Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis
Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis
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DOI：
10.1016/j.joca.2013.08.015
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发表时间：
2013-11-01
影响因子：
7
通讯作者：
Visintin, M.
中科院分区：
文献类型：
--
作者：
Chiusaroli, R.;Visentini, M.;Visintin, M.
目的：ADAMTS 5（聚集蛋白聚糖酶-2）已被证明在骨关节炎（OA）的发展中至关重要，通过使用携带截短的、催化失活的酶或聚集蛋白聚糖酶抗性突变体聚集蛋白聚糖的几种小鼠突变体。我们已经选择了针对ADAMTS 5的重组单克隆抗体，通过使用细胞内抗体捕获技术（IACf）。CRB 0017在Biacore分析中显示出对酶的非常高的亲和力，并且在一组结合测定中显示出非常好的特异性。设计：在5月龄时招募STR/ort雄性小鼠，并用CRB 0017 1.2 μ g、CRB 0017 12 μ g或赋形剂在每个膝关节内治疗。6周后，以相同剂量重复关节内施用CRB 0017。招募3个月后，处死动物，对股胫关节进行组织学处理，并根据Mankin和OARSI方法以盲法进行评分。与赋形剂相比，CRB 0017 12 μ g/膝组的所有组织学评分均显著降低，而CRB 0017 1.2 μ g的给药与相同参数的下降趋势相关。因此，CRB 0017在3个月内给药两次可通过延迟组织学评估的软骨分解来改变STR/ort小鼠中的OA病程。组织学样品的盲法评分程序清楚地显示，在OA的相关动物模型中，膝关节内施用CRB 0017（一种抗ADAMTS 5抗体）剂量依赖性地改善疾病进展。(C)2013年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: ADAMTS5 (aggrecanase-2) has been demonstrated to be crucial in the development of osteoarthritis (OA), by use of several mouse mutants carrying either truncated, catalytically inactive enzymes or aggrecanase-resistant mutant aggrecan. We have selected recombinant monoclonal antibodies directed against ADAMTS5, by using Intracellular Antibody Capture Technology (IACf). CRB0017 revealed very high affinity for the enzyme in Biacore analyses and very good specificity in a panel of binding assays. Therefore, we tested CRB0017 in a relevant spontaneous OA model, the STR/ort mouse.Design: STR/ort male mice were recruited at 5 months of age, and treated intra-articularly in each knee with CRB0017 1.2 mu g, CRB0017 12 mu g, or vehicle. After 6 weeks, the intra-articular administration of CRB0017 was repeated with the same doses. After 3 months from recruitment, the animals were sacrificed and the femorotibial joints processed for histology and scored in a blind fashion according to both Mankin's and the OARSI methods.Results and conclusions: All histological scores were significantly decreased in the CRB0017 12 mu g/knee group compared to vehicle, while administration of CRB0017 1.2 mu g was associated with a trend to a decrease in the same parameters. Therefore, CRB0017 administered twice in 3 months could modify the course of OA in the STR/ort mouse, by delaying cartilage breakdown as assessed histologically. The procedure of blind scoring of the histological samples clearly showed that knee intra-articular administration of CRB0017, an anti-ADAMTS5 antibody, dose-dependently improved disease progression in a relevant animal model of OA. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.