4x80 | pdb_00004x80
Crystal Structure of murine 7B4 Fab monoclonal antibody against ADAMTS5
Structural highlights
Publication Abstract from PubMedOBJECTIVE/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. Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification.,Larkin J, Lohr TA, Elefante L, Shearin J, Matico R, Su JL, Xue Y, Liu F, Genell C, Miller RE, Tran PB, Malfait AM, Maier CC, Matheny CJ Osteoarthritis Cartilage. 2015 Mar 20. pii: S1063-4584(15)00854-7. doi:, 10.1016/j.joca.2015.02.778. PMID:25800415[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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