Could monoclonal antibodies be the key to tackling the growing problem of antimicrobial resistance? A team led by researchers at the University of Cambridge has developed a monoclonal antibody drug that may offer hope. Their study, using engineered mice, demonstrates that these monoclonal antibodies were able to prevent infection with Acinetobacter baumannii derived from clinical samples.
The findings are published in Nature Communications in an article titled, “Exploiting human immune repertoire transgenic mice to identify protective monoclonal antibodies against an extensively antimicrobial resistant nosocomial bacterial pathogen.”
“The use of monoclonal antibodies for the control of drug-resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A. baumannii.”
A. baumannii bacteria can cause life-threatening respiratory illness and sepsis in vulnerable individuals, particularly in newborn babies whose immune systems have not fully developed.
Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge said, “A. baumannii is good at sticking to medical equipment, and if people are vulnerable or don’t have a particularly well-developed immune system, they can succumb to this infection and get aggressive pneumonia requiring ventilation—and in many cases, the patients can acquire the infection from the ventilation itself.
“The bacteria are naturally resistant to many antimicrobials, but as they’re now found in hospitals, they’ve acquired resistance to almost everything we can use. In some hospitals in Asia, where the infections are most common, there isn’t a single antibiotic that will work against them. They’ve become impossible to treat.”
Usually, monoclonal antibodies are developed from the antibodies of patients who have recovered from an infection, or they are designed to recognize and target a particular antigen. In the approach taken by the Cambridge team, however, transgenic mice were exposed to the outer membrane of A. baumannii bacteria, triggering an immune response.
The researchers then isolated almost 300 different antibodies and tested which of these was the most effective at recognizing live bacteria, identifying the single monoclonal antibody mAb1416 as the best.
Baker said: “Using this method, we don’t infect the mice with the live bacteria, but we instead immunize them using multiple different elements and let the mouse’s immune system work out which ones to develop antibodies against. Because these mice have ‘humanized’ immune systems, we wouldn’t then need to reengineer the antibodies to work in humans.”
The team treated mice with mAb1416, and 24 hours later exposed them to A. baumannii isolated from a child with sepsis in an intensive care unit. They found that those mice treated with the drug saw a significant reduction in bacterial load in their lungs a further 24 hours later, compared to mice that were not treated.
All of the isolates used to produce and test the monoclonal antibodies were from patients in Ho Chi Minh City, Vietnam, but the isolate used to test mAb1416 was taken from a patient ten years later than the other isolates. This is important because it shows that mAb1416 was protective against A. baumannii bacteria which may have evolved over time.
Baker said: “Using this technique, you can take any bacterial antigen or cocktail of antigens, rather than waiting for somebody that’s recovered from a particular infection— who you assume has developed an appropriate antibody response—give it to the mice and extract the antibodies you think are the most important.”
More work is now needed to understand the mechanism by which mAb1416 protects against infection.
Baker added: “We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them—what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there’s no reason why this couldn’t become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.”
