Construction and characterization of a bispecific anti-CD20 antibody with potent antitumor activity against B-cell lymphoma.
To develop more effective anti-CD20 reagents for B-cell lymphoma, we designed and constructed a bispecific tetravalent anti-CD20 antibody, 11B8/2F2(ScFvHL)(4)-Fc, derived from two fully human monoclonal antibodies (mAb), 2F2 and 11B8. 2F2 is a type I CD20 mAb, which is potent in complement-dependent cytotoxicity (CDC) assays but poor at inducing apoptosis, whereas 11B8 is a type II CD20 mAb, which is effective in induction of apoptosis but ineffective in CDC. Our results showed that 11B8/2F2(ScFvHL)(4)-Fc possessed apoptosis-inducing activity markedly superior to that of 2F2, and even 11B8, 11B8 plus 2F2, and 2F2(ScFvHL)(4)-Fc, a 2F2-derived monospecific tetravalent antibody developed previously. Interestingly, 11B8/2F2(ScFvHL)(4)-Fc displayed a similar ability to mediate CDC as 2F2(ScFvHL)(4)-Fc, although two of its four antigen-binding arms originated from 11B8. To explore why 11B8/2F2(ScFvHL)(4)-Fc was so potent in both CDC and apoptotic activity, a bispecific divalent antibody composed of 2F2 and 11B8, denoted as 11B8/2F2-ScFvFc, was constructed and characterized. Our results partially explained the reason for the potent CDC and apoptosis-inducing activity of 11B8/2F2(ScFvHL)(4)-Fc. Further in vivo therapy studies showed that 11B8/2F2(ScFvHL)(4)-Fc had a significantly more potent antitumor activity compared with 2F2, 11B8, 2F2 plus 11B8, and 2F2(ScFvHL)(4)-Fc. These data suggest that 11B8/2F2(ScFvHL)(4)-Fc may serve as a potential therapeutic agent for B-cell lymphoma.
Li
Bohua
B
International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
Zhang
Xunming
X
Shi
Shu
S
Zhao
Lei
L
Zhang
Dapeng
D
Qian
Weizhu
W
Zheng
Lei
L
Gao
Jie
J
Wang
Hao
H
Guo
Yajun
Y
D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D016466:CHO Cells; D048708:Cell Growth Processes / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D014162:Transfection
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007128:Immunoglobulin Fragments