Extra Domain B Fibronectin as a Target for Near-Infrared Fluorescence Imaging of Rheumatoid Arthritis Affected Joints In Vivo

We investigated a molecular imaging approach for the detection of collagen-induced arthritis in rats by targeting the extra domain B (ED-B) of the extracellular matrix protein fibronectin. ED-B is a highly conserved domain (identical in human and rats) that is produced by alternative splicing during embryonic development and during vascular remodeling such as angiogenesis. The hallmark of rheumatoid arthritis is synovitis leading to both angiogenesis in the synovium and the promotion of cartilage and bone disruption. For in vivo diagnostics, the ED-B-binding single-chain antibody fragment AP39 was used as a targeting probe. It was covalently linked to the near-infrared dye tetrasulfocyanine (TSC) to be visualized by near-infrared fluorescence imaging. The resulting AP39-TSC conjugate was intravenously administered to rats with collagen-induced arthritis and the respective controls. Ovalbumin-TSC was used as control conjugate. Optical imaging over a time period of 24 hours using a planar imaging setup resulted in a clear enhancement of fluorescence intensity in joints with moderate to severe arthritis compared with control joints between 3 and 8 hours postinjection. Given that AP39 is a fully human antibody fragment, this molecular imaging approach for arthritis detection might be translated to humans.

[1]  L. Dinkelborg,et al.  Imaging of tumor angiogenesis using 99mTc-labeled human recombinant anti-ED-B fibronectin antibody fragments. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  L. Dinkelborg,et al.  Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate , 2005, Clinical Cancer Research.

[3]  J. Kirwan.  The synovium in rheumatoid arthritis: evidence for (at least) two pathologies. , 2004, Arthritis and rheumatism.

[4]  I Petersen,et al.  Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology. , 2002, Pathology, research and practice.

[5]  Maarten Boers,et al.  Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. , 2004, Arthritis and rheumatism.

[6]  R. Moats,et al.  In vivo Near-Infrared Fluorescence Imaging of Integrin αvβ3 in Brain Tumor Xenografts , 2004, Cancer Research.

[7]  R. Holmdahl,et al.  Arthritis induced in rats with non‐immunogenic adjuvants as models for rheumatoid arthritis , 2001, Immunological reviews.

[8]  Ingrid Hilger,et al.  Diagnosis of Arthritis Using Near-Infrared Fluorochrome Cy5.5 , 2004, Investigative radiology.

[9]  A. Rubbert-Roth,et al.  Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review , 2009, Arthritis research & therapy.

[10]  E. Fleck,et al.  ED-B fibronectin (ED-B) can be targeted using a novel single chain antibody conjugate and is associated with macrophage accumulation in atherosclerotic lesions , 2007, Basic Research in Cardiology.

[11]  Richard W. Martin,et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. , 2000, The New England journal of medicine.

[12]  A. Pini,et al.  Design and Use of a Phage Display Library , 1998, The Journal of Biological Chemistry.

[13]  Vasilis Ntziachristos,et al.  Shedding light onto live molecular targets , 2003, Nature Medicine.

[14]  Kai Licha,et al.  Near-infrared fluorescent probes for imaging vascular pathophysiology , 2008, Basic Research in Cardiology.

[15]  J. Scheuermann,et al.  Diagnostic and therapeutic applications of recombinant antibodies: targeting the extra-domain B of fibronectin, a marker of tumor angiogenesis. , 2004, Current pharmaceutical design.

[16]  S. Cnattingius,et al.  Perinatal characteristics, early life infections and later risk of rheumatoid arthritis and juvenile idiopathic arthritis , 2008, Annals of the rheumatic diseases.

[17]  M. Wendland,et al.  MR imaging of antigen-induced arthritis with a new, folate receptor-targeted contrast agent. , 2007, Contrast media & molecular imaging.

[18]  A. Kang,et al.  Autoimmunity to type II collagen an experimental model of arthritis , 1977, The Journal of experimental medicine.

[19]  F. Breedveld,et al.  Appropriate and effective management of rheumatoid arthritis , 2004, Annals of the rheumatic diseases.

[20]  B. Maurer,et al.  Angiogenese – therapeutische Interventionsmöglichkeiten bei rheumatischen Erkrankungen , 2007, Zeitschrift für Rheumatologie.

[21]  W. Kaiser,et al.  Noninvasive Diagnosis of Arthritis by Autofluorescence , 2003, Investigative radiology.

[22]  E. Brahn,et al.  New antiangiogenic strategies for the treatment of proliferative synovitis , 2005, Expert opinion on investigational drugs.

