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

Blood. 2017 Apr 20;129(16):2246-2256. doi: 10.1182/blood-2016-09-738211. Epub 2017 Jan 30.

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.

MeSH terms

  • 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

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • Antineoplastic Agents
  • Interleukins
  • Receptors, Interleukin-21
  • Recombinant Fusion Proteins
  • Interferon-gamma
  • interleukin-21