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

R J Benschop; E C Collins; R J Darling; B W Allan; D Leung; E M Conner; J Nelson; B Gaynor; J Xu; X-F Wang; R A Lynch; B Li; D McCarty; E S Nisenbaum; J L Oskins; C Lin; K W Johnson; M G Chambers

doi:10.1016/j.joca.2014.01.009

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

Osteoarthritis Cartilage. 2014 Apr;22(4):578-85. doi: 10.1016/j.joca.2014.01.009. Epub 2014 Feb 6.

Authors

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

Affiliations

¹ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
² Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
³ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
⁴ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
⁵ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
⁶ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
⁷ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
⁸ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
⁹ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
¹⁰ Eli Lilly & Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: [email protected].
¹¹ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹² Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹³ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹⁴ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹⁵ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹⁶ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
¹⁷ Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].

PMID: 24508775
DOI: 10.1016/j.joca.2014.01.009

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.

Keywords: Antibody; CGRP; MIA model; Meniscal tear; Osteoarthritis; Pain.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Antibodies, Neutralizing / pharmacology*
Antimicrobial Cationic Peptides
Calcitonin Gene-Related Peptide / drug effects*
Cathelicidins / metabolism
Disease Models, Animal
Humans
Male
Osteoarthritis / drug therapy*
Pain / prevention & control*
Rats
Rats, Inbred Lew
Regional Blood Flow
Skin / blood supply

Substances

Anti-Inflammatory Agents, Non-Steroidal
Antibodies, Neutralizing
Antimicrobial Cationic Peptides
Cathelicidins
Calcitonin Gene-Related Peptide