title: Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification.
abstract: OBJECTIVE
  Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA).
  
  
  RESULTS
  Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover.
  
  
  CONCLUSIONS
  This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic.
authors: Experimental Medicine Unit - Immuno-Inflammation Therapeutic Area Unit, GlaxoSmithKline, Upper Merion, PA, USA; Novel Targets Biopharm Discovery Unit - Biopharm R&D, GlaxoSmithKline, Upper Merion, PA, USA. Electronic address: jonathan.2.larkin@gsk.com.
authors: J
authors: J
authors: Larkin
authors: Experimental Medicine Unit - Immuno-Inflammation Therapeutic Area Unit, GlaxoSmithKline, Upper Merion, PA, USA; Novel Targets Biopharm Discovery Unit - Biopharm R&D, GlaxoSmithKline, Upper Merion, PA, USA.
authors: T A
authors: TA
authors: Lohr
authors: Novel Targets Biopharm Discovery Unit - Biopharm R&D, GlaxoSmithKline, Upper Merion, PA, USA.
authors: L
authors: L
authors: Elefante
authors: Biological Sciences, GlaxoSmithKline, Upper Merion, PA, USA.
authors: J
authors: J
authors: Shearin
authors: Biological Sciences, GlaxoSmithKline, Upper Merion, PA, USA.
authors: R
authors: R
authors: Matico
authors: Biological Sciences, GlaxoSmithKline, Upper Merion, PA, USA.
authors: J-L
authors: JL
authors: Su
authors: Novel Targets Biopharm Discovery Unit - Biopharm R&D, GlaxoSmithKline, Upper Merion, PA, USA.
authors: Y
authors: Y
authors: Xue
authors: Quantitative Sciences, GlaxoSmithKline, Upper Merion, PA, USA.
authors: F
authors: F
authors: Liu
authors: ImmunoToxicology - Platform Technology & Science, GlaxoSmithKline, Upper Merion, PA, USA.
authors: C
authors: C
authors: Genell
authors: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, IL, USA.
authors: R E
authors: RE
authors: Miller
authors: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, IL, USA.
authors: P B
authors: PB
authors: Tran
authors: Department of Internal Medicine (Rheumatology), Rush University Medical Center, Chicago, IL, USA.
authors: A-M
authors: AM
authors: Malfait
authors: ImmunoToxicology - Platform Technology & Science, GlaxoSmithKline, Upper Merion, PA, USA.
authors: C C
authors: CC
authors: Maier
authors: Translational Medicine - Biopharm R&D, GlaxoSmithKline, Upper Merion, PA, USA.
authors: C J
authors: CJ
authors: Matheny
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D051379:Mice; D010003:Osteoarthritis / Q000276:immunology* / Q000378:metabolism
chemical_list: D053674:Aggrecans; D000911:Antibodies, Monoclonal; D000939:Epitopes; D051722:ADAM Proteins
keywords: ADAMTS-4; ADAMTS-5; Cartilage; Disease-modifying osteoarthritis drugs (DMOADs); Monoclonal antibody; Osteoarthritis