Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain
Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain
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DOI：
10.1016/j.joca.2014.01.009
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发表时间：
2014-04-01
影响因子：
7
通讯作者：
Chambers, M. G.
中科院分区：
文献类型：
--
作者：
Benschop, R. J.;Collins, E. C.;Chambers, M. G.
目的：研究降钙素基因相关肽（CGRP）在骨关节炎（OA）相关疼痛中的作用。结果：LY 2951742对人和大鼠CGRP均表现出较高的亲和力（KD分别为31和246 pM）。该抗体在体外中和CGRP介导的SK-N-MC细胞中cAMP的诱导和辣椒素诱导的大鼠真皮血流。在OA疼痛的大鼠单碘乙酸盐模型中，通过体重差异测量，CGRP的中和以剂量依赖性方式显著降低疼痛行为。此外，CGRP中和的疼痛减轻独立于甘草次酸发生，因为LY 2951742和NSAID在NSAID响应版本的模型中相加地起作用，并且CGRP中和在NSAID非响应版本的模型中仍然有效。在OA大鼠膝关节撕裂模型中，单次注射LY 2951742后，CGRP的中和作用也呈剂量依赖性，且持续时间超过60天。结论：LY 2951742是一种高亲和力的CGRP中和抗体。CGRP的中和在几种OA疼痛模型中有效，并且独立于NSAID作用机制起作用。LY 2951742有望用于治疗OA患者的疼痛。(C)2014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: Investigate a role for calcitonin gene-related peptide (CGRP) in osteoarthritis (OA)-related pain.Design: Neutralizing antibodies to CGRP were generated de novo. One of these antibodies, LY2951742, was characterized in vitro and tested in pre-clinical in vivo models of OA pain.Results: LY2951742 exhibited high affinity to both human and rat CGRP (K-D of 31 and 246 pM, respectively). The antibody neutralized CGRP-mediated induction of cAMP in SK-N-MC cells in vitro and capsaicin-induced dermal blood flow in the rat. Neutralization of CGRP significantly reduced pain behavior as measured by weight bearing differential in the rat monoiodoacetate model of OA pain in a dose-dependent manner. Moreover, pain reduction with neutralization of CGRP occurred independently of prostaglandins, since LY2951742 and NSAIDs worked additively in the NSAID-responsive version of the model and CGRP neutralization remained effective in the NSAID non-responsive version of the model. Neutralization of CGRP also provided dose-dependent and prolonged (>60 days) pain reduction in the rat meniscal tear model of OA after only a single injection of LY2951742.Conclusions: LY2951742 is a high affinity, neutralizing antibody to CGRP. Neutralization of CGRP is efficacious in several OA pain models and works independently of NSAID mechanisms of action. LY2951742 holds promise for the treatment of pain in OA patients. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.