title: In vivo optical imaging of early osteoarthritis using an antibody specific to damaged arthritic cartilage.
abstract: BACKGROUND
  The lack of specific and sensitive serum and radiographic biomarkers for early diagnosis of osteoarthritis (OA) as well as for monitoring subtle changes in disease activity in clinical trials has hampered the development of treatments for OA. We previously showed that 1-11E, a human single chain fragment variable (scFv) specific to collagen type II that has been post-translationally modified by reactive oxidants (ROS-CII), binds exclusively to arthritic cartilage. Here we test the validity of 1-11E as a radiographic biomarker for early disease in experimental OA.
  
  
  METHODS
  Murine OA was induced by destabilisation of the medial meniscus (DMM) in adult male mice. Immunohistochemistry of destabilised or sham-operated knees was performed from 2 to 8 weeks post-surgery with Cy5.5-labelled 1-11E and negative control scFv, C7. Prospective in vivo optical images were taken 4 and 8 weeks post-DMM following intra-articular injection of Cy5.5-labelled scFvs, or intravenous injection of Cy5.5-labelled full length monoclonal antibodies (mAbs).
  
  
  RESULTS
  Specific cartilage staining with 1-11E was apparent as early as 4 weeks post-DMM at the time of earlier cartilage degradation assessed by histology. Prospective in vivo optical images taken 4 and 8 weeks post-DMM following local intra-articular injection of Cy5.5-labelled scFv (n = 7) showed specific in vivo retention of Cys5.5-1-11E scFv following local administration into the knee joint (tissue half-life >78 hours, n = 7, signal to noise ratio (SNR) > 2.1). Specific localization of Cys-5.5-1-11E-mAb to DMM knees (SNR >1.65) was also observed (p < 0.01, n = 8, SNR >1.65). In both cases the SNR increased with time post-DMM.
  
  
  CONCLUSIONS
  1-11E binds specifically to early osteoarthritic cartilage and can be used as a radiographic biomarker following local or systemic delivery to facilitate early diagnosis and monitor disease progression in OA.
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. n.h.lim@qmul.ac.uk.
authors.forename: Ngee Han
authors.initials: NH
authors.lastname: Lim
authors.affiliation: Arthritis Research UK Centre for OA Pathogenesis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK. tonia.vincent@kennedy.ox.ac.uk.
authors.forename: Tonia L
authors.initials: TL
authors.lastname: Vincent
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. a.nissim@qmul.ac.uk.
authors.forename: Ahuva
authors.initials: A
authors.lastname: Nissim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D002232:Carbocyanines / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism*; D024043:Collagen Type II / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061848:Optical Imaging / Q000379:methods*; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D057127:Single-Chain Antibodies / Q000494:pharmacology*
chemical_list: C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D024043:Collagen Type II; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies