Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain

被引：109
作者：
Benschop, R. J. [1 ]
Collins, E. C. [1 ]
Darling, R. J. [1 ]
Allan, B. W. [2 ]
Leung, D. [2 ]
Conner, E. M. [2 ]
Nelson, J. [2 ]
Gaynor, B. [2 ]
Xu, J. [2 ]
Wang, X-F [2 ]
Lynch, R. A. [1 ]
Li, B. [1 ]
McCarty, D. [1 ]
Oskins, J. L. [1 ]
Lin, C. [1 ]
Johnson, K. W. [1 ]
Chambers, M. G. [1 ]
机构：
[1] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA
[2] Eli Lilly & Co, Lilly Biotechnol Ctr, San Diego, CA 92121 USA
来源：
OSTEOARTHRITIS AND CARTILAGE | 2014年 / 22卷 / 04期
关键词：
CGRP; Antibody; Osteoarthritis; Pain; Meniscal tear; MIA model; CGRP RECEPTOR ANTAGONIST; ROOT GANGLION NEURONS; DERMAL BLOOD-FLOW; PHARMACOLOGICAL CHARACTERIZATION; SENSORY INNERVATION; MONOCLONAL-ANTIBODY; INFLAMMATORY PAIN; MODEL; RAT; JOINT;
D O I：
10.1016/j.joca.2014.01.009
中图分类号：
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学（修复外科学）];
学科分类号：
摘要：
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.
引用
收藏
页码：578 / 585
页数：8
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