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Editors Selection IGR 15-3
Basic Research Animal Studies: Monoclonal antibody doubled ganglion survival time
Comment by David Calkins on:
27577 An agonistic TrkB mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma, Bai Y; Xu J; Brahimi F et al., Investigative ophthalmology & visual science, 2010; 51: 4722-4731
Brain-derived neurotrophic factor (BDNF) is a potent neurotrophin that, like most ligands, can affect different neuronal responses depending on the receptor it binds and activates. Binding of the TrkB receptor elicits a trophic response, while binding of the p75 neurotrophin receptor generates a pro-apoptotic response. Accordingly, attempts to use exogenous BDNF as a neuroprotective agent have met with mixed results, for certainly both BDNF-dependent cascades could be active. To overcome at least some of these obstacles, Bai et al. (1900) have attempted to activate the pro-survival BDNF-dependent pathway exclusively by constructing a custom-made monoclonal antibody to bind and activate TrkB specifically. This they tested in two animal models: optic nerve transection, which results in rapid retinal ganglion cell degeneration, and ocular hypertension induced by episcleral vein cauterization, which affects slower degeneration. A favorite adage among bench scientists is 'Know thy reagents!', and certainly this investigation is an excellent example of such. The team very convincingly demonstrates not only the specificity of the antibody (called mAB1D7) and its TrkB binding domain, but also that it is an effective agonist: it activates TrkB via the expected tyrosine phosphorylation, but at a different site than BDNF.
The use of trophic ligands ultimately remain limited by our poor understanding of their multifarious actions and downstream targets With axotomy via nerve transection, mAb1D7 delivered via intravitreal injection effectively doubled ganglion cell survival measured by retrograde labeling with fluorogold from the colliculus compared to BDNF. Even so, survival remained below 30% two weeks post-injury.
After six weeks of ocular hypertension, survival with two injections of mAb1D7 was about 12% better than BDNF treatment, but only 16% better than no treatment at all. These results were corroborated by OCT measurements of inner retinal thickness, where ganglion cells reside and ramify. Importantly, activation of TrkB by mAb1D7 was sustained in vivo with much greater efficacy than BDNF. That the net results, while statistically significant, were only incremental better than no treatment speaks to another issue entirely. At the end of the day, the use of trophic ligands like BDNF ultimately remain limited by our poor understanding of their multifarious actions and downstream targets.
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