Neutralizing monoclonal antibodies are promising tools in the fight against COVID-19, but their large size typically limits the route of administration to an intravenous infusion.
Now, a research team led by researchers at the University of Pittsburgh School of Medicine has identified an antibody component that is ten times smaller than a full-size antibody. In mice and hamsters, a drug based on it has been shown to be extremely effective in the prevention and treatment of SARS-CoV-2, the new coronavirus behind COVID-19, according to results published in Cell.
Some members of the team have formed a startup called Abound Bio with the aim of bringing the candidate, called Ab8, into clinical trials, possibly as an inhaled drug against COVID-1
“Ab8 not only has the potential as a therapy for COVID-19, but it can also be used to prevent people from getting SARS-CoV-2 infections,” co-author John Mellors, MD, said in a statement. “Larger antibodies have worked against other infectious diseases and have been well tolerated, giving us hope that it can be an effective treatment for patients with COVID-19 and to protect those who have never had the infection and are not. immune.”
The researchers started by screening a library with approx. 100 billion antibody fragments to look for candidates that bind tightly to the tip protein on the surface of SARS-CoV-2, which the virus uses to enter and infect human cells.
The molecule of choice is the variable domain of the heavy chain of an immunoglobulin, which is a type of antibody. A typical antibody consists of two heavy chains and two light chains. The heavy chain variable domain is essential for binding to an antigen.
Ab8 was created by fusing the variable, heavy chain domain with a portion of the immunoglobulin tail region and giving it immune functions, but doing so with a molecule that is about half the size of a full immunoglobulin.
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The small size “could improve therapeutic efficacy for infectious diseases, such as COVID-19 due to greater penetration into infection sites,” the researchers wrote in the study. In addition, because it effectively penetrates tissues, it could be delivered directly through inhalation, another benefit in treating respiratory diseases, they added.
Ab8 completely neutralized SARS-CoV-2 in laboratory dishes. In an adaptive mouse model, animals given Ab8 were then challenged with SARS-CoV-2. The drug effectively inhibited the virus in lung tissue in a dose-dependent manner with significant reduction in virus titers ten-fold, even at the lowest dose of 2 mg / kg compared to untreated controls, the researchers reported.
The team further tested the efficacy of the drug in hamsters, which were recently shown to better represent the clinical signatures of COVID-19. Ab8 treatment successfully reduced the viral load in the lung as well as viral excretion from the nose and mouth in both preventive and therapeutic settings. And hamsters given the drug showed less severe pneumonia than the control animals.
Furthermore, Ab8 does not appear to bind to human cells, a possible good sign that it will not have adverse side effects in humans, the researchers argued.
Drugs with alternative routes of administration could be evaluated as additions to the first wave of COVID-19 therapies and vaccines. Another University of Pittsburgh team recently developed a vaccine candidate, called PittCoVacc, that delivers an immunization through a patch with similar patches with microneedles made of sugar.
Several neutralizing antibodies to SARS-CoV-2 are already in clinical trials. The Pitt-led team believes that Ab8 in small size thanks to its increased diffusion through tissue can be given as an inhaled drug rather than intravenously like most antibodies under development, potentially providing a more convenient option.