Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16.
Patients with chronic lymphocytic leukaemia (CLL) treated with a combination of fludarabine, cyclophosphamide and rituximab show a high response rate. However, only a poor response is observed following rituximab monotherapy. The use of chemo-immunotherapy is often associated with haematological and infectious complications. Thus, an antibody with an enhanced ability to kill CLL cells could lead to better clinical responses to antibody monotherapy and the possibility of lowering drug doses during chemo-immunotherapy. We generated a chimeric anti-CD20 monoclonal antibody (mAb), EMAB-6, which has a low fucose content. Apoptosis and complement activities for EMAB-6 were similar to those seen for rituximab. By contrast, EMAB-6 mAb showed improved Fcgamma receptor IIIA (FcgammaRIIIA)/CD16 binding and FcgammaRIIIA-dependent effector functions. It induced a higher in vitro antibody-dependent cellular cytotoxicity against CLL cells and a higher FcgammaRIIIA-mediated interleukin-2 production by FcgammaRIIIA(+) Jurkat cells in the presence of CLL cells at both low and maximally saturating concentrations. Comparative studies between CLL and lymphoma cells coated with EMAB-6 or rituximab indicated that the difference of efficacy was more pronounced at low doses and when target cells expressed fewer CD20 molecules. Thus, EMAB-6 mAb represents a promising drug candidate for the treatment of CLL by inducing a strong cytotoxicity against tumour cells that express low CD20 levels.
de Romeuf
Christophe
C
LFB Research Department, 70 rue du Dr Yersin, Bioincubateur Eurasanté, 59120 Loos, France. deromeuf@lfb.fr
Dutertre
Charles-Antoine
CA
Le Garff-Tavernier
Magali
M
Fournier
Nathalie
N
Gaucher
Christine
C
Glacet
Arnaud
A
Jorieux
Sylvie
S
Bihoreau
Nicolas
N
Behrens
Christian K
CK
Béliard
Roland
R
Vieillard
Vincent
V
Cazin
Bruno
B
Bourel
Dominique
D
Prost
Jean-François
JF
Teillaud
Jean-Luc
JL
Merle-Béral
Hélène
H
D000368:Aged; D000369:Aged, 80 and over; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D017452:Receptors, IgG / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018951:Antigens, CD20; C496124:FCGR3A protein, human; D007376:Interleukin-2; D017452:Receptors, IgG