Targeting What’s Inside: Exploring Antibody Therapeutics in Neurodegenerative Disease

Biologics Development

antibody therapeutics
Neurodegenerative diseases are devastating attacks on the human body and mind; however, antibody therapeutics could be an important step toward effective treatments.
Image source: Flickr user NIH Image Gallery

Neurons are the basic unit of the brain, excitable cells that transmit and process information via electrical and chemical signals. Together with glial cells, neurons are responsible for everything we do, from walking and running to speaking and learning. However, some diseases attack these cells and thus attack the very essence of our humanity. Termed neurodegenerative diseases, these illnesses (e.g. amyotrophic lateral sclerosis, Parkinson’s, Alzheimer’s disease and other dementias, etc.), through mechanisms still unknown, lead to a progressive loss of the structure and/or function of neurons and sometimes even neuronal death.1 Unsurprisingly, symptoms of these illnesses often include dramatic losses in mobility or drastic alterations in an individual’s personalities and behaviors. Additionally, these diseases are unfortunately incurable at this time, with few effective therapies to thwart disease progression.2

Promising Antibody Therapeutics Targeting Neurodegenerative Diseases

In the study of neurodegeneration, scientists are becoming increasingly aware of the toxic role of protein aggregation and the “prion-like propagation of protein misfolding.”3 Indeed, it is abnormal protein aggregation that leads to alterations in both the structure and function of neurons and can lead to their death. In Alzheimer’s disease, for example, amyloid-B and tau oligomers are believed to contribute to the pathogenesis of the disease, whereas in amyotrophic lateral sclerosis a protein responsible for destroying superoxide radicals in the body is aggregated into cellular tangles that renders it useless and neurons vulnerable.

Antibody therapies targeted against accumulated proteins and, in particular, proteins similar to prions (infectious protein elements that can worsen aggregation in the cell), could provide a series of novel therapeutic options for patients. Previously, because of the blood-brain barrier (BBB), antibody therapies have been considered “off-limits” for the brain.4 However, new research suggests that antibody therapies do cross the brain, albeit it in small quantities (0.1-0.2% of circulating antibodies can be normally found in the brain).

Making Brain-based Antibody Therapeutics a Reality

In order to uncover the best candidates for antibody therapies targeted against the proteins that accumulate in specific neurodegenerative diseases (e.g. tau, beta-secretase, alpha-synuclein, SOD1, etc.), researchers will need to be especially careful in developing specific characteristics of these antibody therapies.

Specificity: The cells in the brain might all appear similar, however there is a great diversity in the types of neurons and other cell types (i.e. glial cells) in the brain. Some specifically release serotonin, others dopamine, and so it is essential that targeted antibody therapeutics are specific for a specific protein. This avoids damaging other cell structures and thus compromising any benefits antibody therapies might have in the fight against neurodegenerative disease.

Size: As discussed, the brain is considered an immunologically privileged organ and many drugs are unable to fit across the blood-brain barrier. In order to address this, researchers will need to determine what components of antibody therapeutics can be modified in order to move across the brain. There might be structural changes to be made or even certain protein groups that need to be added in order to facilitate—for example, the formation of “antibody bundles” that can more easily pass the BBB together. Either way, this process will require that researchers take careful note of the essential components of antibody therapeutics targeting specific proteins, and then consider the necessary size modifications.

Toxicity: Researchers must also consider the toxicity of antibody therapeutics targeted against proteins that likely have normal functions in the brain. In order to prevent such occurrences, they should be screened against multiple neuronal cell lines as well as iPS-derived neurons from those with Alzheimer’s disease. Early screening can identify therapeutics with a significant risk for toxicity and enable focusing on therapeutics with the greatest chance of success while also saving significant amounts of time and money. However, doing so requires that researchers store and have access to large amounts of data.

How can researchers begin to manage the vast amounts of data generated from therapeutic screening and optimization? As discussed, antibody therapies for the brain should be specific and small in order to cross the blood-brain barrier and be non-toxic to neurons. In order to ensure these characteristics are met, researchers need to design a discovery workflow using available software in order to process high volume antibody sequences, while using that sequence information to create even smaller, more specific targeted antibody therapies. Additionally, any software used should also support collaboration and project tracking in order to ensure that researchers’ efforts are not spent in vain or wasted on experiments that have already been performed.

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  1. “Neurodegeneration,” September 25, 2015,
  2. “Neurodegenerative diseases and dementia,” 2015,
  3. “Protein folding and Neurodegenerative Diseases,” March 31, 2014,
  4. “Developing therapeutic antibodies for neurodegenerative disease,” July 10, 2013,

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