Neutralizing monoclonal antibodies are promising tools in the fight against COVID-19, but their large size typically limits the administration route to an intravenous infusion.
Now, a research team led by scientists at the University of Pittsburgh School of Medicine has identified an antibody component that’s 10 times smaller than a full-sized antibody. In mice and hamsters, a drug based on it was found to be highly effective in preventing and treating SARS-CoV-2, the novel coronavirus behind COVID-19, according to results published in Cell.
Some members of the team have formed a startup called Abound Bio with the goal of bringing the candidate, dubbed Ab8, into clinical trials, possibly as an inhaled drug against COVID-19.
“Ab8 not only has potential as therapy for COVID-19, but it also could be used to keep people from getting SARS-CoV-2 infections,” study co-author John Mellors, M.D., said in a statement. “Antibodies of larger size have worked against other infectious diseases and have been well tolerated, giving us hope that it could be an effective treatment for patients with COVID-19 and for protection of those who have never had the infection and are not immune.”
The researchers starting by screening a library of about 100 billion antibody fragments to look for candidates that bound tightly to the spike protein on SARS-CoV-2’s surface, which the virus uses to enter and infect human cells.
The chosen molecule 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 with an antigen.
Ab8 was created by fusing the variable, heavy chain domain with part of the immunoglobulin tail region, giving it immune functions but doing so with a molecule that's about half the size of a full immunoglobulin.
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That small size “could improve therapeutic efficacy for infectious diseases, such as COVID-19 because of greater penetration to sites of infection,” the researchers wrote in the study. In addition, because it efficiently penetrates tissue, it could be directly delivered through inhalation, another advantage for treating a respiratory disease, they added.
Ab8 completely neutralized SARS-CoV-2 in lab dishes. In an adaptive mouse model, animals that got 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 of virus titer by tenfold, even at the lowest dose of 2 mg/kg, as compared to untreated controls, the researchers reported.
The team further tested the drug’s effect in hamsters, which were recently shown to better represent the clinical signatures of COVID-19. Ab8 treatment successfully reduced viral load in the lung, as well as viral shedding from the nose and mouth, in both preventive and therapeutic settings. And the hamsters that got the drug showed less severe pneumonia than did the control animals.
What’s more, Ab8 doesn’t appear to bind to human cells, a possible good sign that it won’t have negative side effects in people, the scientists argued.
Drugs with alternative administration routes could be valued additions to the first wave of COVID-19 therapies and vaccines. Another University of Pittsburgh team recently developed a vaccine candidate, dubbed PittCoVacc, that delivers an immunization through a Band-Aid-like patch with microneedles made of sugar.
Multiple neutralizing antibodies against SARS-CoV-2 are already in clinical trials. The Pitt-led team believes that small-sized Ab8, thanks to its increased diffusion through tissues, might be given as an inhaled drug rather than intravenously like most antibodies in development, potentially providing a more convenient option.