Gearing DP, Huebner M, et al. In vitro and in vivo characterization of a fully felinized therapeutic anti-nerve growth factor monoclonal antibody for the treatment of pain in cats. J Vet Intern Med 2016;30:1129-37.
The search for safe and effective pharmaceuticals for the treatment of chronic pain in cats is an area of ongoing concern and active research. Although a number of pharmaceutical and non-pharmaceutical modalities are currently used for cats in chronic pain, none are consistently both safe and effective in this species, and the pharmaceuticals employed in this area are all being used off-label in the United States. The development of anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) holds promise for long-acting pain relief in felines. A similar anti-NGF mAb developed for dogs has demonstrated good tolerability and efficacy in clinical studies involving osteoarthritic dogs.
Monoclonal antibodies for therapeutic use are generally initially produced by immunization of rodents. The mAbs produced thereby will be immunogenic if injected into other mammals, and after production are modified for injection into the target species by substituting amino acids in the heavy and light chain variable domains in the antibody molecule so that the mAb amino acid composition more closely matches that of the target species. When the target species is man, the modification process is called “humanization”; mAbs for the cat are “felinized.” The amino acid sequence of feline NGF and its receptor are highly conserved among mammalian species.
Nerve growth factor is a peptide hormone that is required for the survival of sensory and sympathetic neurons in growing mammals. In adults, NGF is present at sites of injury and inflammation, and plays a significant role in promoting pain and hyperalgesia. It will increase short-term and long-term excitability of nociceptive neurons, and also causes sprouting of nerve endings into sites of inflammation. Anti-NGF antibodies are very effective at relieving pain in animal models of inflammatory, arthritic, neoplastic, and bone fracture pain. In humans, anti-NGF mAbs have shown promise in treating osteoarthritis, low back pain, and cystitis, and were well tolerated.
These researchers hypothesized that a fully felinized anti-NGF mAb would be effective in a model of experimentally induced inflammatory pain in cats. The mAb, NV-02, was first evaluated in vitro for potency, binding affinity to murine NGF, and immunoreactivity. In vivo testing of the pharmacokinetics and safety of NV-02 was evaluated in eight cats as a next step. No safety concerns were identified in cats receiving single subcutaneous doses of NV-02 up to 28 mg/kg, based on evaluation of behavior, weight change, blood chemistry, and hematology in the subjects. The NGF mAbs do not impact the central nervous system in adults, as they do not cross the blood-brain barrier in adult animals.
Analgesic efficacy of NV-02 was then tested in 30 cats. The experimental model involved giving the sedated cats an injection of kaolin into the right rear footpad, which induces a swelling and lameness that appears within 24 hours and self-resolves within 7 to 14 days. The cats were divided into two groups of 15 cats each. One group, the negative control group, received phosphate-buffered solution (PBS) subcutaneously, while the second group was treated with 2.0 mg/kg NV-02 administered subcutaneously. Lameness scores in the experimental cats were assessed before kaolin injection, pre-kaolin injection on day 0, and then 6 hours, one day, and daily for up to 7 days subsequent to kaolin injection
No differences were detected in mean paw circumference or mean rectal temperature between the treatment and placebo groups on any day during the study, similar to results of studies done with anti-NGF mAbs in other species. Mean lameness scores on all days evaluated following initiation of treatment were significantly lower in the treatment group than in the control group. Moreover when cats received the NV-02 injection subcutaneously 4 days prior to the kaolin injection, it reduced the severity of lameness subsequent to the kaolin treatment and maintained protection from lameness over the following week, suggesting that anti-NGF mAb could be used pre-emptively against anticipated pain from surgery or other painful procedures.
A study of caninized anti-NGF mAb in a kaolin-based experimental model in dogs demonstrated a similar duration of effect; longer effects were observed in dogs with degenerative joint disease (DJD). Another recently published study describes the safety and approximately 6-week efficacy of a single injection of NV-02 in cats with DJD; NV-02 has recently received the proprietary name frunevetmab. [PJS]
Gruen Me, Thomson AE, et al. A feline-specific anti-nerve growth factor antibody improves mobility in cats with degenerative joint disease-associated pain: A pilot proof of concept study. J Vet Intern Med. 2016 Jun 22.