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Papers of the Week

Papers: 25 Apr 2020 - 1 May 2020

Animal Studies, Pharmacology/Drug Development

2020 Jan-Dec




In vitro affinity optimization of an anti-BDNF monoclonal antibody translates to improved potency in targeting chronic pain states .


Stack E, McMurray S, McMurray G, Wade J, Clark M, Young G, Marquette K, Jain S, Kelleher K, Chen T, Lin Q, Bloom L, Lin L, Finlay W, Suzuki R, Cunningham O
MAbs. 2020 Jan-Dec; 12(1):1755000.
PMID: 32329655.


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.