title: Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis.
abstract: OBJECTIVE
  ADAMTS5 (aggrecanase-2) has been demonstrated to be crucial in the development of osteoarthritis (OA), by use of several mouse mutants carrying either truncated, catalytically inactive enzymes or aggrecanase-resistant mutant aggrecan. We have selected recombinant monoclonal antibodies directed against ADAMTS5, by using Intracellular Antibody Capture Technology (IACT). CRB0017 revealed very high affinity for the enzyme in Biacore analyses and very good specificity in a panel of binding assays. Therefore, we tested CRB0017 in a relevant spontaneous OA model, the STR/ort mouse.
  
  
  METHODS
  STR/ort male mice were recruited at 5 months of age, and treated intra-articularly in each knee with CRB0017 1.2 μg, CRB0017 12 μg, or vehicle. After 6 weeks, the intra-articular administration of CRB0017 was repeated with the same doses. After 3 months from recruitment, the animals were sacrificed and the femorotibial joints processed for histology and scored in a blind fashion according to both Mankin's and the OARSI methods.
  
  
  CONCLUSIONS
  All histological scores were significantly decreased in the CRB0017 12 μg/knee group compared to vehicle, while administration of CRB0017 1.2 μg was associated with a trend to a decrease in the same parameters. Therefore, CRB0017 administered twice in 3 months could modify the course of OA in the STR/ort mouse, by delaying cartilage breakdown as assessed histologically. The procedure of blind scoring of the histological samples clearly showed that knee intra-articular administration of CRB0017, an anti-ADAMTS5 antibody, dose-dependently improved disease progression in a relevant animal model of OA.
authors: R&D Division, Rottapharm S.p.A., 20900 Monza, Italy. Electronic address: riccardo.chiusaroli@rottapharm.com.
authors: R
authors: R
authors: Chiusaroli
authors: M
authors: M
authors: Visentini
authors: C
authors: C
authors: Galimberti
authors: C
authors: C
authors: Casseler
authors: L
authors: L
authors: Mennuni
authors: S
authors: S
authors: Covaceuszach
authors: M
authors: M
authors: Lanza
authors: G
authors: G
authors: Ugolini
authors: G
authors: G
authors: Caselli
authors: L C
authors: LC
authors: Rovati
authors: M
authors: M
authors: Visintin
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D000071116:ADAMTS5 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007270:Injections, Intra-Articular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010003:Osteoarthritis / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse
keywords: ADAMTS5; Animal model; Monoclonal antibody; Osteoarthritis; STR/ort mouse