A monoclonal antibody targeting heroin (11D12) is effective in blocking the euphoric and lethal effects of this widely abused opioid, reported a study in 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.
Kim Janda, PhD, professor of chemistry at Scripps Research is the lead author of the study
“Our results suggest that a monoclonal antibody-based therapy will be more effective than a vaccine and should target heroin itself rather than its psychoactive metabolites,” said Kim Janda, PhD, Ely R. Callaway, Jr. ., professor of chemistry. , director of Scripps Research’s Worm Institute for Research & Medicine and lead author of the study.
“The work of 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 like cocaine and methamphetamine,” he said. Marco Pravetoni, PhD, a professor in the department of psychiatry and behavioral medicine at the University of Washington School of Medicine, whose team is developing vaccines and monoclonal antibodies (mAbs) against heroin, oxycodone, fentanyl, and analogs of fentanyl. “The results show that target selection is critical to advancing effective therapy.” Pravetoni did not participate in the current study. “
“This work provides compelling data that challenge our current understanding of the pharmacodynamics of heroin. It continues to show the utility of high-affinity antibodies, not only as biological tools, but as viable therapeutics to combat the opioid crisis in course,” said Nicholas Jacob, PhD, senior research scientist at Cessation Therapeutics. Jacob did not participate in the current study.
Political and scientific leaders around the world have been trying to quell the exponentially growing opioid epidemic for decades. However, current medications and behavioral interventions have failed to reduce this public health crisis. Instead, cases of opioid abuse and overdose have increased to unprecedented levels since the start of the COVID-19 pandemic.
Small molecule medications approved by the FDA for opioid use disorders (METADONE, 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 offers a viable alternative. This treatment approach uses antibodies to block the action of illicit substances, keeping the compounds in the peripheral circulation.
Decades of studies have attributed the psychoactive and lethal effects of heroin to its metabolites: 6-monoacetylmorphine (6-AM) and morphine. Therefore, previous immunopharmacotherapeutics have used active and passive vaccines to target heroin metabolites rather than heroin itself. “Passive vaccines” often involve the injection of monoclonal antibodies (mAbs) against the target or its metabolites, while active vaccines use immunostimulatory proteins that mimic the target or its metabolites to activate 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 anti-heroin vaccines that Janda’s team and others were developing failed to succeed in clinical trials prompted Janda to step back and assess perceptions and misperceptions in the drug addiction field. drugs
“Most researchers saw heroin as simply a ‘prodrug’ that crosses the blood-brain barrier very quickly and that its ‘prodrug’ ability was simply to transport the major mu opioid receptor drugs, 6-acetylmorphine and , finally, morphine, in the brain.” Janda said. “Based on that reasoning, targeting heroin was an afterthought.”
When previous heroin vaccines failed to counteract the effects of a dose of heroin as expected, poor adjuvants in the vaccine cocktail were pointed to as the culprit.
Janda said, “Actually, the general formulation of the vaccines was correct, but the targeting of 6-acetylmorphine and morphine with the antigen was wrong.”
Building on previous efforts to develop an effective immunopharmacotherapeutic to treat heroin abuse, the current study analyzed four unique mAbs that target 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 a previous study by the same group. The researchers profiled the binding affinities of these mAbs using surface plasmon resonance (SPR), which allowed them to select four different antibody clones with superior abilities to bind heroin or one of the metabolites.
“By using these antibodies, we were able to dissect which of these three drugs was important for (antibody) vaccine development,” Janda said.
The researchers then performed pharmacokinetic assays, overdose assays, and hot-plate and tail-flick assays for pain perception, to identify targets that would effectively neutralize the behavioral, toxic, and lethal effects of heroin. These in vitro and in vivo tests showed that mAb 11D12 targeting heroin was, unexpectedly, the optimal therapeutic to suppress the effects of heroin, compared to the other mAbs that targeted its two main metabolites.
This study reveals that the monoclonal antibody 11D12 abolishes the psychoactive and lethal effects of heroin in mice. [Adapted from Lee et al., ACS Central Science]The authors showed that 11D12 blocks the analgesic effects of heroin and prevents heroin from slowing breathing and heart rate, the direct causes underlying heroin’s lethality. mAb 11D12 achieved this with a high degree of potency required for human clinical trials.
Pravetoni said, “Lee et al., provide evidence that mAb can be used to reverse opioid overdose and to reduce lethality after 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 idea that the vaccine and mAb warrant clinical investigation.”
In addition, the researchers found that 11D12 remained active in circulation for weeks, unlike previous therapies that were cleared from circulation within hours. This is a key advantage against poor patient adherence to treatment regimens, which is common among patients with addiction.
The effectiveness of 11D12 in counteracting the effects of heroin surprised Janda and his team because, unlike the other three antibodies tested, it targets heroin with the highest binding affinity and does not to its metabolites. Because esterase enzymes in the blood rapidly convert heroin to morphine and 6-acetylmorphine through sequential deacetylation, scientists have so far identified the metabolites as better targets.
“The focus on metabolites fundamentally misled the field: our report will reset research in a direction where successful clinical trials can now be achieved,” said Janda. The current findings shed light on the reasons underlying the failure of previous attempts to develop therapeutics targeting only heroin metabolites.
“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 remains to be assessed eventually in human subjects through clinical trials,” said Pravetoni. “For example, targeting heroin and 6-AM would be important to reduce the acute toxicity and reward of heroin, but it is unclear whether targeting morphine would also be necessary to counteract the chronic effects of heroin metabolites. heroin in patients with OUD”.
“We are always trying to optimize the ability of opioids and other drugs of abuse to generate antibodies, as high levels of antibodies are needed to counteract the toxic and lethal effects of drugs of abuse, especially fentanyl-related opioids.” , said Thomas Kosten. , MD, the Wagoner Professor of Psychiatry, Pharmacology, Neuroscience and Immunology at Baylor College of Medicine. “While this work focuses on heroin and this class of opioids, similar work by this research group has greatly contributed to our ability to develop vaccines and monoclonals for other classes of drugs of abuse, including fentanyl-related opioids, which are the most lethal and resistant. to our existing FDA-approved treatments of methadone, buprenorphine, and depot naltrexone. This article provides an excellent contribution to our field of immunotherapy for addictions”. Kosten did not participate 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, have translational value for clinical trials if humanized.”[ad_2]
Source: Heroin antibodies fare better than previous therapies that targeted its metabolites