A recent study from Scripps Research found that a monoclonal antibody that targets heroin can stop this drug from making mice feel high or killing them. This is a new way to treat heroin addiction and overdose.
The study, which was published on October 6, 2022 in ACS Central Science, involved the isolation of a number of unique variations (or “clones”) of antibodies that had a strong affinity for heroin and its main metabolites. They found that one of these monoclonal antibodies was very good at blocking both the pain-relieving and heart-slowing effects of heroin, which are the main reasons why people die from heroin overdoses.
Furthermore, the findings indicated that heroin itself is the ideal target for such treatments, as opposed to previous studies that focused on heroin’s two main metabolites, morphine and 6-acetylmorphine.
Monoclonal antibody use is frequently referred to as a “passive” vaccination approach. Active heroin vaccines, which induce the patient’s own antibodies through the use of immune-stimulating proteins that imitate heroin or its metabolites, have not yet been proven to be efficacious enough for clinical studies.
Kim Janda, PhD, the study’s lead author and the Ely R. Callaway, Jr. Professor of Chemistry and director of the Worm Institute for Research & Medicine at Scripps Research, says, “Our findings suggest that a monoclonal antibody-based therapy will be more effective than a vaccine and should be aimed at heroin itself rather than its psychoactive metabolites.”
The number of drug overdose deaths in the US increased by about 15% between 2020 and 2021, according to the Centers for Disease Control and Prevention (CDC). Most of these fatalities were caused by opioids like heroin and fentanyl. The small-molecule medication naloxone is one of the current treatments. However, they are far from perfect, and heroin usage relapses are frequent after treatment.
In the latest research, Janda and his team administered a novel heroin-impersonating chemical to mice that may trigger antibody reactions to heroin, 6-acetylmorphine, and morphine. This gave them the opportunity to select four distinct antibody clones for their higher capacities to bind heroin or one of the metabolites, and they discovered that one performed significantly better than the others.This antibody, 11D12, might protect mice from an otherwise fatal heroin overdose and block the painkilling effects of heroin. It could do this with a very high level of potency, about the same as what would be needed to treat people.
In mice, a single dose of 11D12 circulated and stayed active for weeks, whereas conventional pharmacological treatments normally pass through the body in a matter of hours. When patient compliance is a problem, as it frequently is in the treatment of addiction, this greater durability can give antibody therapies a significant benefit.
Since 11D12 has its highest binding affinity for the heroin molecule directly, as opposed to the other three antibodies the team studied, Janda says it was unexpected that it would perform so effectively. For many years, researchers thought that the best targets were morphine and 6-acetylmorphine, which heroin is quickly transformed into by blood-borne enzymes.
Janda says, “The focus on metabolites fundamentally misled the field. Our report will refocus research in a way that should make it possible to do clinical trials that work.”
By making a human version of the mouse antibody 11D12 and testing it, he and his team hope to move forward with their monoclonal antibody plan to fight heroin.
The team has also been working on a human monoclonal antibody that neutralizes the synthetic opioids fentanyl, carfentanil, and closely related substances in addition to its anti-heroin initiatives. After being made in a biopharma manufacturing facility, this antibody is ready for clinical tests.
Co-authors Jinny Claire Lee, Lisa M. Eubanks, Bin Zhou, and Kim D. Janda wrote, “Development of an effective monoclonal antibody against heroin and its metabolites shows that therapeutics have been wrongly aimed at 6-monoacetylmorphine and morphine instead of heroin.”
The Skaggs Institute for Chemical Biology and the Shadek Family Foundation funded the study.
