Sign up to SCR Digest, our FREE weekly newsletter, and receive our Notes emailed directly to you. Click here.

PMN.TO: Vectorized Antibodies: Cutting Edge Neurodegenerative Therapy

06/16/2020

By John Vandermosten, CFA

TSX:PMN.TO | OTC:ARFXF

Neurodegenerative diseases continue to afflict millions of people worldwide and effective therapies have remained elusive. The best known, most prevalent neurodegenerative pathosis is Alzheimer’s Disease (AD) but others, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are also important diseases that lack an effective therapy. There are no approved disease modifying therapies available for these conditions and only symptomatic treatments are available. However, the latest developments in gene therapy have added another dimension to the fight against neurodegenerative disease with the introduction of intrabodies. These intracellular antibodies have several beneficial characteristics including an ability to bind to misfolded proteins inside the cell and prevent the formation and spread of unwanted aggregates. Combined with output from ProMIS’ (TSX:PMN.TO) (OTC:ARFXF) computational algorithm, the intrabodies can be very specific, neutralizing only the toxic forms of proteins while sparing normal forms that have important physiological functions.

Antibodies in Neurodegenerative Disease

In all of its forms, neurodegenerative disease is one of the most pressing challenges that modern healthcare faces. It presents detrimental physiological, economic and social effects. Families watch as their loved ones become unable to conduct normal daily tasks and lose the ability to think and control their bodies1. AD, ALS and FTD are all characterized by the accumulation of toxic aggregates that kill neurons. Harnessing the body’s cellular machinery by applying recent advances in viral vectors allows the cell to be used to manufacture the very antibodies that are necessary to stem the spread of neurodegenerative disease.

Antibodies, also known as immunoglobulins, are proteins produced by the body in response to foreign antigens, most commonly bacteria and viruses. Antibodies can be thought of as flags to mark pathogens for sequestering and destruction; the properties of the antibody binding sites determine the antibody’s specificity. Antibodies can now be engineered to target specific antigens, a technique currently being exploited across a multitude of indications2. Antigens can include proteins, sugars, or even nucleic acids. The antigen’s binding site is called the epitope3. Monoclonal antibodies (mAb) can be designed to target the epitope and be recognized by the human immune system.

Shortcomings in Current Approaches

Previous AD-targeted antibody therapies included Roche's gantenerumab, Eli Lilly's solanezumab, and Pfizer's bapineuzumab; these candidates made it to the final stages of clinical trials, but did not progress further. The results showed poor efficacy, highlighting the importance of 1) specificity and 2) identifying the right target.

Of recent interest has been Biogen’s aducanumab, another amyloid-β directed antibody. Aducanumab’s clinical trials showed that higher doses aducanumab had statistically significant benefits4. While aducanumab showed that intravenous Aβ-targeted mAb could be effective, modest efficacy, possible dose-limiting edema (ARIA-E) and the necessity of large, frequent dosing indicated there was still more work to be done.

The previous mAb trials have taught invaluable lessons about developing therapies for neurodegenerative diseases, and have elucidated fundamental flaws in intravenously administered mAb. These shortcomings include high cost, frequent dosing, low permeability across the blood-brain barrier, absence of intracellular activity5 and low specificity. A new approach, known as vectorized antibodies, can be used to neutralize misfolded proteins before the leave the cell and dramatically improve the efficacy and safety of neurodegenerative therapies.

Vectorized Intrabodies

Vectorized intrabodies may provide a new treatment pathway that can address the shortcomings of intravenous mAb approaches. To achieve lasting benefit at the minimum dose necessary, viral vectors can be used to deliver the genetic sequence for therapeutic mAb expression in target cells.

A variety of viral vectors have been explored, each with its own advantages. In general, a viral vectors’ desirability relates to its expression duration, payload capacity and immunogenicity. The most common viral vectors for gene therapy are adenoviruses, adeno-associated viruses (AAV), herpes simplex viruses (HSV), and retroviruses. AAVs and retroviruses can achieve expression in cells that will last for years. The virus with the highest carrying capacity is the HSV at 40kB and the viruses with least immunogenicity are AAVs and retroviruses. Retroviruses integrate their payload into the host genome, causing a permanent modification, but risk mutagenesis. With low immunogenicity and long duration of expression, AAVs have become popular in gene therapy applications6.

