title: A fully caninised anti-NGF monoclonal antibody for pain relief in dogs.
abstract: BACKGROUND
  Monoclonal antibodies are a major class of biological therapies in human medicine but have not yet been successfully applied to veterinary species. We have developed a novel approach, PETisation, to rapidly convert antibodies for use in veterinary species. As an example, anti-nerve growth factor (anti-NGF) monoclonal antibodies (mAbs) which are effective in reducing acute and chronic pain in rodents and man are potentially useful for treating pain in dogs but a fully caninised mAb is required in order to avoid an immune response. The aim of this study was to determine the optimal properties of a caninised anti-NGF mAb for safe, repeated administration to dogs, to determine its pharmacokinetic properties and to evaluate its efficacy in a model of inflammatory pain in vivo.
  
  
  RESULTS
  Starting with a rat anti-NGF mAb, we used a novel algorithm based on expressed canine immunoglobulin sequences to design and characterise recombinant caninised anti-NGF mAbs. Construction with only 2 of the 4 canine IgG heavy chain isotypes (A and D) resulted in stable antibodies which bound and inhibited NGF with high-affinity and potency but did not bind complement C1q or the high-affinity Fc receptor gamma R1 (CD64). One of the mAbs (NV-01) was selected for scale-up manufacture, purification and pre-clinical evaluation. When administered to dogs, NV-01 was well tolerated, had a long serum half-life of 9 days, was not overtly immunogenic following repeated dosing in the dog and reduced signs of lameness in a kaolin model of inflammatory pain.
  
  
  CONCLUSIONS
  The combination of stability, high affinity and potency, no effector activity and long half-life, combined with safety and activity in the model of inflammatory pain in vivo suggests that further development of the caninised anti-NGF mAb NV-01 as a therapeutic agent for the treatment of chronic pain in dogs is warranted.
authors.affiliation: Nexvet Biopharma Pty Ltd, Level 39, 385 Bourke St, Melbourne, Victoria 3000, Australia. dave.gearing@nexvet.com.
authors.forename: David P
authors.initials: DP
authors.lastname: Gearing
authors.forename: Elena R
authors.initials: ER
authors.lastname: Virtue
authors.forename: Robert P
authors.initials: RP
authors.lastname: Gearing
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Drew
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D059350:Chronic Pain / Q000628:therapy / Q000662:veterinary; D004283:Dog Diseases / Q000276:immunology / Q000628:therapy*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay / Q000662:veterinary; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000662:veterinary; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000276:immunology*; D010146:Pain / Q000276:immunology / Q000662:veterinary*; D059408:Pain Management / Q000009:adverse effects / Q000379:methods / Q000662:veterinary*; D011994:Recombinant Proteins; D016415:Sequence Alignment / Q000662:veterinary
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D020932:Nerve Growth Factor