Lead Antibody Targeting Toxic TDP-43 Protein to Advance, ProMIS Says
The candidate antibody therapy, called PMN267, has shown promise in preclinical experiments conducted at independent institutions, the company also reported in a press release.
Nearly all cases of ALS are characterized by aggregates, or clumps, of the TDP-43 protein within the brain and spinal cord. While this protein is important for the healthy function of brain cells, aggregated TDP-43 is toxic and thought to help drive disease progression.
Through previous platform work, ProMIS generated monoclonal antibodies that selectively bind to TDP-43 in aggregated forms. Antibodies are proteins made by the immune system that are able to stick, or bind, to a specific target seen to be a threat with extremely high specificity. Monoclonal antibodies refers to lab-created antibodies that are clones of an initial antibody and have an identical target; in nature, many slightly different antibodies may all recognize the same target.
Based on its binding profile and activity in cell models, PMN267 was selected as ProMIS’s leading monoclonal antibody candidate.
A contract research organization also tested PMN267 in an aggressive mouse model of ALS and frontotemporal dementia (FTD), a related disease often characterized by TDP-43 toxic protein clumps.
Results indicated that injections of the antibody helped to prevent disability from developing. Notably, since TDP-43 aggregates are found within cells, these results are in line with the idea that certain effector antibodies can enter neurons, or nerve cells, to bind their targets.
Separate research, conducted at the University of California San Diego, evaluated an “intrabody” version of PMN267, where a gene therapy vector was used to deliver the genetic sequence of the antibody directly inside of cells, allowing these cells to produce their own intrabody therapy.
Motor neurons are the nerve cells mostly affected in ALS. The university’s work in motor neurons derived from ALS patients found this intrabody significantly reduced levels of TDP-43 aggregates.
“These are encouraging findings that support the activity of PMN267 as a conventional antibody and as an intrabody constructed from PMN267,” said Neil Cashman, ProMIS’s chief science officer.
In addition to an antibody against TDP-43, ProMIS is also working on approaches to target a protein called RACK1. This protein has been found to co-aggregate with TDP-43 in ALS patients, suggesting the two may interact in the disease’s development.
At the American Academy of Neurology Annual Meeting last month, the company presented new data showing that lowering levels of the RACK1 protein reduced TDP-43 aggregation in cell models of ALS. Knocking down RACK1 also lessened nerve damage and improved motor function in a TDP-43-associated model of ALS in fruit flies.