Comparison of Viral Vectors for Gene Therapy7

Depending on the target cells, a variety of vector-administration approaches can be used. In the case of the brain, crossing the blood brain barrier is a challenge for viruses and delivery is accomplished either via intracerebral or intraventricular injection. Intracerebral injections allow delivery to a specific part of the brain, while intraventricular exposes the whole brain. Once administered, the AAVs deliver the genetic sequences for mAbs to the target cells and the cells produce the mAb. Intracerebral injection of AAVs has been shown to be safe in humans8.

Apart from the convenience and potential cost savings of lasting mAb expression, by expressing the antibody in the cell (intrabody), targeted proteins can be destroyed before ever leaving the cell. For AD, intrabodies can be used to mark neurotoxic Aβ-oligomers for degradation9. In tauopathy, such as AD and PD, the majority of pathogenic (hyperphosphorylated) tau remains in the cell, and a tau-targeted intrabody can mark hyperphosphorylated tau for degradation, or simply competitively bind tau, minimizing the formation of tau-inclusions10. Externally administered mAb would have limited, if any, efficacy against targets inside cells.

Anti-tau intrabodies have already been studied in mice and the results support neuroprotectivity of tau-targeted immunotherapy11. Gallardo et al. fused ubiquitin, an intracellular degradation signaling molecule, to tau-targeting antibodies, transfected using AAV, and observed substantially decreased intracellular tau levels. While this particular study did not evaluate the mice behaviorally, others have, and tau-directed immunotherapy was shown to elicit behavioral improvements. The therapeutic genre has shown efficacy in mice, and remains to be seen whether it is effective in man.

Specificity and ProMIS’ Discovery Engine

The importance of specificity has been emphasized by ProMIS in many of its presentations. Many developed antibodies target with a scattershot approach in the hope that enough drug will sufficiently bind to disease causing proteins to have a beneficial effect overall without being diluted by binding non-disease related proteins. ProMIS’ approach to disease modifying therapy relies not on hope, but rather specificity. Only misfolded toxic species of amyloid-β, α-synuclein and TDP43 should be bound. Normal forms of these proteins have important physiological functions. Amyloid-β aids in synaptic remodeling, α-synuclein helps with DNA repair and TDP43 monomer and homodimer play a role in RNA transport. Broadly targeting both toxic and normal forms of proteins will not only miss the intended therapeutic effect but also result in serious side effects that may be as debilitating as the disease itself. To combat the extensive reach of non-specific antibodies, ProMIS employs its proprietary discovery platforms that are able to predict unique epitopes on misfolded toxic forms of proteins implicated in disease. This specificity allows for lower doses of drug to be used and avoids negative outcomes from binding to necessary healthy proteins.

The scientists leading ProMIS have been able to merge chemistry, biology and physics to optimize drug design by employing proprietary algorithms that are able to identify high probability conformations of misfolded proteins. In other words, they have used cutting edge technology to make a better drug.

This type of achievement would not have been possible years ago due to the computational burden required to solve the complex algorithm. However, as technology plays an even larger role in the advancement of medicine and science, ProMIS is in a position to specifically neutralize misfolded proteins in neurodegenerative disease.

Summary

Neurodegenerative diseases persist as a modern healthcare challenge. With the aging population, the number of patients suffering from this affliction will become an increasingly large burden unless we can find an effective solution. There are no disease modifying therapies for the group of neurodegenerative diseases that dominate the space; however, much progress has been made. We now understand that it is the toxic forms of certain proteins that cause many of the neurodegenerative diseases. We also understand that the normal forms of these proteins have beneficial physiological functions that cannot be disrupted without causing negative and damaging side effects. With increased understanding of these pathologies at the protein/cellular level combined with the use of viral vectors to deliver DNA medicines and the ability to identify epitopes specific to the damaging forms of misfolded proteins we have achieved material advancements. This approach provides a new paradigm of therapy that can address neurodegenerative disease even before it leaves the cell.

SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR. 

DISCLOSURE: Zacks SCR has received compensation from the issuer directly, from an investment manager, or from an investor relations consulting firm, engaged by the issuer, for providing research coverage for a period of no less than one year. Research articles, as seen here, are part of the service Zacks provides and Zacks receives quarterly payments totaling a maximum fee of $40,000 annually for these services. Full Disclaimer HERE.

 
User ID:
Password:
Remember my ID: