CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody.
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 FcgammaRIIIa. 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 Fcgamma 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.
Awan
Farrukh T
FT
Division of Hematology-Oncology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
Lapalombella
Rosa
R
Trotta
Rossana
R
Butchar
Jonathan P
JP
Yu
Bo
B
Benson
Don M
DM
Roda
Julie M
JM
Cheney
Carolyn
C
Mo
Xiaokui
X
Lehman
Amy
A
Jones
Jeffrey
J
Flynn
Joseph
J
Jarjoura
David
D
Desjarlais
John R
JR
Tridandapani
Susheela
S
Caligiuri
Michael A
MA
Muthusamy
Natarajan
N
Byrd
John C
JC
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000502:physiology*; D018941:Antigens, CD19 / Q000276:immunology*; D017209:Apoptosis; D015153:Blotting, Western; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D010587:Phagocytosis; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D007141:Immunoglobulin Fc Fragments; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D053804:Granzymes