title: A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγ(null) mouse lymphoma model.
abstract: Engineering the Fc region of monoclonal antibodies (mAb) in order to enhance effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC) is likely to a be promising approach for next-generation mAb therapy. Here, we report on such an antibody, 113F, a novel CDC-enhancing variant of rituximab, and determine the tumor-associated factors influencing susceptibility to 113F-induced CDC. The latter included the quantity of complement inhibitors present, such as CD55 and CD59. We report that compared to rituximab, 113F mediated highly enhanced CDC against primary CD20-expressing lymphoma cells in vitro. Currently, a major problem in the field of immunotherapy research is the lack of suitable small animal models to evaluate human CDC in vivo. Therefore, we established a novel human tumor-bearing NOD/Shi-scid, IL-2Rγ(null) mouse model, in which human complement functions as the CDC mediator. We demonstrated that rituximab exerted significant antitumor effects via human CDC in this humanized mouse. The finding of specific localization of human C1q on CD20-expressing tumor cell membranes was consistent with the observation that human CDC indeed contributed to the antitumor effect in this model. Moreover, 113F exerted significantly more potent antitumor effects than rituximab in this in vivo model. The detection of more abundant dense signals from C1q using 113F compared to rituximab was consistent with the concept that this reagent represented a CDC-enhancing mAb. In the near future, the efficacy of this type of CDC-enhancing antibody will be determined in clinical trials in humans.
authors: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors: Fumihiko
authors: F
authors: Sato
authors: Asahi
authors: A
authors: Ito
authors: Takashi
authors: T
authors: Ishida
authors: Fumiko
authors: F
authors: Mori
authors: Hisashi
authors: H
authors: Takino
authors: Atsushi
authors: A
authors: Inagaki
authors: Masaki
authors: M
authors: Ri
authors: Shigeru
authors: S
authors: Kusumoto
authors: Hirokazu
authors: H
authors: Komatsu
authors: Shinsuke
authors: S
authors: Iida
authors: Noriko
authors: N
authors: Okada
authors: Hiroshi
authors: H
authors: Inagaki
authors: Ryuzo
authors: R
authors: Ueda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000069283:Rituximab; D003165:Complement System Proteins