The lymphoid cell surface receptor NTB-A: a novel monoclonal antibody target for leukaemia and lymphoma therapeutics.
NTB-A is a CD2-related cell surface protein expressed primarily on lymphoid cells including B-lymphocytes from chronic lymphocytic leukaemia (CLL) and lymphoma patients. We have generated a series of monoclonal antibodies (mAbs) against NTB-A and assessed their therapeutic potential for CLL. Selective mAbs to NTB-A were further tested in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicty (ADCC) assays in cell lines and B lymphocytes freshly isolated from CLL patients. While lower levels of NTB-A were detected in T and natural killer (NK) cells, CDC activity was demonstrated primarily in B cells isolated from CLL patients and B lymphoma cell lines. Knockdown of NTB-A by small interfering RNA in target cells results in lower cytotoxicity, demonstrating the specificity of the mAbs. Furthermore, anti NTB-A mAbs demonstrated anti-tumour activity against CA46 human lymphoma xenografts in nude mice and against systemically disseminated Raji human lymphoma cells in severe combined immunodeficient mice. Taken together, these results demonstrate NTB-A as a potential new target for immunotherapy of leukaemia and lymphomas.
Korver
Wouter
W
Nuvelo, Inc., San Carlos, CA, USA. wkorver@nuvelo.com
Singh
Shweta
S
Liu
Shouchun
S
Zhao
Xiaoxian
X
Yonkovich
Shirlee
S
Sweeney
Allison
A
Anton
Kristin
K
Lomas
Woodrow E
WE
Greenwood
Rachel
R
Smith
Ashley
A
Tran
Denise Hoang
DH
Shinkawa
Pauline
P
Jimenez
Mark
M
Yeung
Patricia
P
Aguilar
Gerard
G
Palencia
Servando
S
Vatta
Paolo
P
Mueller
Matthew
M
Zhan
Xiaoming
X
Newton
Elizabeth M
EM
Liu
Yi
Y
Zhao
Jingsong
J
Emtage
Peter
P
Levy
Michael D
MD
Hsi
Eric D
ED
Funk
Walter D
WD
Abo
Arie
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000627:therapeutic use*; D000937:Antigen-Antibody Reactions; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006825:Hybridomas; D007116:Immunization, Passive / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D011956:Receptors, Cell Surface; C000604060:SLAMF6 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604063:Slamf6 protein, mouse; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1