Human antibodies manufactured in cattle for treatment of MERS are found safe in first phase 1 study

Human antibodies manufactured from transchromosomic cattle could represent a novel technique for rapidly producing antibodies for passive immunotherapy for emerging infectious diseases.

Human antibodies manufactured from the plasma of cattle and targeting the Middle East respiratory syndrome (MERS) coronavirus have been found safe in healthy volunteers, according to a phase 1 clinical trial published in The Lancet Infectious Diseases journal.

This is the first study to investigate whether these types of antibodies are safe for human use, and is the first novel treatment option to be developed against MERS. Further research will need to assess the efficacy of these antibodies in people infected with MERS coronavirus.

The human antibodies were manufactured in transchromosomic cattle, which represents a novel technique for producing antibodies for passive immunotherapy - where externally produced antibodies are given to people with a disease to provide immunity.

In severe and emerging diseases such as influenza, severe acute respiratory syndrome (SARS), MERS and Ebola virus disease, it has often been recommended that plasma be harvested from people whose immune systems have successfully fought the disease. This plasma is then given to other patients to provide them with specific antibodies that can directly fight the virus.

However, this is not always possible when a disease emerges rapidly, or where the donor supply may be limited because of difficulties collecting sufficient amounts of human plasma to be able to implement this procedure on a large scale. In these situations, the use of transchromosomic cattle to manufacture specific antibodies potentially could help to overcome these difficulties because these animals can produce large amounts of different types of antibodies.

Transchromosomic cattle have human DNA that codes for human antibodies incorporated into their genome. The cattle are then injected with a part of the MERS coronavirus, which stimulates their immune system to produce antibodies against the virus. These antibodies are then extracted from the cattle's blood and purified before being given to healthy volunteers. The treatment is called SAB-301 and has previously been tested in mice.

"The process of creating antibody treatments by harvesting antibodies from human donors is slow and often small-scale because the antibodies can only be taken from recently infected or vaccinated individuals. However, the cattle-produced antibodies could be created as soon as three months after an immunogen becomes available," says Dr John Beigel, Leidos Biomedical Research Inc, USA. "This is the first study to show the safety and immune effects of a potential treatment for MERS. It is also the first study to test human antibodies produced in transchromosomic cattle. The data from our study suggest that SAB-301 is safe, and further research into the treatment is warranted." [1]

The MERS coronavirus varies in severity, but in the most severe cases requires intensive care and ventilation. Overall, the MERS coronavirus kills 35% of people who are infected.

In the trial, 38 healthy volunteers aged 18-60 years were randomised to receive either a dose of SAB-301 (28 people) or a placebo (ten people) to determine the treatment's safety. The trial also looked at how the treatment affected the immune system.

Those given the antibody treatment were split into six groups and given either a dose of 1 milligram for every kilogram they weighed (mg/kg) (two people), 2.5 mg/kg (two people), 5 mg/kg (four people), 10 mg/kg (four people), 20 mg/kg (eight people), or 50 mg/kg (eight people).

Participants' blood samples were taken at the start of the trial, 1 and 6 hours after they were given the antibodies, and 1, 3, 7, 21, 42, and 90 days later, and they were asked about any symptoms they had experienced since the injection.

The most common adverse events experienced by the participants were headache, albuminuria, higher levels of creatine kinase (a muscle enzyme), and common cold. Rates of most adverse events were the same in people given SAB-301 and placebo, but low blood bicarbonate, fatigue, loose stools, and a sore throat were more common in people given the cattle-produced treatment.

The cattle-produced antibodies persisted for more time than the MERS coronavirus typically remains in the body, with antibodies still found in the bloodstream after 90 days for participants given either the 10 mg/kg, 20 mg/kg, or 50 mg/kg doses. This finding suggests that the treatment could be effective in countering the virus.

However, this type of passive immunotherapy will need to be tested in clinical trials with patients infected with MERS coronavirus in order to determine whether it is effective in limiting disease and reducing mortality.

Writing in a linked Comment, Professor David Weiner, Wistar Institute, USA, says: "The transchromosomic cattle used to produce SAB-301 were developed over the course of a decade in a remarkable feat of genetic engineering... The therapeutic and protective efficacy of SAB-301 in human infection or lethal animal challenge has not been reported, underscoring that this is an early technology requiring further clinical investigation... The study of transchromosomic cattle with the ability to produce polyclonal antibody responses against emergent pathogens advances a platform worthy of further consideration, possibly in outbreak situations as well as for protection of at-risk populations."

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NOTES TO EDITORS

This study was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and and the Biomedical Advanced Research and Development Authority. It was conducted at the NIH Clinical Center by researchers from Leidos Biomedical Research Inc, National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, The Henry Jackson Foundation for the Advancement of Military Medicine, and Naval Medical Research Center.

[1] Quote direct from author and cannot be found in the text of the Article.

For interviews with the Article authors, Dr John Beigel or Dr Richard Davey, please contact Ken Pekoc in the National Institute of Allergy and Infectious Diseases press office: E) kpekoc@niaid.nih.gov T) +1 301 402 1663

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