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AAIC 2021 | Using antibodies and intrabodies to target pathogenic TDP-43 in ALS

Neil Cashman, MD, University of British Columbia, Vancouver, BC, Canada, describes the identification of misfolded TDP-43 as a potential target for monoclonal antibodies and intrabodies as an amyotrophic lateral sclerosis (ALS) therapeutic. In its misfolded form, TDP-43 is pathogenic, with aggregation playing a role in ALS. A region of TDP-43 only exposed when misfolded has been identified. As a result, monoclonal antibodies that recognize diseased TDP-43 have been developed and shown to work extracellularly to neutralize its prion-like cell-to-cell propagation. Additionally, intrabodies have been designed which can be vectorized and delivered intracellularly in affected neurons and other neural cells, with the expectation that they can trigger degradation of aggregates of misfolded TDP-43. This interview took place during the Alzheimer’s Association International Conference (AAIC), 2021.

Transcript (edited for clarity)

I am a Professor in the Department of Neurology at the University of British Columbia, but I am also a founder and I am the Chief Scientific Officer of a Canadian biotech company called ProMIS Neurosciences. And ProMIS Neurosciences has been funding my work or the work of my lab in trying to identify targets in neurodegenerative disease that can be neutralized by monoclonal antibodies or by intrabodies which are delivered via a viral vector...

I am a Professor in the Department of Neurology at the University of British Columbia, but I am also a founder and I am the Chief Scientific Officer of a Canadian biotech company called ProMIS Neurosciences. And ProMIS Neurosciences has been funding my work or the work of my lab in trying to identify targets in neurodegenerative disease that can be neutralized by monoclonal antibodies or by intrabodies which are delivered via a viral vector. One of the most important targets that the whole field is going toward is the protein TDP-43, which is misfolded or aggregated in diseases like ALS and about half of frontotemporal dementia. It seems to play some role in certain types of Alzheimer’s as well. The trouble with targeting TDP-43 is that it is vitally important for cell survival, especially neuronal cell survival. So whatever we target has to be the abnormal misfolded form of TDP-43 and spare the normal form from its physiological function.

So that was the basis of this project. We were able to identify a misfolding specific epitope, a region of TDP-43 which is only exposed when the protein is misfolded in disease, ALS, FTD, and others. We have such monoclonal antibodies and they do appear to block the cell-to-cell spread of TDP-43 misfolding, kind of prion-like cell to cell spread. But we’ve more recently been able to construct intrabodies, which have the antigen binding domains of the monoclonals, and those are coupled with a lysosomal targeting sequence that will enhance degradation.

So what we have now is a proof of principle of monoclonal antibodies that recognize only disease TDP-43 and intrabodies, which when expressed inside cells, including neuronal cell lines, it triggers the degradation of misfolded TDP-43 and completely spares normal, healthy TDP-43 to perform its vital functions.

We are planning to try both the monoclonal antibody, which can act, as I said, on cell-to-cell spread of TDP-43 misfolding. That’s the basis of the prion-like propagation of TDP-43 misfolding that results in disease. That monoclonal antibody can only get into the extracellular space so it could potentially block or perhaps even arrest the cell-to-cell spread of TDP-43 in the nervous system. But more to the point, we now have intrabodies, which can be vectorized, put into a virus or other vector, which can be delivered intracellularly in affected neurons and other neural cells like astrocytes. And these intrabodies are expected to clear misfolded TDP-43 from performing its gain of function toxicities while sparing normal TDP-43 within the cell, mostly within the nucleus, from autoimmune recognition.

So the hope is that we now have a viable therapeutic for humans which can block cell-to-cell spread, and even more importantly, trigger the degradation of aggregated TDP-43 in the cytoplasm, while again sparing the normal form from degradation. I’m an ALS neurologist and I have been working for decades on developing a viable therapeutic for ALS or motor neuron disease as it’s called in the UK. And I’m very happy, very excited to be in a position where some of our misfolding specific antibodies and other techniques can be applied to patients with ALS. It’s long overdue to have an effective treatment for this disease.

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