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
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.
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.
Osteoarthritis Cartilage. 2015 Aug;23(8):1254-66. doi: 10.1016/j.joca.2015.02.778. Epub 2015 Mar 20.
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).
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.
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.
目的/方法：聚集蛋白聚糖酶活性，尤其是ADAMTS-5，与致病性软骨降解有关。生成了针对ADAMTS-5和ADAMTS-4的选择性单克隆抗体（mAb），并利用体外、离体和体内系统评估靶点结合、聚集蛋白聚糖酶抑制以及疾病相关终点的调节，旨在选择一种用于骨关节炎（OA）临床开发的候选药物。
结构图谱预测，最有效的单克隆抗体通过交联催化结构域和整合素结构域采用独特的抑制模式。在OA的手术小鼠模型中，ADAMTS-5和ADAMTS-4特异性单克隆抗体在全身给药后均能穿透软骨，表明可到达预期的作用部位。用ADAMTS-5单克隆抗体治疗可观察到结构疾病改善以及相关疼痛相关行为的缓解。通过外植体培养中ARGS新表位释放的测定，人OA软骨治疗表明ADAMTS-5抑制比ADAMTS-4具有更优先的作用。ADAMTS-5单克隆抗体活性在一部分患者来源的组织中最为明显，并且在人外植体和食蟹猴单次治疗后数周内，ARGS新表位释放的抑制持续存在，这与高亲和力靶点结合和ADAMTS-5的缓慢周转一致。
这些数据支持了基因敲除小鼠研究提出的一个假设，即ADAMTS-5是参与软骨降解的主要聚集蛋白聚糖酶，并提供了一条生物学途径与药理学之间的联系，这在人体组织、非人类灵长类动物模型中得到体现，并指向目标OA患者群体。因此，一种人源化的ADAMTS-5选择性单克隆抗体（GSK2394002）作为一种潜在的OA疾病改善治疗药物进入研发阶段。
