CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody

Farrukh T. Awan, Rosa Lapalombella, Rossana Trotta, Jonathan P. Butchar, Bo Yu, Don M. Benson, Julie M. Roda, Carolyn Cheney, Xiaokui Mo, Amy Lehman, Jeffrey Jones, Joseph Flynn, David Jarjoura, John R. Desjarlais, Susheela Tridandapani, Michael A. Caligiuri, Natarajan Muthusamy, John C. Byrd

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

CD19 is a B cell-specific antigen expressed on chronic lymphocytic leukemia (CLL) cells but to date has not been effectively targeted with therapeutic monoclonal antibodies. XmAb5574 is a novel engineered anti-CD19 monoclonal antibody with a modified constant fragment (Fc)-domain designed to enhance binding of FcγRIIIa. Herein, we demonstrate that XmAb5574 mediates potent antibody-dependent cellular cytotoxicity (ADCC), modest direct cytotoxicity, and antibody-dependent cellular phagocytosis but not complement-mediated cytotoxicity against CLL cells. Interestingly, XmAb5574 mediates significantly higher ADCC compared with both the humanized anti-CD19 nonengineered antibody it is derived from and also rituximab, a therapeutic antibody widely used in the treatment of CLL. The XmAb5574-dependent ADCC is mediated by natural killer (NK) cells through a granzyme B-dependent mechanism. The NK cell-mediated cytolytic and secretory function with XmAb5574 compared with the nonengineered antibody is associated with enhanced NK-cell activation, interferon production, extracellular signal-regulated kinase phosphorylation down-stream of Fcγ receptor, and no increased NK-cell apoptosis. Notably, enhanced NK cell-mediated ADCC with XmAb5574 was enhanced further by lenalidomide. These findings provide strong support for further clinical development of XmAb5574 as both a monotherapy and in combination with lenalidomide for the therapy of CLL and related CD19+ B-cell malignancies.

Original languageEnglish (US)
Pages (from-to)1204-1213
Number of pages10
JournalBlood
Volume115
Issue number6
DOIs
StatePublished - Feb 11 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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