Bispecific Nanobodies to inhibit cell death and stimulate cell regrowth in CTE

Symptoms

CTE’s symptoms are delayed and progress over time, following earlier minor brain traumas. There has been a lot of research into CTE but ultimately, there is no current treatment.

Part 1 of Novel treatment: Inhibiting cell death and stimulate cell regrowth in CTE

In mechanical trauma such a Traumatic Brain Injuries, the brain’s glial cells (non-neuronal cells) release TNF- α (pro-inflammatory cytokine small protein) to the site of injury. Unfortunately, repetitive TBI’s such as those seen in impact sports, can lead to the development of CTE. During immune activation, glial cells in the Central Nervous System release TNF-α cytokine, to initiate TNFR#1 and TNFR2 response. The issue in CTE is that excessive amounts of TNF- α can lead to neuron excitotoxity as well, as self-reactivation, leading to further amounts of TNF-alpha being produced. (2)(3) Many clinically approved treatments, known as anti-TNF drugs, can suppress this response by blocking the over expressed TNF- α. However, by doing so, it also inhibits the beneficial activation of TNFR2 which can stimulate neurogenesis (neuron renewal). (4)

Potential TNF-alpha initiated pathways

Approach

The suggested novel drug must show high affinity to each target receptor to compete with and overcome, the naturally high levels of TNF-α in patients suffering with CTE. The weakened blood brain barrier allows for easier transport to its target, combined with a suggested, nanoparticle targeted delivery. By adding the nanoparticle component to a bispecific antibody, this will facilitate the above requirements with an effective therapeutic effect.

Tissue specific responses must be researched to ensure TNFR2 activation, promotes its agonist effects. Clinical trials will need to be initiated to support the effect of TNFR1 and TNFR2 on different areas. (6)

Anti-TNF-α drugs have been researched for other diseases and has shown promising effects on TNFR1 and TNFR2 inhibition. This research on anti-TNF-α therapies in other diseases include Crohn's disease and Rheumatoid arthritis. By combining this approach, it can target excess TNF-α, which reduces Chronic neuroinflammation. (7) However, this also prevents TNFR2 activation, which has beneficial functions that we would like to promote in our novel treatment. See functions of both TNFR1 and TNFR2 in table below.

Dual Treatment

By manipulating a dual treatment method using, Step 1: anti-TNF-α drugs with, Step 2: our proposed bispecific nanobody which functions on TNF-α, absence. This could supress the effects of chronic neuroinflammation, while selectively inhibiting TNFR1 activation and promoting TNFR2 stimulation. We would hope to see a reduction in the TNF cell death signalling blockade and an enhancement of neural growth with little side effects. (10)

Part 2 of Novel treatment: Targeting TNFR1 and TNFR2 (Receptors) with Bispecific Nanobodies

What are Bispecific Nanobodies?

• Bispecific antibodies have been largely studied over the past decade to target/bind to specific antigens (can generate an immune response), to improve the effectiveness of a treatment against a particular disease. (11).

• In the context of nanomedicine, nanoparticle-based antibodies have been used to trigger structural changes to targeted area which can reduce its stability and allow for targeted drug delivery. Additionally, these nanotechnology-based antibodies have been used to facilitate the release of a drug at a specific target tissue. (12)

Nanobodies targeting TNRF 1 and TNFR 2

• Previous research has shown that nanobodies have promoted the agonist (anti-inflammatory) role of TNFR2, whilst also promoting the antagonist (inflammatory) role of TNFR1.

• With our proposed dual treatment, the anti-TNF-α drug would help reduce and counteract the harmful inflammatory TNFR1 activation that trigger’s cell death.

• The bispecific nanobody will then stimulate different signalling pathways, which will lead to the beneficial anti-inflammatory effects, helping relieve symptoms of a CTE patient. (13)

For our novel treatment, both the anti-TNF-α drug and bispecific nanobodies will be used to target both receptors TNFR1 and TNFR2 which would be delivered intravenously (via the vein) to patient. (14) See illustration below for how the Bispecific nanobody solely reacts with TNFR1 and TNFR2.

Conclusion

In conclusion, the novel treatment of using an anti-TNF-α drug, followed by a bispecific nanobody to reduce inflammation (TNFR1) and to promote its anti-inflammatory functions (TNFR2), with the enhanced therapeutic effect from the antibody nanoparticle component. This approach could be analysed for its effectives across multiple inflammatory diseases and hopefully have life changing impacts. Chronic Traumatic Encephalopathy CTE could affect any of us from playing the sports we love, it is so important we continue to research potential novel treatments!