The role of brain-derived neurotrophic factor (BDNF) signaling in chronic pain has been well documented. Given the important central role of BDNF in long term plasticity and memory, we sought to engineer a high affinity, peripherally-restricted monoclonal antibody against BDNF to modulate pain. BDNF shares 100% sequence homology across human and rodents; thus, we selected chickens as an alternative immune host for initial antibody generation. Here, we describe the affinity optimization of complementarity-determining region-grafted, chicken-derived R3bH01, an anti-BDNF antibody specifically blocking the TrkB receptor interaction. Antibody optimization led to the identification of B30, which has a > 300-fold improvement in affinity based on BIAcore, an 800-fold improvement in potency in a cell-based pERK assay and demonstrates exquisite selectivity over related neurotrophins. Affinity improvements measured translated to pharmacological activity, with B30 demonstrating a 30-fold improvement in potency over parental R3bH01 in a peripheral nerve injury model. We further demonstrate that peripheral BDNF plays a role in maintaining the plasticity of sensory neurons following nerve damage, with B30 reversing neuron hyperexcitability associated with heat and mechanical stimuli in a dose-dependent fashion. In summary, our data demonstrate that effective sequestration of BDNF via a high affinity neutralizing antibody has potential utility in modulating the pathophysiological mechanisms that drive chronic pain states.
Department of Psychiatry, Center for Health Outcomes and Interdisciplinary Research, Massachusetts General Hospital, 1 Bowdoin Square, Suite 106, Boston, MA, 02114, USA.
Chronic orofacial pain (COFP; i.e., musculoskeletal, neurovascular, or neuropathic pain in the face, mouth, or jaw that lasts for at least 3 months) is prevalent and debilitating.
Knee osteoarthritis is a chronic degenerative disease associated with pain and decreased mobility that affects advanced-age individuals, thus causing further debilitation. Radiofrequency ablation can benefit patients who are not ideal candidates for surgical intervention and for whom conservative management has been unsatisfactory. Currently, radiofrequency ablation is performed using either ultrasonography or fluoroscopy.
Introduction: For patients with acute intermittent porphyria (AIP), a true attack could be difficult to distinguish from chronic abdominal pain. This study focused on treatment responses from two patients with confirmed elevated biochemical data (delta-aminolevulinic acid (ALA), porphobilinogen (PBG)) and clinical evidence for acute attacks before starting givosiran.
Methods: Data from patients who participated in the phase III givosiran trial in Taiwan between May 2018 and May 2021 were reviewed.
Objective: Neuroimaging investigations are critical to provide a more direct assessment of brain disturbances associated with osteoarthritis (OA)-related pain, and to better understand its pathophysiology to develop new treatment strategies. This viewpoint aims to summarize the importance of the brain in OA pain.
Method: A European working group on pain in osteoarthritis GO-PAIN (Going Inside Osteoarthritis-related Pain Phenotyping) has been created to work on a global assessment of the OA-related pain.
Introduction: Ischaemic stroke, primarily caused by thromboembolic events, typically arises as a consequence of underlying vascular or cardiac pathology. Non-thrombotic embolic strokes, although rare, are increasingly seen in interventional and intravascular procedures. Oxygen-ozone therapy (OOT) is one of the popular treatments for lumbar disc herniation, providing pain relief.
