Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

• Published in: Blood 2017-04, Vol.129 (16), p.2246-2256
• Main Authors: Bhatt, Shruti, Parvin, Salma, Zhang, Yu, Cho, Hyun-Mi, Kunkalla, Kranthi, Vega, Francisco, Timmerman, John M., Shin, Seung-Uon, Rosenblatt, Joseph D., Lossos, Izidore S.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Murine-Derived - genetics; Antibodies, Monoclonal, Murine-Derived - immunology; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Antineoplastic Agents - immunology; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Apoptosis - drug effects; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cytotoxicity, Immunologic - drug effects; Gene Expression; Half-Life; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukins - genetics; Interleukins - immunology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - genetics; Lymphoma, Non-Hodgkin - immunology; Lymphoma, Non-Hodgkin - pathology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular Targeted Therapy; Receptors, Interleukin-21 - genetics; Receptors, Interleukin-21 - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacokinetics; Signal Transduction
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-09-738211

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. •Delivering IL-21 to tumor B cells by fusion with anti-CD20 antibody (αCD20-IL-21 fusokine) is a potent antilymphoma therapeutic strategy.•αCD20-IL-21 fusokine demonstrated superior antilymphoma activity compared with its individual components.