by – L. Richardson

In a landmark breakthrough, therapeutic nanobodies offer a promising national solution to neutralize the devastating impacts of the COVID-19 bioweapon and lethal vaccine spike proteins. These nanobodies, unique and small antibodies derived from camelids, possess exceptional tissue permeability, thermostability, and the ability to bind cryptic epitopes, surpassing conventional antibodies. Their distinctive characteristics make them a fascinating subject of study, engaging the audience’s interest in their potential [9].

A novel series called Nanosota-1, developed by screening a camelid library against the SARS-CoV-2 receptor-binding domain (RBD), has demonstrated potent in vitro inhibition of viral infection and in vivo preventative and therapeutic efficacy in hamster models, heralding a path-breaking remedy for long-COVID, spike protein infestation, and vaccine injury via intranasal or intravenous administration of high neutralizing nanobodies like Nanosota-1C-Fc as endorsed by Dr. Peter McCullough. 1 1

Understanding Therapeutic Nanobodies

Nanobodies, derived from heavy chain-only antibodies found in members of the Camelidae family, are monomeric antigen-binding fragments with several advantages over conventional antibodies. Their low immunogenicity, high specificity, stability, and affinity make them a fascinating subject of study.

Definition and Characteristics

Due to their small size (2.5 nm by 4 nm; 12–15 kDa) and unique binding domains, nanobodies offer many advantages, such as the ability to bind cryptic epitopes (regions on an antigen that are not readily accessible to conventional antibodies), high tissue permeability, ease of production, and thermostability [10] [11]. 1 1 Despite their small size, nanobodies bind their targets with high affinity and specificity due to an extended antigen-binding region [10]. 1 3 They have low toxicity and immunogenicity in humans, if any. 1 3

One drawback of nanobodies is their quick clearance by kidneys due to their small size, which can be overcome by adding tags to increase the molecular weight to a desired level [10]. 1 1 Underscoring their potency and safety as human therapeutics, a nanobody drug was recently approved for clinical use in treating a blood clotting disorder [10]. 1 1

How They Differ from Traditional Antibodies

Nanobodies differ from conventional antibodies in several ways:

1. Structure: Nanobodies consist of a single variable domain from the heavy chain of camelid antibodies, while conventional antibodies have both heavy and light chains. 4
2. Size and Molecular Weight: Nanobodies are around 2.5 nm in diameter and 4 nm in length, with a molecular weight of 12-15 kDa, significantly smaller than conventional antibodies (e.g., IgG antibodies are around 150 kDa) [12]. 4
3. Half-life: Nanobodies have a shorter half-life of 0.5-2 hours compared to several days or weeks for conventional antibodies due to their small size and rapid kidney clearance [13]. 4
4. Tissue Penetration: Their small size allows nanobodies to provide fast and deep penetration into tissues and rapid distribution. 4
5. Antigen Binding: Nanobodies have an extended Complementarity Determining Region 3 (CDR3) compared to conventional antibodies, allowing them to bind cryptic epitopes and antigen cavities inaccessible to other antibody variable regions. 4
6. Stability: Nanobodies generally form fewer disulfide bonds than conventional antibodies, contributing to superior strength. 4
7. Blood-Brain Barrier (BBB) Permeability: While conventional antibodies cannot cross the BBB without alteration, some studies suggest that nanobodies may have the potential to cross the BBB. 4

These unique properties of nanobodies make them attractive candidates for various therapeutic applications, including COVID-19 diagnostics and treatments. 2 2

Mechanism of Action Against COVID-19

The primary mechanism of action of therapeutic nanobodies against COVID-19 involves targeting the spike (S) glycoprotein of the SARS-CoV-2 virus and blocking viral entry into host cells.

Targeting the Spike Protein

The S-glycoprotein of SARS-CoV-2 contains multiple epitopes that serve as primary targets for antibodies. 5 The receptor-binding domain (RBD) of the S-protein exists in two conformations: “up” and “down .”The “up” conformation is preferred as it is more accessible to antibodies than the “down” state. 5

Nanobodies have been shown to target and bind to the RBD of the S-protein with high affinity and specificity. 1 5 6 For instance, the Nanosota-1 series of nanobodies binds to the RBD, blocking the interaction between the S-protein and the human ACE2 receptor, which is crucial for viral entry. 1

Blocking Viral Entry into Cells

1. Preventing S-protein and ACE2 Interaction: Nanobodies like Nanosota-1C bind to the RBD of the S-protein, sterically hindering the interaction between the S-protein and the ACE2 receptor on host cells. 1 This prevents the virus from attaching to and entering the host cells.
2. Stabilizing RBD Conformation: Some nanobodies can stabilize the RBD in the “up” conformation, making it more accessible for binding and neutralization. 5 This further enhances the neutralizing effect against COVID-19 infection.
3. Activating Fusion Cascade: The binding of nanobodies to the S-protein can trigger conformational changes that activate the fusion cascade within host cells, leading to the neutralization of the virus inside the cells. 5
4. Broad Neutralization: Nanobodies like VHH60 have been shown to inhibit infections by the ancestral SARS-CoV-2 strain and pseudotyped viruses harboring various mutations or variants at nanomolar levels. 6
5. Increased Potency: Fc-fusion of nanobodies, such as Nanosota-1C-Fc, can significantly enhance their neutralizing activity against SARS-CoV-2, up to 6000 times more potent than the ACE2 receptor. 1

Therapeutic nanobodies, with their unique ability to target the S-protein and block viral entry, offer a promising approach to combating COVID-19 and its variants. More importantly, they hold the potential to provide long-term protection against future outbreaks, instilling a sense of hope and optimism in the fight against the pandemic.