[23]  R. Weissleder,et al.  In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. , 2004, Arthritis and rheumatism.

[24]  L. Zardi,et al.  Structural differences in the cell binding region of human fibronectin molecules isolated from cultured normal and tumor‐derived human cells , 1985, FEBS letters.

[25]  Ralph Weissleder,et al.  Arthritis imaging using a near-infrared fluorescence folate-targeted probe , 2005, Arthritis research & therapy.

[26]  Christopher I. Amos,et al.  A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2 , 2008, PLoS genetics.

[27]  R. Weissleder,et al.  Methotrexate-Induced Accumulation of Fluorescent Annexin V in Collagen-Induced Arthritis , 2005, Molecular imaging.

[28]  W. Semmler,et al.  Near-infrared fluorescent dyes for enhanced contrast in optical mammography: phantom experiments. , 2001, Journal of biomedical optics.

[29]  R. Noelle,et al.  Collagen-induced arthritis as a model of rheumatoid arthritis. , 1994, Clinical immunology and immunopathology.

[30]  H. Kosmehl,et al.  Evidence of ED-B+ fibronectin synthesis in human tissues by non-radioactive RNA in situ hybridization. Investigations on carcinoma (oral squamous cell and breast carcinoma), chronic inflammation (rheumatoid synovitis) and fibromatosis (Morbus Dupuytren) , 1998, Histochemistry and Cell Biology.

[31]  A. Drosos,et al.  Epidemiology of adult rheumatoid arthritis. , 2005, Autoimmunity reviews.

[32]  J. Levick.  Permeability of rheumatoid and normal human synovium to specific plasma proteins. , 1981, Arthritis and rheumatism.

[33]  A. Wunder,et al.  Albumin-Based Drug Delivery as Novel Therapeutic Approach for Rheumatoid Arthritis1 , 2003, The Journal of Immunology.

[34]  P. Lipsky,et al.  Why does rheumatoid arthritis involve the joints? , 2007, The New England journal of medicine.

[35]  Rainer Macdonald,et al.  Assessment of unspecific near-infrared dyes in laser-induced fluorescence imaging of experimental arthritis. , 2006, Academic radiology.

[36]  Jürgen Beuthan,et al.  Entwicklung eines Fingergelenkphantoms zur optischen Simulation früher entzündlich-rheumatischer Veränderungen - Development of a Finger Joint Phantom for the Optical Simulation of Early Stages of Rheumatoid Arthritis , 1997 .

[37]  J. Cañete,et al.  Etanercept is effective in patients with rheumatoid arthritis with no response to infliximab therapy. , 2004, Annals of the rheumatic diseases.

[38]  S. Malhotra,et al.  Efficacy of Biologicals in the Treatment of Rheumatoid Arthritis , 2008, Pharmacology.

[39]  M. Ostergaard,et al.  Established rheumatoid arthritis - new imaging modalities. , 2007, Best practice & research. Clinical rheumatology.

[40]  P. Taylor.  The value of sensitive imaging modalities in rheumatoid arthritis , 2003, Arthritis research & therapy.

[41]  F. Baralle,et al.  Transformed human cells produce a new fibronectin isoform by preferential alternative splicing of a previously unobserved exon. , 1987, The EMBO journal.

[42]  P Barton,et al.  A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. , 2006, Health technology assessment.

[43]  A. Boskey,et al.  Molecular imaging promotes progress in orthopedic research. , 2006, Bone.

[44]  A. Kang,et al.  Immunopathogenesis of Collagen Arthritis , 2003, Springer Seminars in Immunopathology.

[45]  P. Petrow,et al.  Expression of fibronectin splice variants and oncofetal glycosylated fibronectin in the synovial membranes of patients with rheumatoid arthritis and osteoarthritis , 2004, Rheumatology International.

[46]  Anthony F. P. Nash,et al.  Improved wrist pannus volume measurement from contrast-enhanced MRI in rheumatoid arthritis using shuffle transform. , 2007, Magnetic resonance imaging.

[47]  Volker Tresp,et al.  Assessment of proximal finger joint inflammation in patients with rheumatoid arthritis, using a novel laser-based imaging technique. , 2002, Arthritis and rheumatism.

[48]  P. Emery,et al.  Aspects of early arthritis. Biological therapy in early arthritis – overtreatment or the way to go? , 2007, Arthritis research & therapy.

[49]  W. Kaiser,et al.  In vivo imaging of experimental arthritis with near-infrared fluorescence. , 2004, Arthritis and rheumatism.

[50]  G. Firestein.  Every Joint Has a Silver Lining , 2007, Science.