Naloxone is the closest thing there is to a silver bullet in medicine. By competing for opioid receptors in the brain, it can rapidly revive and potentially save the life of a nonresponsive patient experiencing an opioid overdose.

But naloxone only works in acute cases. Once it’s cleared from the body, a patient can have another overdose right away. People can enter a bitter cycle of overdose, recovery, and relapse. For better health outcomes and better chances at breaking addiction cycles, patients need a longer lasting solution. 

Using a bit of molecular trickery, a group led by Kim Janda, a chemist at the Scripps Research Institute, may have developed one: a vaccine that protects patients from heroin’s narcotic and painkilling effects (1).

Heroin is a prodrug, a molecule that doesn’t have a strong effect on its own but is converted in the body into molecules that do. Enzymes in the brain rapidly metabolize heroin into two other compounds, 6-acetylmorphine and morphine. The conversion into these metabolites, particularly morphine, ultimately produces heroin’s euphoric and narcotic effects. Past attempts at a vaccine didn’t target heroin at all, but instead acted against those metabolites.

Heroin is kind of a Dr. Jekyll and Mr. Hyde type molecule.
Kim Janda, Scripps Research Institute

“Heroin is kind of a Dr. Jekyll and Mr. Hyde type molecule,” said Janda. “Morphine is the ultimate drug that comes out of this. But morphine doesn’t cross the blood-brain barrier very quickly. That’s why heroin came about. It crosses the blood-brain barrier very quickly and then degrades to morphine. These past vaccines just weren't developing enough antibodies and with high enough affinity to do the trick, and they were also mistargeting the source. We didn't know that when we got started.”

Janda’s goal was to vaccinate against all three compounds, heroin, 6-acetylmorphine, and morphine. The team began by replacing some of the hydrogen atoms in heroin with deuterium, a heavy isotope of hydrogen, to create a deuterated form of the drug. In previous research, Janda’s group learned that the body converts this form more slowly into its metabolites, which elicits a stronger antibody response. The deuterated form also prompts the body to produce antibodies against both heroin and its metabolites, unlike normal heroin (2).

To produce the vaccine, Janda’s team injected mice with deuterated heroin. They then removed the spleens, isolated B cells from them, and fused those cells with myeloma cells to create hybridomas, which are fusion cells that create monoclonal antibodies. The team next screened the hybridomas for drug binding capabilities. From an initial pool of 17 cell lines, they winnowed down to two that produced antibodies that bound strongly to heroin and 6-acetylmorphine. 

Janda’s group then injected a new batch of mice with the antibodies. Thirty minutes later, they dosed them with heroin. The antibodies administered prophylactically protected mice from the narcotizing effects of the drug. Mice that received the antibodies were more responsive to heat applied to their skin than mice that only received heroin. In another test, the antibodies revived mice that had been injected with heroin first, indicating the potential for development into a therapy like naloxone to rescue a patient who has already taken a dose of heroin. The antibodies persisted in the mice’s bodies for weeks at a time, a significant improvement over naloxone’s 30 to 80 minutes. 

     

Heroin metabolizes rapidly on its own, with a half-life of less than a minute. The antibodies prolonged the drug’s half-life to more than 40 minutes, slowing its conversion into morphine. Having protective antibodies increased a mouse’s chance of surviving a lethal heroin dose by 30% in comparison to mice that didn’t have protection. The dose killed 80% of unprotected mice within 90 seconds.

These past vaccines just weren't developing enough antibodies and with high enough affinity to do the trick, and they were also mistargeting the source. We didn't know that when we got started.
Kim Janda, Scripps Research Institute

While the work is impressive, a vaccine is not a cure all for addiction, warned Marco Pravetoni, a pharmacologist at the University of Washington who wasn’t involved in this research. “If somebody has already had multiple overdoses and a physician deemed them at risk of recurring overdoses, for that critical window where they’re most likely to use and die of an overdose, monoclonal antibodies can provide that two or three weeks of protection.” 

Janda’s group is working on a similar antibody-based vaccine against fentanyl in collaboration with Cessation Therapeutics. Like heroin, fentanyl is an opioid, but fentanyl can bind to a broader set of receptors in the brain than heroin, which only binds to opioid receptors. Since naloxone works by outcompeting recreational drugs for opioid receptors, it is not as effective at treating fentanyl overdoses. An antibody-based vaccine would be receptor agnostic.

“If you have a monoclonal antibody that will bind the drug and prevent it from interacting with any receptor, you would be able to counteract an opioid’s effect regardless of the underlying mechanism,” said Pravetoni.

References

1. Lee, J. C., Eubanks, L. M., Zhou, B. & Janda, K. D. Development of an Effective Monoclonal Antibody against Heroin and Its Metabolites Reveals Therapies Have Mistargeted 6-Monoacetylmorphine and Morphine over Heroin. ACS Cent. Sci. 8, 1464–1470 (2022).
2. Belz, T. F. et al. Enhancement of a Heroin Vaccine through Hapten Deuteration. J. Am. Chem. Soc. 142, 13294–13298 (2020).