1. MONOCLONAL ANTIBODIES AGAINST NERVE GROWTH FACTOR IN PAIN MANAGENT
Ioannis Milioglou, Georgios Geropoulos, Dimochristos Papadimitriou, Maria Mironidou- Tjouveleki
A' Laboratory of Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece.
Neuronal Growth Factor (NGF)
Was first isolated by Rita Levi-Montalcini in 1950s as a protein that induces the growth of nerves and prevents apoptosis . Τhere are 2 NGF receptors, one with higher (tropomyosin receptor kinase A or Trk A) and one with lower (p75 neurotrophin receptor or p75NTR) affinity for NGF.
General Mechanism of Action
NGF binds to TrkA on cell membranes, leading to the phosphorylation of tyrosine in amino acid residues. It is believed that during an inflammatory response NGF is required for the repair of the injured peripheral nerve. However, it also, acts on the healthy surrounding sensory nerves, thereby inducing pain. Under these circumstances, an analgesic that could block NGF/TrkA signaling would be extremely useful for relieving the nociceptive pain.
NGF Antibodies
Tanezumab is a humanized monoclonal antibody with high selectivity and specificity for NGF. It binds both to circulating and to local tissue NGF, thereby preventing interaction with the trkA and p75 receptors. Fulranumab and Fasinumab are two less studied monoclonal antibodies in clinical and pre-clinical level
Potential uses Include:
Osteoarthritis, Chronic Back Pain and Neuropathic Pain (diabetic peripheral neuropathy or DPN and postherpetic neuralgia or PHN)
Figure 1. Biochemical pathway of the TrkA activation by NGF
Osteoarthritis (OA)
Different doses of tanezumab as monotherapy or combined with other analgesics have been used to treat OA in several clinical trails. The effectiveness of tanezumab was evaluated according to the WOMAC index which assesses pain, stiffness, and physical function in patients with hip and / or knee OA.
Tanezumab treatment significantly reduced knee pain while walking and improved patient’s global assessment
The clinical improvement of the patients does not appear to be dose- dependent
A risk for rapidly progressive OA was reported as a side effect, the risk was dose- dependent and higher in the tanezumab/NSAID combination therapy groups
Chronic Low Back Pain (LBP)
Tanezumab has a small to moderate effect on pain relief and a small effect on functional improvement
The statistical importance isn't accompanied by clinically important results
The mean change in the daily average Low Back Pain Intensity score and Roland Morris Disability Questionnaire were not clinically important
Neuropathic Pain
Clinical trials exploring the efficacy of tanezumab in the treatment of DPN and PHN have been conducted
Concerning DPN the studies concluded that tanezumab reduces the pain significantly with presenting any serious side effects
Regarding PHN tanezumab also reduced the pain significantly in a dose- dependent manner without presenting any serious side effects
Conclusion
Clinical trials have shown that tanezumab relieves pain and improves function to a clinically meaningful extent compared to placebo, NSAIDs, and opioids. Further research is indicated so as to determine the precise therapeutic protocols for tanezumab but also to investigate its role in the treatment of other chronic pain conditions such as cancer pain, interstitial cystitis or chronic pancreatitis.