Translational Development of an ADAMTS-5 Antibody for Osteoarthritis Disease Modification

Osteoarthritis Cartilage. 2015 Aug;23(8):1254-66. doi: 10.1016/j.joca.2015.02.778. Epub 2015 Mar 20.

Abstract

Objective/method: 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.

Conclusion: 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.

Keywords: ADAMTS-4; ADAMTS-5; Cartilage; Disease-modifying osteoarthritis drugs (DMOADs); Monoclonal antibody; Osteoarthritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / immunology*
  • Aggrecans / metabolism
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology*
  • Disease Models, Animal
  • Epitopes / metabolism
  • Humans
  • Mice
  • Osteoarthritis / immunology*
  • Osteoarthritis / metabolism

Substances

  • Aggrecans
  • Antibodies, Monoclonal
  • Epitopes
  • ADAM Proteins