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A panel of nanobodies recognizing conserved hidden clefts of all sars cov-2 spike variants including omicron

15st Jul 2022

  • Publication

Since the new coronas are RNA viruses, the emergence of mutant forms was expected from the beginning. (Sakyo-ku, Kyoto; CEO: Akihiro Imura) has developed a technology to overcome this problem, and through joint research with four universities, has established antibodies with extremely high infection-protective activity against all mutated forms. This was achieved by learning and mathematically analyzing a large amount of genetic information obtained from vaccinated alpacas. The collaboration between bio-experts and IT engineers was a key factor in overcoming all the mutations more than a year before the Omicron strain was introduced. In addition, cryo-EM analysis revealed that these antibodies bind to deep grooves in the viral proteins (weak spots where they cannot mutate). In addition, because of their extremely strong binding to viruses and high stability, these antibodies can be applied not only to medical testing but also to detection of viruses in sewage environments. This research was conducted by a joint research team of COGNANO Corporation, Kyoto University, Osaka University, Yokohama City University, and the University of Tokyo, and was published online in the British scientific journal Communications Biology on July 6, 2022.

Scene of strategy meeting between bioman and engineer at the biolab in Kyoto.

1. Background

As of July 2022, more than two and a half years later, the new coronavirus disease (COVID-19) has not been contained, infecting approximately 700 million people worldwide and killing 7 million. The new coronavirus (SARS-CoV-2) spreads through repeated mutations, and the Omicron strain, which is currently the mainstream strain, has far more mutated spike proteins than the previous VOCs (alpha, beta, gamma, and delta strains), and can infect people who have been previously infected or vaccinated. The Omicron strain also infects previously infected persons and vaccinators. It has also become clear that most therapeutic antibodies (neutralizing antibodies) developed prior to the emergence of new coronavirus infections caused by the Omicron strain are no longer effective.

2. Research methods and results

COGNANO Corporation (https://www.cognano.co.jp/) has developed an algorithmic technology to select optimal antibodies by learning the antibody genes of vaccinated alpacas in order to solve the mutation problem characteristic of RNA viruses. Using this program, we have succeeded in establishing single-domain antibodies (nanobodies) that are more active against all mutant strains, including the Omicron strain, than any therapeutic antibody formulation used to date. Furthermore, cryo-electron microscopic structural analysis showed that these nanobody antibodies epitope a deep groove in the spike protein on the surface of the novel coronavirus. This epitope is a region where human antibodies cannot reach and where viral mutations are rarely seen.

URL of the paper:

A panel of nanobodies recognizing conserved hidden clefts of all SARS-CoV-2 spike variants including Omicron | Communications Biology
A panel of nanobodies are presented that can detect the spike proteins of five SARS-CoV-2 variants of concern and structural analyses show that one clone targets conserved epitopes on the receptor-binding domain and contacts the N-terminal domain.
iconhttps://www.nature.com/articles/s42003-022-03630-3
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Key Points of Results

  • COGNANO obtained a large number of genetic profiles of useful antibodies from alpacas obtained after vaccination, and through a program to identify candidate antibodies, selected potent antibody candidates that do not lose activity against mutant viruses. The fact that this was accomplished in about six months from the start of the project demonstrates the speed and effectiveness of COGNANO's computerized drug discovery algorithms. The fact that no other group has been able to develop mutant-competent antibodies before the Omicron strain emerged also confirms the superiority of COGNANO's algorithm. URL for video commentary:
  • A joint research team of Kyoto University, Osaka University, Yokohama City University, and the University of Tokyo has confirmed that their candidate antibodies neutralize the Omicron strain, which is now the mainstream of pandemics. This achievement was made possible by an academic grant (https://www.amed.go.jp/) from the National Institute of Biomedical Research and Innovation (NIBIO).
  • Genetic mutation of novel coronaviruses, such as the Omicron strain, enables them to escape from antibodies induced by vaccines and therapeutic preparations. The antibodies created in this study showed higher efficacy than any previously reported antibodies.
  • The alpaca antibodies created in this study are one-tenth the size of human antibodies. Therefore, it can penetrate deep grooves in spike proteins that human antibodies cannot reach. A cryo-EM team from the Graduate School of Frontier Biosciences, Osaka University, the Graduate School of Pharmaceutical Sciences, Osaka University, the Osaka University Research Institute for Infectious Diseases, and JEOL (https://www.jeol.co.jp/) captured images of the antibody binding to the spike protein. The team's cryo-EM images show that the algorithm-selected antibodies bind to the "weak spots" of the virus. This work was supported by the BINDS (https://www.binds.jp/), a project supported by the National Institute for Biomedical Research and Development (BINDS) of the Japan Agency for Medical Research and Development.
  • Nanobody antibodies can be easily modified by genetic engineering and produced at a lower cost than conventional antibodies. The antibodies are highly environmentally tolerant and can detect all novel coronavirus mutants. Therefore, it can be used not only for medical testing, but also for enrichment and monitoring of viruses in the sewage environment.

3. Ripple effects, future plans

It is known that many of the neutralizing antibodies induced by vaccines and therapeutic antibodies developed to date bind to the surface of spike proteins on novel coronaviruses and suppress infection. Smaller nanobody antibodies can bind to a deeper groove (referred to in this paper as a "crevasse" or "hidden crevice") that is deeper than the surface of the spike protein. Human antibodies are too large to penetrate this deeper groove, and there is no selective pressure for antibody immunity by the host, which is thought to be a weakness that retains a common structure in all mutant strains of the new coronavirus. The drug discovery theory successfully developed this time represents a general mathematical solution logic to the problem of viral mutation, not only in new coronas, but also in AIDS, influenza, and other viruses.

In addition to infectious diseases, COGNANO will continue to develop new technologies and products to solve undiscovered cancers with molecular target markers (triple negative breast cancer, pancreatic cancer, bile duct cancer, undifferentiated thyroid cancer, glioblastoma, etc.), including Machine Learning, and IT infrastructure to support biotechnologies. We have developed technologies and products, and drug discovery is underway. We are also developing environmental water monitoring and medical tests using the superior properties of nanobody antibodies. We also see these projects as opportunities to contribute to society by making use of biotechnology information resources as IT tech. Development other than drug discovery is supported respectively by Kyoto Industrial 21 "Industry-Academia-Public Forest" Foundation (https://www.ki21.jp/), Anatech/Yanaco Joint Development Corporation (http://yanaco.jp/), and Yamato Scientific Co. (https://www.yamato-net.co.jp/) for their support.