An unexpected new discovery: antibodies weaken the lethality of heroin

According to a new study from the Scripps Research Institute, a monoclonal antibody against heroin could effectively block the psychoactive and lethal effects of this drug abuse on mice, providing a new strategy
for heroin addiction and overdose treatment.

The study, published on October 6, 2022 by ACS Central Science in the United States, identified several antibody variants (or "clones")
that bind tightly to heroin and its major metabolites.
They found that one of the monoclonal antibodies was highly effective at blocking the pain-relieving effects of heroin and slowing breathing and heart rate, which is the cause of
overdose deaths.

The findings also suggest that heroin itself is the best target for this type of treatment, whereas past researchers have only targeted the two main metabolites of heroin, morphine and 6-acetylmorphine
.

The use of monoclonal antibodies is often referred to as a "passive" vaccine strategy
.
Active vaccines against heroin, which use an immune-stimulating protein that mimics heroin or its metabolites to induce the patient's own antibodies, have so far been ineffective
in clinical trials.

"Our findings suggest that monoclonal antibody-based treatments will be more effective than vaccines and should target heroin itself, not its psychoactive metabolites," said study lead author Kim Janda, Ph.
D.
, the Ely R.
Callaway, Jr.
Professor of Chemistry and director
of research and medicine at the Scripps Research Institute's Worm Institute.

The Centers for Disease Control and Prevention (CDC) estimates that about 108,000 people died from drug overdoses in the United States in 2021, up nearly 15%
from 2020 figures.
The vast majority of these deaths involved opioids
such as heroin and fentanyl.
Current treatments, including the small molecule drug naloxone, are far from fully effective, and reuse of heroin after treatment is common
.

In the new study, Janda and his team inoculated mice with their patented heroin-mimicking molecule, which can elicit antibody responses
to heroin, 6-acetylmorphine and morphine.
This allowed them to choose four different antibody clones because of their superior ability to bind heroin or one of the metabolites – one of which they found to be significantly superior to the others
.
This antibody, 11D12, not only blocks the pain-relieving effects of heroin, but also protects mice from heroin overdose death, and has a very high titer, comparable
to the titer required for clinical use in humans.

A single dose of 11D12 also circulates and remains active in mice for weeks, whereas conventional drug treatments typically disappear
within hours.
When patient compliance is problematic, this greater persistence can give antibody therapy substantial advantages, just as
it does when treating addiction.

It was unexpected that 11D12 worked so well because, unlike the other three antibodies the team evaluated, it had the highest binding affinity
for the heroin molecule itself, Janda said.
For decades, scientists have believed that morphine and 6-acetylmorphine are better targets, and heroin is rapidly converted to acetylmorphine
under the action of enzymes in the blood.

"The focus on metabolites has largely misled the field, and our report will reorient research to enable it to achieve successful clinical trials
," Janda said.

He and his team now hope to advance their monoclonal antibody approach
against heroin by creating and testing a human antibody version of mouse antibody 11D12.

While fighting heroin, the team is also developing a human monoclonal antibody that neutralizes the synthesis of the opioid fentanyl, carfentanil and closely related compounds
.
The antibody has been manufactured at a biopharmaceutical manufacturing facility and is currently being prepared for clinical trials
.

References:

“Development of an effective monoclonal antibody against heroin and its metabolites reveals therapies have mistargeted 6-monoacetylmorphine and morphine over heroin” was co-authored by Jinny Claire Lee, Lisa M.
Eubanks, Bin Zhou and Kim D.
Janda.