A heroin-targeting monoclonal antibody (11D12) is effective in blocking the euphoric and lethal effects of this much-abused opioid, reported a study conducted on mice by scientists at the Scripps Research Institute in La Jolla, CA. The findings offer a promising new strategy for treating heroin addiction and overdose.

“Our findings suggest that a monoclonal antibody-based therapy will be more effective than a vaccine and should be targeted to heroin itself rather than its psychoactive metabolites,” said Kim Janda, PhD, the Ely R. Callaway, Jr., professor of chemistry, director of the Worm Institute for Research & Medicine at Scripps Research, and the senior author of the study.

“The work from Dr. Janda and colleagues is very interesting and timely given the importance of developing new strategies to address the opioid epidemic and the dramatic increase in fatal overdoses attributable to opioids or mixtures of opioids and stimulants such as cocaine and methamphetamine,” said Marco Pravetoni, PhD, professor at the department of psychiatry and behavioral medicine at the University of Washington School of Medicine, whose own team is developing vaccines and monoclonal antibody (mAb) against heroin, oxycodone, fentanyl, and fentanyl analogs. “The findings show target selection is critical to advance an effective therapy.” Pravetoni was not involved in the current study. “

“This work provides compelling data that challenges our current understanding of heroin pharmacodynamics. It continues to show the utility of high-affinity antibodies, not only as biological tools, but as viable therapeutics to fight the ongoing opioid crisis,” said Nicholas Jacob, PhD, senior research scientist at Cessation Therapeutics. Jacob was not involved in the current study.

Political leaders and scientists around the globe have been trying to quash the exponentially growing opioid epidemic for decades. However, current medications and behavioral interventions have failed to abate this public health crisis. Instead, opioid abuse and overdose cases have escalated to unprecedented levels since the start of the COVID-19 pandemic.

FDA-approved small molecule medications for opioid use disorders (OUDs)—methadone, buprenorphine, naltrexone, and naloxone—are limited by adverse side effects, short half-lives, limited availability, high cost, lack of adherence to medication regimen, potential for abuse, and relapse to addiction once the medication is discontinued. Immunopharmacotherapy provides a viable alternative. This treatment approach uses antibodies to block the action of illicit substances, retaining the compounds in peripheral circulation.

Decades of studies have attributed heroine’s psychoactive and lethal effects to its metabolites: 6-monoacetylmorphine (6-AM) and morphine. Therefore, earlier immunopharmacotherapeutics have used active and passive vaccines to target heroin’s metabolites instead of heroin itself. “Passive vaccines” often involve injection of monoclonal antibodies (mAbs) against the target or its metabolites, while active vaccines use immune-stimulating proteins that mimic the target or its metabolites to trigger the patient’s own immune system. However, these therapies have had limited success, underscoring the need to reassess the selection of therapeutic targets.

That the heroin vaccines Janda’s team and others were developing did not meet with success in clinical trials, prompted Janda to take a step back and evaluate perceptions and misperceptions in the drug addiction field.

“Most researchers viewed heroin to be simply a ‘prodrug’ that crosses the blood-brain barrier very quickly and that its ‘prodrug’ ability was simply to transport the main mu-opioid receptor drugs, 6-acetylmorphine and ultimately morphine, into the brain,” said Janda. “Based upon this reasoning, targeting heroin was an afterthought.”

When the earlier heroin vaccines failed to counter the effects of a heroin dose as was anticipated, poor adjuvants in the vaccine cocktail were singled out as the culprit.

Janda said, “In reality, the overall formulation of the vaccines was correct but the targeting of 6-acetylmorphine and morphine with the antigen was misguided.”

Departing from earlier efforts in developing an effective immunopharmacotherapeutic to treat heroin abuse, the current study analyzed four unique mAbs that target either heroin, 6-AM, or morphine, or both heroin and 6-AM. The development of these mAbs using a deutero-heroin hapten with broad-spectrum affinity for heroin and its metabolites, was reported in an earlier study by the same group. The researchers profiled the binding affinities of these mAbs using surface plasmon resonance (SPR), enabling them to select four distinct antibody clones with superior abilities in binding heroin or one of the metabolites.

“By using these antibodies, we were able to dissect, which of these three drugs was important to target for vaccine (antibody) development,” said Janda.

The researchers then conducted pharmacokinetic assays, overdose assays, and hot plate and tail flick assays for pain perception, to identify the targets that would effectively blunt the behavioral, toxic, and lethal effects of heroin. These in vitro and in vivo tests showed that the heroin-targeting mAb 11D12 was, unexpectedly, the optimal therapeutic to suppress the effects of heroin, over the other mAbs that targeted its two major metabolites.

The authors showed that 11D12 blocks heroin’s analgesic effects and prevents heroin from slowing breathing and heart rates—the direct causes underlying heroin’s lethality. The mAb 11D12 accomplished these at a high degree of potency needed for human clinical trials.

Pravetoni said, “Lee et al., provide evidence that mAb can be used in reversal of opioid overdose and to reduce lethality post exposure. These results are consistent with our work on anti-opioid mAbs (Baehr et al., JPET 2020; Baehr et al., JPET 2022; Hicks et al., HVI 2022), and support the notion that vaccine and mAb warrant clinical investigation.”

Moreover, the investigators found that 11D12 remained active in circulation for weeks, unlike earlier therapies that were cleared from circulation within hours. This is a key advantage against poor patient compliance in adhering to treatment regimens, which is common among patients with addiction.

The efficacy of 11D12 in countering the effects of heroin took Janda and his team by surprise, since unlike the other three antibodies tested, it targets heroin with the highest binding affinity and not its metabolites. Since esterase enzymes in the blood rapidly convert heroin to morphine and 6-acetylmorphine through sequential deacetylation, scientists have, until now, identified the metabolites as better targets.

“The focus on the metabolites basically misguided the field—our report will reset research in a direction where successful clinical trials should now be achievable,” said Janda. The current findings clarify the reasons underlying the failure of earlier attempts in developing therapeutics that targeted heroin’s metabolites alone.

“From work in the field, we know that targeting heroin, 6-AM, and morphine may be equally important. However, the impact of individual vaccines or mAb formulations will be ultimately assessed in human subjects through clinical trials,” said Pravetoni. “For instance, targeting heroin and 6-AM would be important to blunt the acute toxicity and reward from heroin, but it is not clear whether targeting morphine would also be necessary to counteract the chronic effects of heroin metabolites in OUD patients.”

“We are always trying to optimize the ability of opioids and other abused drugs to generate antibodies, since high levels of antibodies are needed to counteract the toxic and lethal effects of the drugs that are abused, particularly fentanyl-related opioids,” said Thomas Kosten, MD, the Waggoner professor of psychiatry, pharmacology, neuroscience, and immunology at Baylor College of Medicine. “While this work focuses on heroin and that class of opioids, similar work from this research group has contributed much to our ability to develop vaccines and monoclonals for other classes of abused drugs including the fentanyl-related opioids, which are the most lethal and resistant to our existing FDA-approved treatments of methadone, buprenorphine, and depot naltrexone. This paper provides an excellent contribution to our field of immunotherapy for addictions.” Kosten was not involved in the current study.

In future studies, the team will test a human version of the mouse monoclonal antibody 11D12, and parallel mAbs to neutralize the synthetic opioids fentanyl, carfentanil, and other related compounds.

Janda said, “Our heroin antibody could in theory hold translation value for clinical trials if humanized.”

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