[Enhancement of antibody-dependent cellular cytotoxicity by tandem Fc multimerization].
Monoclonal antibodies are being used as therapeutics for a number of cancers, such as leukemia, breast and colon cancers, and a lot of monoclonal antibodies specific for tumor-related antigens have been on clinical trials. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms by which antibodies exert anti-tumor effects. ADCC occurs through interaction between the Fc domains of IgG antibodies bound to target cells and Fcgamma receptors on the surface of effector cells. In our study, a chimeric antibody, designated M-Ab, was constructed with the V regions from mouse anti-CD20 mAb 1F5 and the C regions from human IgG1 and kappa chain. Two or three Fc domains were tandemly repeated downstream of the C-terminus of the M-Ab to give D0-Ab (Fc dimer Ab without a linker), T0-Ab (Fc trimer Ab without a linker), and T3-Ab (Fc trimer Ab with a (GGGGS)(3) linker in front of the second and third hinge regions). Here, we show that Fc tandem repeat antibodies bind to all the low-affinity Fcgamma receptors with very potent avidities and have greatly enhanced ADCC activity. T3-Ab is about 100 times more potent than the parental 1F5 chimeric antibody in terms of both Fcgamma receptor binding and exerted ADCC activity at a 50-100 times less concentration as compared with the parental antibody. Thus, Fc tandem repeat antibodies are anticipated to be candidates for anti-tumor therapeutics and useful tools to elucidate the biological roles of Fcgamma receptors.
Nagashima
Hiroaki
H
Tokyo University of Science, Noda, Chiba, Japan. nagashimahra@chugai-pharm.co.jp
Masuho
Yasuhiko
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D051379:Mice; D055503:Protein Multimerization; D017452:Receptors, IgG; D020080:Tandem Repeat Sequences
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG