Margaret Haney, Ph.D.
Associate Professor of Clinical Neuroscience
Columbia University
New York State Psychiatric Institute
Supported by National Institute of Drug Abuse
Immunotherapies for the Treatment
of Drug Dependence
Outline
Drug Abuse
Immunological strategies
Latest clinical findings: Cocaine and nicotine
Drug Dependence: Major public health problem
Human costs (lives damaged by addiction) and financial costs ($67 billion/year in health care, crime, lost job productivity, etc.)
46 million adult cigarette smokers in U.S.: 70% want to quit but < 5% succeed
1.7 million dependent on cocaine in U.S.: 53% seeking treatment
Addiction: Compulsive behavior, characterized by a loss of control in limiting drug intake
Drug users often enter treatment with strong intentions, but a variety of factors (drug cues, drug exposure, stress) often make it difficult to maintain abstinence for long periods
Never expect to ‘cure’ drug dependence. Goal is to decrease likelihood of relapse and increase length of abstinence
Chronic Relapsing Disorder
Pharmacotherapy
Cigarettes: Nicotine replacement, bupropion
Heroin: Methadone, naltrexone, buprenorphine
Alcohol: Naltrexone, acamprosate, disulfiram
Cocaine: --
Methamphetamine: --
Mimic drug of abuse Methadone, Nicotine
patch
Block drug of abuse Naltrexone
Decrease ‘craving’
or withdrawal Bupropion
Medications act at CNS
Drugs of abuse are small molecules that rapidly cross the blood-brain barrier, and bind at sites mediating reward, cognition, emotion, memory
Treatment medications often target the same CNS pathways, and therefore can affect normal function as well (side effects)
Even effective medications do not work for many people
More treatment options are needed
Novel Approach: Target Drug rather than Brain
Immunotherapy blocks the effects of abused drugs peripherally, before they reach the brain
No CNS side effects
Unlike bacteria or viruses, drugs of
abuse alone do not elicit an immune
response
To generate anti-drug antibodies, a
derivative of the drug is irreversibly
bound to an antigenic protein carrier
Drugs bound to antibody cannot cross
the blood-brain barrier
Antibodies typically have high affinity and high specificity (not binding to drug metabolites or other drugs or medications)
Mechanism of action: do not block drug effects completely (unlike vaccines for infectious disease), but act by slowing the rate in which abused drugs get into brain
For all drugs of abuse: faster onset of effect, greater abuse liability, so slowing rate of entry decreases drug reinforcment
Smoked cocaine produces comparable effects as IV cocaine
Pre-vaccine Post-vaccine
Blood/Brain Barrier Blood/Brain Barrier
Drug in CirculationDrug in Circulation
Plasma concentrations of drug are higher following vaccination, but drug bound to antibody, so not toxic
In rats, cocaine-specific antibodies reduced early cocaine distribution to brain and heart by 25-80% (Kantak et al., 2000)
Antibody response fades over time, so boosters needed to maintain serumantibody levels
Immunological Approaches
Passive Immunization: Administer
monoclonal antibodies generated in vitro
Active Immunization: Vaccinate to
generate antibodies
Catalytic Antibodies: Enhance drug
metabolism
Passive Immunization
Pros: Precisely controlled dosingImmediate protection
Cons: High doses neededCost
Drugs tested to date: Cocaine, nicotine, PCP
Active Immunization
Pros: Easy, relatively inexpensive
Antibodies long-lasting (e.g., 3-6 months), a particular benefit in treating drug addiction
Presence of abused drug does notinterfere with immunological response, so vaccinations can occur while drug use is ongoing
Active Immunization (cont’d)
Cons: Takes time for antibodies to be generated (repeated vaccinations overabout 2 months)
Enormous individual variability in amount of antibody generated
Surmountable
Substitution
Drugs tested to date: Cocaine, nicotine, methamphetamine
Catalytic Antibodies
Pros: Not easily surmounted
Cons: Limited to drugs metabolized by simple hydrolysis (e.g., cocaine)
Effects short-lived
Large quantities of antibody needed
Drugs tested to date: Cocaine
COCAINE
Xenova Research Ltd: TA-CD
subunit of recombinant cholera toxin: Highly immunogenic protein eliciting potent antibody response
Covalently linked to succinyl norcocaine
Aluminum hydroxide adjuvant
Cocaine self-administration
Cocaine Self-Administration in rats (Fox et al., 1996)
Passive Immunization
0
2
4
10
8
6
Infu
sio
ns
per
ho
ur
baseline 1 2 3 4 5
Day
Cocaine
Cocaine + Antibody
Saline
Degree to which cocaine self-administration
is decreased depends on plasma antibody
concentration
There is a threshold concentration of
plasma antibody needed to block cocaine
self-administration
In humans, relapse to drug use can be triggered by low doses of abused drug
e.g., one drink for an abstinent alcoholic may
trigger a return to pre-abstinent levels of drinking
In animal models, low doses of cocaine trigger a return to cocaine-seeking
Vaccinated rats did not show this response(Kantak et al., 2000)
Suggests vaccine may help prevent relapse
Relapse
Clinical Data: TA-CD
Phase II trial conducted at Yale School of Medicine
Cocaine-dependent outpatients (n=21): TA-CD (82, 360 g) administered 3-5 times over 12 wks
Data from Xenova website, Kosten et al., 2002
Clinical Data: TA-CD (cont’d)
Large variability in plasma antibody levels, but
efficacy dose-dependent: Individuals receiving
