Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2)
Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2)
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开发 ADAMTS4 (aggrecanase-1) 和 ADAMTS5 (aggrecanase-2) 人类中和抗体
DOI：
10.1016/j.bbrc.2015.11.072
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kanehisa Kojoh and Yasunori Okada
中科院分区：
文献类型：
--
作者：
Aya Shiraishi;Satsuki Mochizuki;Akira Miyakoshi;Kanehisa Kojoh and Yasunori Okada
ADAMTS4(aggrecanase-1)和ADAMTS5(aggrecanase-2)是ADAMTS(一种带有血栓反应蛋白基序的去整合素和金属蛋白酶)基因家族的成员，被认为在人类骨关节炎关节软骨的聚集性降解中起关键作用。在这里，我们通过筛选人的组合抗体库，开发了针对这些聚集聚糖酶的中和抗体。在5个候选抗体中，1个抗体同时与ADAMTS4和ADAMTS5免疫反应，与ADAMTS、ADAM(去整合素和金属蛋白酶)和基质金属蛋白酶(MMPs)基因家族的10种不同相关金属蛋白酶没有或几乎不发生交叉反应。该抗体几乎完全抑制ADAMTS4和ADAMTS5的聚集聚糖酶活性，部分抑制ADAMTS5聚集聚糖酶活性。它还抑制白细胞介素1刺激的骨关节炎软骨细胞产生的聚集聚糖酶活性。这些数据表明，该抗体是针对ADAMTS4和ADAMTS5的，并在分子和细胞水平上抑制它们的聚集聚糖酶活性，并提示该抗体可能用于治疗骨关节炎等病理情况。
ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2), members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, are considered to play a key role in aggrecan degradation of articular cartilage in human osteoarthritis. Here, we developed a neutralizing antibody to these aggrecanases by screening human combinatorial antibody library. Among the five candidate antibodies, one antibody was immunoreactive with both ADAMTS4 and ADAMTS5, showing no or negligible cross-reactivity with 10 different related metalloproteinases of the ADAMTS, ADAM (a disintegrin and metalloproteinase) and MMP (matrix metalloproteinase) gene families. This antibody almost completely and partially inhibited aggrecanase activity of ADAMTS4 and ADAMTS5, respectively. It also suppressed the aggrecanase activity derived from interleukin-1-stimulated osteoarthritic chondrocytes. These data demonstrate that the antibody is specific to ADAMTS4 and ADAMTS5 and inhibits their aggrecanase activity at molecular and cellular levels, and suggest that this antibody may be useful for treatment of pathological conditions such as osteoarthritis.