Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Issue 8 (August 2015)

• Record Type: Journal Article
• Authors: Larkin, J.; Lohr, T.A.; Elefante, L.; Shearin, J.; Matico, R.; Su, J.-L.; Xue, Y.; Liu, F.; Genell, C.; Miller, R.E.; Tran, P.B.; Malfait, A.-M.; Maier, C.C.; Matheny, C.J.
• Is Part Of: Osteoarthritis and cartilage. Volume 23:Issue 8(2015)
• Page Start: 1254
• Page End: 1266
• Publication Date: 2015-08
• Subjects: ADAMTS-5 -- ADAMTS-4 -- Osteoarthritis -- Monoclonal antibody -- Cartilage -- Disease-modifying osteoarthritis drugs (DMOADs); Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Arthrose -- Périodiques; Articulations -- Maladies -- Périodiques; 616.7223005
• DOI: 10.1016/j.joca.2015.02.778
• Languages: English
• ISSNs: 1063-4584

Abstract

Summary: 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.