA.
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Seung-Uon
authors.initials: SU
authors.lastname: Shin
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Rosenblatt
authors.affiliation: Department of Molecular and Cellular Pharmacology.|Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000276:immunology; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015870:Gene Expression; D006207:Half-Life; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics*; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D007378:Interleukins; D053655:Receptors, Interleukin-21; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D000098546:Interleukin-21