Journal
OSTEOARTHRITIS AND CARTILAGE
Volume 23, Issue 8, Pages 1254-1266Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2015.02.778
Keywords
ADAMTS-5; ADAMTS-4; Osteoarthritis; Monoclonal antibody; Cartilage; Disease-modifying osteoarthritis drugs (DMOADs)
Categories
Funding
- GlaxoSmithKline
- US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR060364, R01AR064251]
- Ruth L. Kirschstein National Research Service Award (Individual NIH Post-doctoral fellowship)
- Arthritis Foundation
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [F32AR062927, R01AR060364, R01AR064251] Funding Source: NIH RePORTER
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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. (C) 2015 The Authors. Published by Elsevier Ltd and Osteoarthritis Research Society International.
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