title: Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain.
abstract: OBJECTIVE
  Investigate a role for calcitonin gene-related peptide (CGRP) in osteoarthritis (OA)-related pain.
  
  
  METHODS
  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.
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: rbenschop@lilly.com.
authors: R J
authors: RJ
authors: Benschop
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: collins_emily_catherine@lilly.com.
authors: E C
authors: EC
authors: Collins
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: darling_ryan@lilly.com.
authors: R J
authors: RJ
authors: Darling
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: allan_barrett@lilly.com.
authors: B W
authors: BW
authors: Allan
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: leung_donmienne@lilly.com.
authors: D
authors: D
authors: Leung
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: conner_elaine_m@lilly.com.
authors: E M
authors: EM
authors: Conner
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: nelson_james@lilly.com.
authors: J
authors: J
authors: Nelson
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: gaynor_barbra@lilly.com.
authors: B
authors: B
authors: Gaynor
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: xu_jianghuai@lilly.com.
authors: J
authors: J
authors: Xu
authors: Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: wang_xiao_fen@lilly.com.
authors: X-F
authors: XF
authors: Wang
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: lynch_renee_a@lilly.com.
authors: R A
authors: RA
authors: Lynch
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: li_baolin@lilly.com.
authors: B
authors: B
authors: Li
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: drmccarty@aol.com.
authors: D
authors: D
authors: McCarty
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: oskins_jennifer_leigh@lilly.com.
authors: E S
authors: ES
authors: Nisenbaum
authors: J L
authors: JL
authors: Oskins
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: lin_chaohua@lilly.com.
authors: C
authors: C
authors: Lin
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: johnson_kirk_w@lilly.com.
authors: K W
authors: KW
authors: Johnson
authors: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: chambers_mark_geoffrey@lilly.com.
authors: M G
authors: MG
authors: Chambers
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects*; D054804:Cathelicidins / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy*; D010146:Pain / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D057134:Antibodies, Neutralizing; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D015740:Calcitonin Gene-Related Peptide
keywords: Antibody; CGRP; MIA model; Meniscal tear; Osteoarthritis; Pain