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.