Research and Development

Current Studies and Trials

Nanobodies have shown remarkable potential in diagnosing and treating various diseases, and the COVID-19 pandemic has driven the generation of several nanobodies against SARS-CoV-2. 7 Before the pandemic, nanobody-based therapeutic approaches were developed against viruses like HIV-1, influenza, hepatitis C, respiratory syncytial (RSV), and enteric viruses. 7 Notably, ALX-0171, a trivalent nanobody that neutralizes RSV, substantially decreased the viral load in children and became the first nanobody-based treatment delivered by nebulization through the airway. 7

In response to COVID-19, significant efforts have been made to develop efficient vaccines, with global vaccination initiatives covering 56% of the world’s population with two doses. 7 However, vaccine inaccessibility and refusal to be vaccinated have limited the success of global vaccination. 7 Additionally, over 2000 clinical trials have been registered on www.clinicaltrials.gov, exploring various topics, including contact tracing, dietary supplements, and antiviral therapies. 7

The development of antibodies against SARS-CoV-2 has focused on neutralizing antibodies targeting the spike protein. 7 7 In the early stages of the pandemic, plasmapheresis of convalescent SARS-CoV-2 patients was implemented to supplement antibodies for those at risk. 7 7

The first neutralizing nanobodies against SARS-CoV-2 targeted the receptor-binding domains (RBDs) of SARS-CoV-1 and MERS-CoV. Still, they exhibited remarkable cross-reactivity and neutralization capability against SARS-CoV-2. 7 7 Subsequently, nanobodies were identified from synthetic libraries (“bodies”) against SARS-CoV-2, with partially humanized framework regions to reduce potential immune responses. 7 7

Other strategies included generating SARS-CoV-2-specific single-domain antibodies of human origin, humanizing the nanobody backbone, and fusing nanobodies to the human IgG1-Fc region to improve binding and neutralizing capabilities. 7 7 Additionally, researchers designed bivalent and trivalent nanobodies from a yeast surface-displayed synthetic library, resulting in a 2000-fold increase in inhibitory activity against SARS-CoV-2. 7

Potential for Future Treatments

Researchers have described a less expensive way to isolate and identify nanobodies, making it easier for scientists worldwide to discover nanobodies targeting SARS-CoV-2 or other viruses [14]. 8 The optimized method has identified multiple nanobodies that work against key SARS-CoV-2 variants, including Omicron, demonstrating their therapeutic potential. 8

Nanobodies’ compact size allows them to access parts of the SARS-CoV-2 virus that more significant antibodies cannot reach, and their unique physical properties enable potential inhalation delivery. 8 Camelids naturally produce nanobodies when exposed to a virus, and researchers have developed enormous libraries of promising SARS-CoV-2 nanobodies by exposing llamas to COVID-19 proteins. 8

The relatively simple and low-cost procedure described in the study could empower laboratories in low-resource areas to generate nanobodies against SARS-CoV-2 and other viruses [14]. 8 For COVID-19, the long-term goal is to lower the entry barrier for nanobody research and ultimately produce therapies that prevent infection. 8

Conclusion

In light of the remarkable potential of therapeutic nanobodies in combating the devasting effects of the exotic COVID-19 bioweapon and lethal vaccine spike proteins, these groundbreaking antibody fragments offer a patriotic solution to safeguard our nation’s health. The compact size, high specificity, and ability to target cryptic epitopes make nanobodies a formidable weapon against the viral spike protein, preventing cellular entry and neutralizing the virus. With clinical trials underway and promising results demonstrated in animal studies, nanobodies hold the key to remedying spike protein infestation from the COVID bioweapon and lethal injections.

The development of potent nanobodies like the Nanosota-1 series heralds a new era in COVID-19 therapeutics, paving the way for innovative treatments and long-term protection against future outbreaks. As researchers continue to optimize nanobody production and explore novel delivery methods, we stand at the cusp of a breakthrough in our battle against this insidious virus and its deadly consequences. By embracing this revolutionary antibody technology, we can fortify our defenses and emerge victorious in safeguarding the health and well-being of our nation.

FAQs

1. What are nanobodies used for in COVID-19 vaccines?

• Nanobodies are being researched for their potential to combat COVID-19, explicitly targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. While their development is ongoing, none have yet been tested for therapeutic efficacy in live models.

1. How do nanobodies function?

• Nanobodies are highly effective due to their strong affinity, solubility, and stability. Their small size allows them to bind to areas that traditional antibodies cannot reach. This breakthrough comes from research into single-domain camel antibodies, known as nanobodies, which avoid many issues with conventional commercial antibodies.

1. What does VHH stand for?

• VHH stands for Variable domain of Heavy chain of Heavy-chain antibody. These are also known as nanobodies and originate from camelid antibodies. Due to their unique properties, VHHs are utilized in diagnostics, research, and various therapeutic applications.

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