Antirheumatic effects of humanized anti-Fas monoclonal antibody in human rheumatoid arthritis/SCID mouse chimera.
OBJECTIVE
Anti-Fas monoclonal antibodies (Mab) are considered to be a potential therapeutic agent for rheumatoid arthritis (RA). However, Fas mediated liver and chondrocyte damage is a serious problem in its clinical application. m-HFE7A, a novel anti-Fas Mab, selectively induces apoptosis in inflammatory cells. We succeeded in humanizing m-HFE7A to obtain h-HFE7A. We investigated the therapeutic effects of h-HFE7A Mab in RA.


METHODS
We investigated the apoptosis-inducing activities of h-HFE7A on human Fas ligand transfected cells and cultured human activated lymphocytes (human peripheral blood mononuclear cells and isolated human RA synovial lymphocytes), synoviocytes, and chondrocytes. We then examined the effects of h-HFE7A Mab in vivo using SCID-HuRAg mice implanted with human RA tissue.


RESULTS
Administration of h-HFE7A Mab alone did not induce apoptosis in cultured human Fas ligand transfected cells and activated lymphocytes. However, apoptosis-inducing activities were noted by this Mab crosslinking with a secondary antibody or Fcgamma receptor positive cells. In contrast, no apoptosis induction by h-HFE7A was observed on cultured synoviocytes and chondrocytes with or without crosslinking. Thus the crosslinking with Fcgamma receptor positive cells is essential for the efficacy of this Mab in vivo. In the implanted tissue of the SCID-HuRAg mice, the number of inflammatory cells was significantly decreased in the h-HFE7A Mab treated group compared to the IgG treated control group. Moreover, there were only negligible effects in synoviocytes and chondrocytes with the h-HFE7A Mab.


CONCLUSIONS
Administration of this novel humanized anti-Fas Mab may provide a new treatment for RA by inducing Fas mediated apoptosis in inflammatory cells.
Department of Orthopaedic Surgery, Toyama Medical and Pharmaceutical University, Japan. matsuno@ms.toyama-mpu.ac.jp
Hiroaki
H
Matsuno
Kazuo
K
Yudoh
Fujio
F
Nakazawa
Takashi
T
Sawai
Miwa
M
Uzuki
Kusuki
K
Nishioka
Sin
S
Yonehara
Junichi
J
Nakayama
Masahiko
M
Ohtsuki
Tomoatsu
T
Kimura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D002678:Chimera; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D016511:Severe Combined Immunodeficiency; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D013585:Synovitis / Q000276:immunology / Q000628:therapy*; D014162:Transfection; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor