title: Development of novel tetravalent anti-CD20 antibodies with potent antitumor activity.
abstract: Despite the effectiveness of the anti-CD20 monoclonal antibody (mAb) Rituximab (C2B8) in the treatment of B-cell lymphoma, its efficacy remains variable and often modest. It seems likely that a combination of multiple mechanisms, such as complement-dependent cytotoxicity (CDC) and apoptotic signaling, underlies the therapeutic success of anti-CD20 mAbs. Unfortunately, all the current anti-CD20 mAbs effective in CDC are relatively inactive in signaling cell death and vice versa. In this study, we developed two genetically engineered tetravalent antibodies (TetraMcAb) respectively derived from the anti-CD20 mAbs C2B8 and 2F2. TetraMcAbs, with a molecular mass only 25 kDa higher than native divalent antibodies (DiMcAb), were shown not only to be as effective in mediating CDC and antibody-dependent cellular cytotoxicity against B-lymphoma cells as DiMcAbs but also to have antiproliferative and apoptosis-inducing activity markedly superior to that of DiMcAbs. Interestingly, whereas 2F2 and C2B8 were equally effective in inducing cell growth arrest and apoptosis, the functions of their tetravalent versions, 2F2(ScFvHL)(4)-Fc and C2B8(ScFvHL)(4)-Fc, were significantly different. 2F2(ScFvHL)(4)-Fc exhibited exceptionally more potent antiproliferative and apoptosis-inducing activity than that of C2B8(ScFvHL)(4)-Fc. Immunotherapeutic studies further showed that 2F2(ScFvHL)(4)-Fc was far more effective in prolonging the survival of severe combined immunodeficient mice bearing systemic Daudi or Raji tumors than C2B8, 2F2, and C2B8(ScFvHL)(4)-Fc, suggesting that it might be a promising therapeutic agent for B-cell lymphoma.
authors.affiliation: International Joint Cancer Institute, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Shi
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D017730:Ki-1 Antigen / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D017730:Ki-1 Antigen; D000069283:Rituximab