title: Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody.
abstract: The presence of thrombin-cleaved form of osteopontin well correlated with various inflammatory disease activities in not only rodents, but also humans. We previously demonstrated that the blocking of the interaction of a cryptic epitope within osteopontin, which is exposed by thrombin cleavage, with its integrins by specific antibody recognizing cryptic epitope of mouse osteopontin, could significantly inhibits the development of arthritis in mice. We generated a murine monoclonal antibody, 2K1, specifically recognizing a cryptic epitope of human osteopontin, SVVYGLR. We constructed a chimeric antibody, C2K1 in which variable region of 2K1 was fused with human IgG1 constant region. In the present study, we investigated whether the therapeutic administration of C2K1 could ameliorate the established collagen-induced arthritis in cynomolgus monkey. Thus, C2K1 was injected after the onset of arthritis. The inhibition of joint swelling by C2K1 became evident at 4 to 5 weeks after initiation of arthritis, when blood level of C2K1 was peaked. Joint swelling reappeared along with the sharp decline of C2K1 blood levels at 6 weeks. Importantly, destruction of bone and cartilage in joints was still significantly prevented at 10 weeks when blood level of C2K1 was quite low if any and anti-C2K1 antibody emerged. These results demonstrate that neutralizing antibody against the cryptic epitope of osteopontin can be a future therapeutic choice for patients with rheumatoid arthritis.
authors.affiliation: Molecular Medicine Research Laboratories, Astellas Pharmaceutical Inc., Miyukigaoka 21, Tsukuba, Ibaraki, 300-8585, Japan. nobuchika.yamamoto@jp.astellas.com
authors.forename: Nobuchika
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakashima
authors.forename: Masaharu
authors.initials: M
authors.lastname: Torikai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naruse
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Sakai
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use; D000906:Antibodies / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D003094:Collagen / Q000276:immunology* / Q000633:toxicity*; D005260:Female; D008252:Macaca fascicularis / Q000276:immunology*; D008969:Molecular Sequence Data; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D011994:Recombinant Proteins; D053495:Osteopontin; D003094:Collagen