Tiny antibody component completely neutralizes the SARS-CoV-2 virus

Wei Lee, PhD, Pitt K, demonstrates a step in the process of obtaining a potential drug against COVID-19. Sincerely: UPMC

Scientists at the Pittsburgh School of Medicine have isolated the smallest biological molecule to date that completely and specifically neutralizes SARS-CoV-2 Virus, cause COVID-19. This antibody component, which is 10 times smaller than a full-size antibody, has been used to manufacture a drug – known as AB8 – as a therapeutic and prophylactic against SARS-COV-2. For possible use in.

Researchers report today (September 14, 2020) in the journal Cell That Ab8 is highly effective in preventing and treating SARS-CoV-2 infection in mice and hamsters. Its small size not only enhances its ability of proliferation in tissues to better neutralize the virus, but also makes it possible to administer the drug via alternative routes including inhalation. Crucially, it is not bound to human cells – a good sign that it will not have negative side effects in people.

Ab8 was evaluated with scientists from the University of North Carolina at Chapel Hill (UNC) and the University of Texas Medical Branch (UTMB) at Galveston, as well as the University of British Columbia and the University of Saskatchewan.

“Ab8 not only has potential as a therapy for COVID-19, but it can also be used to protect people from getting SARS-CoV-2 infection,” co-author John Mellors, MD, who at UPMC Heads the Division of Infectious Diseases. And pit. “Large-sized antibodies have worked against and tolerate other infectious diseases, we hope that this can be an effective treatment for patients with COVID-19 and to protect those who ever have Not infected and not immune. ”

John Mellors, MD, Head of Infectious Diseases, UPMC and University of Pittsburgh, discusses a scientific breakthrough that is a major step toward a potential drug for the treatment and prevention of COVID-19. Sincerely: UPMC

The small antibody component is the variable, heavy chain (VH) domain of an immunoglobulin, a type of antibody found in blood. The SARS-COV-2 spike protein was used as bait by “fishing” in a pool of over 100 billion potential candidates. Ab8 is formed when the VH domain fuses to part of the immunoglobulin tail region, adding to the immune functions of full-size antibodies without bulk.

The newly formed company Abound Bio, a UPMC-backed company, has licensed Ab8 for worldwide development.

Dmitry Dimitrov

Dimitar Dimitrov, Ph.D. Sincerely: University of Pittsburgh

Dimitri Dimitrov, PhD, senior author Cell The publication and director of the Pitts Center for Antibody Therapeutics was one of the first to discover neutral antibodies for the original SARS coronovirus in 2003. In the following years, his team discovered powerful antibodies against many infectious diseases, including MERS-CoV. , Dengue, Hendra and Nippa viruses. Antibodies against Hendra and Nippa viruses have been evaluated in humans and approved for clinical use in Australia on compassionate grounds.

Clinical trials are convocation tests Plasma – which contains antibodies to those who already had COVID-19 – as a treatment for people struggling with infection, but does not have enough plasma for those who may need it, and it Not proven to work.

This is why Dimitrov and his team determined to isolate genes for one or more antibodies that block the SARS-COV-2 virus, which would allow for mass production. In February, Wei Lee, PhD, assistant director of the Pitts Center for Therapeutic Antibodies and co-lead author of the research, began transferring through large libraries of antibody components created using human blood samples and many therapeutic antibodies. Candidates found, including Ab8. In record time.

Then Chien-Te Kent Tseng, Ph.D. A team from UTMB’s Center for Biodefense and Emerging Diseases and Galveston National Laboratory, under the leadership, tested Ab8 using the live SARS-CoV-2 virus. At very low concentrations, Ab8 completely inhibited the virus from entering cells. With those results in hand, Ralph Baric, PhD, and his UNC colleagues tested AB8 at varying concentrations in mice using a modified version of SARS-COV-2. Even at the lowest doses, the amount of infectious virus in those mice decreased by 10-fold compared to their untreated counterparts in AB8. Ab8 was also effective in treating and preventing SARS-CoV-2 infection in hamsters, as assessed by Darrick Falgerano, PhD, and colleagues at the University of Saskatchewan. Shriram Subramaniam, PhD, and his colleagues at the University of British Columbia demonstrated in a unique way that Ab8 neutralizes viruses so effectively using sophisticated electron microscopic techniques.

“The COVID-19 pandemic is a global challenge facing humanity, but there is potential to overcome it with biomedical science and human ingenuity,” said Mellors, also a distinguished professor of medicine who is Endear Chairperson of Global Elimination and AIDS at Pitt . “We hope that the antibodies we have discovered will contribute to that victory.”

References: Wei Lee, Alexandra Shaffer, Swaralee S. Kulkarni, Zhenglei Liu, David R. Martinez, Chuan Chen, Zhua Sun, Sarah R. “High power of an insular human VH domain in a SAS-COV-2 animal model” by List. , Alexandra Drelich, Liang Zhang, Marcin L. Ura, Alison Berejuk, Sagar Chittori, Caroline Leopold, Dheeraj Mannar, Shanti S. Shriram Subramaniam, Ralph S. Barik and Dimeter s. Dimitrov, accepted 31 August 2020, Cell.
DOI: 10.1016 / j.cell.2020.09.007

Additional co-lead authors of this research are Pitt’s Jianglei Liu, MD, PhD; Alexandra Schaefer, PhD, and David R. Martinez, PhD, both of the University of North Carolina at Chapter Hill; And Swarley s. Kulkarni, M.Sc. of Saskatchewan University. Additional authors are Chuan Chen, PhD, Zhua Sun, PhD, Liang Zhang, PhD, all of Pitt; Sarah R. of the University of North Carolina at Chapel Hill Leist, PhD; Alexandra Drelich, Ph.D. of the University of Texas Medical Branch Marcin L. Ura, Ph.D., and Eric Peterson, MS, both of Abound Bio; And Alison Berejuk, PhD, Sagar Chittori, PhD, Caroline Leopold, PhD, Dheeraj Mannar, B.Sc., Shanti S. Srivastava, Ph.D., and Jing Zhu, Ph.D. ., All of the University of British Columbia.

This research was funded by the National Institutes of Health F32 AI152296, T32 AI007151, AI132178, AI108197 and P30CA016086, as well as UPMC; Burox Welcome Fund; Canada Excellence Research Chair Award; Genome BC, Canada; Canadian Institute for Health Research; And Canadian Foundation Innovation.