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

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

来源：Blood, 2010, 115(6): 1204-1213.

DOI：10.1182/blood-2009-06-229039

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 Fc gamma RIIIa. 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 downstream of Fc gamma 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. (Blood. 2010;115:1204-1213)

• 出版日期2010-2-11