TY - JOUR
T1 - CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody
AU - Awan, Farrukh T.
AU - Lapalombella, Rosa
AU - Trotta, Rossana
AU - Butchar, Jonathan P.
AU - Yu, Bo
AU - Benson, Don M.
AU - Roda, Julie M.
AU - Cheney, Carolyn
AU - Mo, Xiaokui
AU - Lehman, Amy
AU - Jones, Jeffrey
AU - Flynn, Joseph
AU - Jarjoura, David
AU - Desjarlais, John R.
AU - Tridandapani, Susheela
AU - Caligiuri, Michael A.
AU - Muthusamy, Natarajan
AU - Byrd, John C.
PY - 2010/2/11
Y1 - 2010/2/11
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-06-229039
DO - 10.1182/blood-2009-06-229039
M3 - Article
C2 - 19965644
AN - SCOPUS:77949499778
SN - 0006-4971
VL - 115
SP - 1204
EP - 1213
JO - Blood
JF - Blood
IS - 6
ER -