R J Benschop1, E C Collins2, R J Darling3, B W Allan4, D Leung5, E M Conner6, J Nelson7, B Gaynor8, J Xu9, X-F Wang10, R A Lynch11, B Li12, D McCarty13, E S Nisenbaum14, J L Oskins, C Lin15, K W Johnson16, M G Chambers17. 1. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: rbenschop@lilly.com. 2. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: collins_emily_catherine@lilly.com. 3. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: darling_ryan@lilly.com. 4. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: allan_barrett@lilly.com. 5. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: leung_donmienne@lilly.com. 6. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: conner_elaine_m@lilly.com. 7. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: nelson_james@lilly.com. 8. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: gaynor_barbra@lilly.com. 9. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: xu_jianghuai@lilly.com. 10. Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: wang_xiao_fen@lilly.com. 11. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: lynch_renee_a@lilly.com. 12. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: li_baolin@lilly.com. 13. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: drmccarty@aol.com. 14. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: oskins_jennifer_leigh@lilly.com. 15. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: lin_chaohua@lilly.com. 16. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: johnson_kirk_w@lilly.com. 17. Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: chambers_mark_geoffrey@lilly.com.
Abstract
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 (KD 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.
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 ratCGRP (KD 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 ratmonoiodoacetate 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.
Authors: S Takano; K Uchida; M Miyagi; G Inoue; J Aikawa; H Fujimaki; A Minatani; M Sato; K Iwabuchi; M Takaso Journal: Clin Exp Immunol Date: 2015-10-28 Impact factor: 4.330