Nanobodies in Therapeutics

 

In the 1990s, scientists discovered heavy chain antibodies in camelids, including camels, llamas, and alpacas. These antibodies differ from standard antibodies in their structure, as they are composed only of 2 heavy chains and a single variable antigen-binding domain (VHH). The VHH is of particular interest, as it retains its ability to bind to antigens even when it’s isolated. At 15kDa, these regions were termed “nanobodies” and are the smallest known naturally derived fragment with antigen binding capabilities..

Nanobodies offer many advantages:

• High affinity
• High specificity
• High solubility
• Ability to handle high temperature and pressure
• Ability to withstand a wide range of pH conditions
• Ability to refold and recover after chemical denaturation
• Easy and inexpensive to produce

Because of these advantages, research is being conducted with nanobodies in many fields. Here is a look at a couple of the applications of nanobodies below.

COVID

With the outbreak of the pandemic in 2019, scientists have been researching and developing treatments for the virus. One area of study is the use of nanobodies as therapeutics.

When a person is infected with SARS-CoV-2, the viral S-glycoprotein binds to the ACE2 receptor of the host cell. Conformational changes result in the fusion of the virus with the cell membrane of the host cell. Nanobodies have been developed to target different stages of this process, disrupting the process and preventing the infection of host cells. In particular, nanobodies have been developed to block the spike protein from binding to the ACE2 receptor, break the bond between the spike protein and ACE2 receptor, and prevent the fusion of the membranes.

Nanobodies offer a number of advantages as a potential therapeutic for SARS-CoV-2. One of its greatest benefits is the ability to neutralize epitopes inaccessible to typical monoclonal antibodies. Nanobodies also have conformational adaptability, increasing their effectiveness by allowing them to adapt to the structure of their targets. In addition to the original SARS-CoV-2 virus, nanobodies have shown promising results in response to evolving variants of the virus.

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Cancer

Nanobody research is being explored in two areas with regards to cancer - diagnostics and therapeutics. Compared to standard antibodies, nanobodies have been found to yield higher tumor to background ratios, which provides clearer imaging identification of tumors in the body. The use of nanobodies has been explored with molecular imaging techniques such as PET and SPECT as well as with optical imaging techniques, such as MRI and ultrasound. Numerous compounds have been targeted for imaging, the most advanced targeting human epidermal growth factor receptor 2.

Nanobodies offer a number of advantages in the treatment of cancer. Due to their small size, nanobodies are able to penetrate deeper into tumors than conventional antibodies. In addition, the hydrophilic areas of nanobodies result in low accumulation of nanobodies in non-target regions. In 2007, nanobodies were first shown to delay tumor growth in vivo through the targeting of EGFR. Since then, nanobodies have been developed against numerous compounds, such as EGF, HGF, and a few receptors, all with the result of delaying tumor development.

Researchers are also evaluating the pairing of nanobodies with other cancer therapeutics to increase the efficacy of treatment. The penetration ability of nanobodies offers potential advantages to traditional T cell therapy, natural killer cell activation therapy, and dendritic cell vaccines, as lack of tissue penetration limits efficacy of these treatments alone. Scientists are also studying the conjugation of nanobodies and cancer drugs to increase anti-cancer activity.

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References

• Bhattacharya M, Chatterjee S, Lee SS, Chakraborty C. Therapeutic applications of nanobodies against SARS-CoV-2 and other viral infections: Current update. Int J Biol Macromol. 2023 Feb 28;229:70-80. doi: 10.1016/j.ijbiomac.2022.12.284. Epub 2022 Dec 28. PMID: 36586649; PMCID: PMC9797221.
• Jumapili, N.A., Zivalj, M., Barthelmess, R.M., Raes, G., De Groof, T.W.M., Devoogdt, N., Stijlemans, B., Vincke, C. and Van Ginderachter, J.A. (2023), A few good reasons to use nanobodies for cancer treatment. Eur. J. Immunol., 53: 2250024. https://doi.org/10.1002/eji.202250024
• Minatel VM, Prudencio CR, Barraviera B and Ferreira RS Jr (2024) Nanobodies: a promising approach to treatment of viral diseases. Front. Immunol. 14:1303353. doi: 10.3389/fimmu.2023.1303353
• Yang EY and Shah K (2020) Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics. Front. Oncol. 10:1182. doi: 10.3389/fonc.2020.01182