Antirheumatic Effects of Humanized Anti-Fas Monoclonal Antibody in Human Rheumatoid Arthritis/SCID Mouse Chimera

HIROAKI MATSUNO, KAZUO YUDOH, FUJIO NAKAZAWA, TAKASHI SAWAI, MIWA UZUKI, KUSUKI NISHIOKA, SIN YONEHARA, JUNICHI NAKAYAMA, MASAHIKO OHTSUKI, and TOMOATSU KIMURA

ABSTRACT.

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 Fcg 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 Fcg 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.

Conclusion. Administration of this novel humanized anti-Fas Mab may provide a new treatment for RA by inducing Fas mediated apoptosis in inflammatory cells. (J Rheumatol 2002;29:1609-14)

Key Indexing Terms:

APOPTOSIS
RHEUMATOID ARTHRITIS
SCID MOUSE
TREATMENT
LYMPHOCYTES

---

From the Department of Orthopaedic Surgery, Toyama Medical and Pharmaceutical University, Toyama; Department of Pathology, Iwate Medical School, Morioka; Institute of Medical Science, St. Marianna University, Kawasaki; Institute for Virus Research, Kyoto University, Kyoto; and Neuroscience and Immunology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.

Supported by grants from the research foundation of the Japan Educational Ministry (no. 11470306).

H. Matsuno, MD, PhD, Associate Professor; K. Yudoh, MD, PhD, Senior Lecturer; F. Nakazawa, MD, Senior Lecturer, Department of Orthopedic Surgery, Toyama Medical and Pharmaceutical University; T. Sawai, MD, PhD, Professor; M. Uzuki, MD, PhD, Department of Pathology, Iwate Medical University; K. Nishioka, MD, PhD, Professor, Institute of Medical Science, St. Marianna University; S. Yonehara, PhD, Professor, Institute for Virus Research, Kyoto University; J. Nakayama, PhD, Research Associate; M. Ohtsuki, PhD, Chief Researcher, Neuroscience and Immunology Research Laboratories, Sankyo Co. Ltd.; T. Kimura, MD, PhD, Professor, Department of Orthopedic Surgery, Toyama Medical and Pharmaceutical University.

Address reprint requests to Dr. H. Matsuno, Department of Orthopaedic Surgery, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: matsuno@ms.toyama-mpu.ac.jp

Submitted October 31, 2001; revision accepted February 7, 2002.

---