The novel tribody [(CD20)(2)xCD16] efficiently triggers effector cell-mediated lysis of malignant B cells.
Bispecific antibodies (bsab) offer a promising approach for optimizing antibody-based therapies. In the present study, [(CD20)(2)xCD16], a recombinant CD20- and CD16-directed bsab in the tribody format, was designed to optimize recruitment of FcγRIII (CD16)-positive effector cells. [(CD20)(2)xCD16] retained the antigen specificities of the parental monoclonal antibodies and binding to FcγRIIIa was not compromised by the F/V polymorphism at amino-acid position 158. [(CD20)(2)xCD16] mediated potent lysis of lymphoma cell lines and freshly isolated tumor cells from patients, even at low picomolar concentrations (∼10 pM). Irrespective of the CD16a allotype, potency as well as efficacy of lysis obtained with the tribody was significantly higher than lysis triggered by rituximab. Tumor cell killing also occurred when autologous NK cells were used as effector cells. Compared with rituximab, the tribody demonstrated depletion of autologous B cells in ex vivo whole blood assays at 100-fold lower antibody concentration. In mice with a reconstituted humanized hematopoietic system, established by transplantation of human CD34-positive cord blood cells, this novel tribody significantly depleted autologous human B cells. Thus, tribodies such as [(CD20)(2)xCD16], recruiting CD16-positive effector cells, may represent promising candidates for clinical development.
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts University, Kiel, Germany.
P
P
Glorius
A
A
Baerenwaldt
C
C
Kellner
M
M
Staudinger
M
M
Dechant
M
M
Stauch
F J
FJ
Beurskens
P W H I
PW
Parren
J G J van de
JG
Winkel
T
T
Valerius
A
A
Humpe
R
R
Repp
M
M
Gramatzki
F
F
Nimmerjahn
M
M
Peipp
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015448:Leukemia, B-Cell / Q000276:immunology / Q000628:therapy*; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism
D018033:Antibodies, Bispecific; D018951:Antigens, CD20; C496124:FCGR3A protein, human; D017452:Receptors, IgG