Scientists at The Scripps Research Institute (TSRI),
one of the world's largest independent, non-profit biomedical research
organizations, have shown that an injectable solution can protect mice from an
otherwise lethal overdose of cocaine. The findings could lead to human clinical
trials of a treatment designed to reverse the effects of cocaine in case of
emergency. Cocaine is involved in more than 400,000 emergency-room visits and
about 5,000 overdose deaths each year in the United
States.
The findings, reported recently in the journal
Molecular Pharmaceutics, demonstrate the therapeutic potential of a human
antibody against cocaine.
“This would be the first specific antidote for cocaine
toxicity,” said Scripps Research Kim Janda, PhD, senior author of the report. A
pioneer in the field of vaccines against drugs of abuse, Janda is the Ely R.
Callaway, Jr. Chair in Chemistry, a professor in the Department of Immunology
and Microbial Science, and director of The Worm Institute for Research and
Medicine, all at Scripps Research. “It’s a human antibody so it should be
relatively safe, it has a superior affinity for cocaine, and we examined it in
a cocaine overdose model that mirrors a real-life scenario,” he said.
Janda and his laboratory colleagues have been
developing candidate vaccines against cocaine, heroin, nicotine, and even
Rohypnol, the “date-rape” drug. But most of these have been active
vaccines—solutions of drug-mimicking molecules that provoke a long-term
antibody response against a drug, greatly reducing its ability to reach the
brain. These are potentially useful against addiction and relapse, but take
weeks to stimulate an effective antibody response and thus are of limited value
in drug overdose emergencies, which require a fast-acting antidote. Cocaine is
a leading cause of illegal-drug overdoses in developed countries; it can cause
hyperthermia, irregular heartbeats, seizures and death.
One possibility for an antidote is a “passive” cocaine
vaccine, a ready-made solution of antibodies much like those used to treat
snakebite. As Janda and his colleagues have shown in previous research,
injected drug-specific antibodies can swiftly remove drug molecules from the
bloodstream. This immediately reduces a drug’s direct effects on the heart and
nearby organs, but it also pulls the drug from the organ where it does the most
damage—the brain. If the drug molecules are small enough to cross the
blood-brain barrier, the sudden lowering of their bloodstream concentration
causes them to diffuse rapidly out of brain tissue.
Cocaine molecules are small enough to diffuse this
way, and in 2005 Janda and his lab reported that injections of a mouse-derived
anti-cocaine antibody, GNC92H2, could keep mice alive despite cocaine doses
that killed unprotected mice. Mouse antibodies are not ideal for use in humans,
though; they are “foreign” enough that human immune systems eventually develop
a reaction against them.
In the new study, Janda and Jennifer B. Treweek, PhD,
a research associate in Janda’s laboratory, used a genetically engineered mouse
that can produce fully human antibodies against cocaine molecules. The best of
these antibodies, GNCgzk, showed ten times the cocaine-binding affinity of
GNC92H2, the molecule in the 2005 study.
In a preliminary test, the scientists showed an
injection of GNCgzk antibodies 30 minutes before an injection of a lethal
cocaine dose greatly reduced the signs of overdose—such as awkward movements
and seizures—and kept all treated mice alive. By contrast, about half of
untreated mice and 15 per cent of GNC92H2-treated mice died.
In a test that better simulated a real-life emergency
situation, mice were first given a cocaine overdose, and three minutes later
were infused with GNCgzk. About half of untreated mice were killed by such a
dose. While GNC92H2 reduced that rate to about 28 percent, the new GNCgzk
antibodies reduced the mortality rate further, to 20 percent.
More strikingly, a stripped-down version of
GNCgzk—F(ab’)2-gzk, which contains only the antibody’s cocaine-binding
segments—reduced the mortality to zero, as well as significantly reducing
overdose signs such as seizures. It also did so at a much smaller, clinically
feasible dose than GNC92H2’s. “There was a reversal of the signs of cocaine
toxicity within seconds of the injection,” said Treweek.
Janda and Treweek are now trying to find ways to
produce their F(ab’)2-gzk antidote economically and in large quantities. “If we
can do that, then there would be no reason not to push it into clinical
trials,” Janda said.
He notes that such a treatment could be useful not
only in reducing the immediate effects of an overdose, but also in preventing
near-term relapses. “A lot of people that overdose end up going back to the
drug rather quickly,” Janda said, “but this antibody would stay in their
circulation for a few weeks at least, and during that time the drug wouldn’t
have an effect on them.” Likewise, this antibody could be administered to
patients in addiction recovery or detox programs as a prophylactic treatment to
supplement other medications, such as antidepressants, and counseling. An
acute relapse during this recovery period would be immediately nullified by the
antibody dose that is already in circulation.
The research in the paper “An Antidote for Acute
Cocaine Toxicity” was supported by the National Institute on Drug Abuse of the
National Institutes of Health and Scripps Research’s Skaggs Institute of
Chemical Biology.
The Scripps Research Institute is one of the world's
largest independent, non-profit biomedical research organizations. Scripps
Research is internationally recognized for its discoveries in immunology,
molecular and cellular biology, chemistry, neuroscience, and vaccine
development, as well as for its insights into autoimmune, cardiovascular, and
infectious disease.
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float: none; ">In a test that better simulated a real-life emergency
situation, mice were first given a cocaine overdose, and three minutes later
were infused with GNCgzk. About half of untreated mice were killed by such a
dose. While GNC92H2 reduced that rate to about 28 percent, the new GNCgzk
antibodies reduced the mortality rate further, to 20 percent.
More strikingly, a stripped-down version of
GNCgzk—F(ab’)2-gzk, which contains only the antibody’s cocaine-binding
segments—reduced the mortality to zero, as well as significantly reducing
overdose signs such as seizures. It also did so at a much smaller, clinically
feasible dose than GNC92H2’s. “There was a reversal of the signs of cocaine
toxicity within seconds of the injection,” said Treweek.
Janda and Treweek are now trying to find ways to
produce their F(ab’)2-gzk antidote economically and in large quantities. “If we
can do that, then there would be no reason not to push it into clinical
trials,” Janda said.
He notes that such a treatment could be useful
not only in reducing the immediate effects of an overdose, but also in
preventing near-term relapses. “A lot of people that overdose end up going back
to the drug rather quickly,” Janda said, “but this antibody would stay in their
circulation for a few weeks at least, and during that time the drug wouldn’t
have an effect on them.” Likewise, this antibody could be administered to
patients in addiction recovery or detox programs as a prophylactic treatment to
supplement other medications, such as antidepressants, and counseling. An
acute relapse during this recovery period would be immediately nullified by the
antibody dose that is already in circulation.
The research in the paper “An Antidote for Acute
Cocaine Toxicity” was supported by the National Institute on Drug Abuse of the
National Institutes of Health and Scripps Research’s Skaggs Institute of
Chemical Biology.
The Scripps Research Institute is one of the
world's largest independent, non-profit biomedical research organizations.
Scripps Research is internationally recognized for its discoveries in
immunology, molecular and cellular biology, chemistry, neuroscience, and
vaccine development, as well as for its insights into autoimmune,
cardiovascular, and infectious disease.