more frequent vaccinations at higher doses of
TA-CD had higher antibody levels and showed
fewer cocaine+ urines
Peak antibody levels: 3 months
Levels persist up to 6 months
Boosters (n=8): antibody response in 2-4 wks
Ongoing large Phase II trial in methadone-
maintained cocaine-dependent patients
Preclinical Human Laboratory Study
Determine direct relationship between plasma antibody levels, and cocaine’s subjective and cardiovascular effects
Cocaine-dependent volunteers not seeking treatment for cocaine use
Vaccinations: weeks 1, 3, 5, 9
Inpatient 2 nights/wk for 13 weeks3 cocaine sessions/week, each testing
one dose of smoked cocaine (0, 25, 50 mg)
Cocaine Sessions
Minute Event-30 Baseline Cardiovascular and Mood Scales
-8 Baseline Plasma Cocaine and Antibody Measures
0 First Cocaine Administraton 4 Mood Scales
Plasma Measures 15 Mood Scales 20 Second Cocaine Administration 24 Mood Scales
Plasma Measures 35 Mood Scales
Plasma Measures 50 Mood Scales
Plasma Measures
Preliminary Data
Data collection ongoing: 82 g TA-CD (n=4)360 g TA-CD (n=4)
Well tolerated; side effects minor and infrequent
*No evidence of attempts to surmount. Participants report that if they do not feel cocaine’s effects they stop using
0 2 4 6 8 10 12 14 16 18 20 22 24 260
200
400
600
800
1000
1200
1400
Tit
er
Weeks
Plasma Antibody (n=7)
82 ug360 ug
Laboratory study: PET
PET imaging to determine brain cocaine concentrations and dopamine transporter occupancy (DAT) before and after vaccination
Determine whether vaccine effectively reduces the transport of cocaine into brain, and reduces blockade of DAT by cocaine
Data not yet analyzed
NICOTINE
Nicotine may be especially promising as a target drug for immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)
Presumably, lower serum antibody levels needed to decrease nicotine’s effects
Animal Models: Vaccination
nicotine distribution to the rat brain by 40-60%
nicotine self-administration
nicotine-induced drug seeking
blocks nicotine alleviation of withdrawal **may block relapse
related to relief of withdrawal
Nicotine replacement
Vaccination most effective at blocking earlydistribution of nicotine to brain
Not as effective blocking slow, continuous infusions as with nicotine patch
May be possible to combine nicotine patch and nicotine vaccine therapy
Clinical Data: NicVAX
Nabi Biopharmaceuticals: Phase II trial (n=68)
Doses: 0, 50, 100, 200 gVaccinate: Day 0, 28, 56 and 182
Well-toleratedStopped smoking placebo: 9%
200 g: 33%
Data from Nabi website
Additional Clinical Data
Xenova Group (TA-NIC) Nicotine butyric acid covalently linked to recombinant cholera toxin B. Phase I testing (n=60)
Cytos Biotechnology (CYT002-NicQb): Phase II study (n=300)
Data from company websites
Active Immunization: Vaccine produced antibodies but did not alter locomotor activity
Passive Immunization: Decreased drug distribution by > 60% but not w/i first 15 min ofadministration (not rapid binding). No robust decrease in locomotor or reinforcing effects
Issue: Methamphetamine metabolized to pharmacologically active metabolites not bound by antibody Conclusion: Methamphetamine immunotherapy
shows promise, but higher affinity antibodies and a combination of different antibodies may be needed
METHAMPHETAMINE
Overall Conclusions
Current results encouraging: few side effects, reliable antibody production, and safe in combination with drug of abuse
Never expect to ‘cure’ drug dependence. Goal is to improve treatment options
Need a variety of approaches: Immuno-therapy may be one tool, along with behavioral and pharmacologic treatment, to facilitate abstinence
If vaccinated patient relapses, a portion of dose will bind the antibody and not enter the brain
Patient may feel a muted drug effect, and opt not to waste money on more drug
Treatment approaches requiring minimal compliance by patient ideal
Impact of immunotherapy may be most profound for drugs with no effective pharmacotherapy (cocaine, methamphetamine, PCP)
Chronic Relapsing Disorder
Binding Capacity
Surprising result is that immunotherapies appear effective even when amount of drug substantially exceeds calculated binding capacity of antibodies
ex: nicotine vaccine reduced drug distribution to brain even when single nicotine doses exceeded estimated binding capacity by 67-fold
Binding Capacity
Immunization appears to preferentially decrease drug distribution to the brain compared to other tissues
Vaccination sequesters nicotine both in the serum and in fat or lung tissue, depending on dosing regimen
Tissue-specific effects may explain how vaccination reduces drug distribution to brain at doses that exceed binding capacity
Time to build antibody titers (approx 8 wks)
*Start vaccinating while drug use ongoing or during
stay in inpatient treatment facility
*Combine passive and active immunization?
Individual variability in antibody production
* Vaccine won’t be effective for everybody
Antibody response fades
* Need boosters approx 4 month intervals
Issues
Substitution* Realistic to presume some will switch to
alternate drugs of abuse, yet shouldn’t discourage pursuit of effective therapy
Involuntary vaccination or vaccination of minors?* Given surmountability, not advised; need active
participation of individual receiving immunotherapy for it to work
safely
Issues (cont’d)
Stimulant and tobacco dependence are global
problems
Immunotherapy is a novel approach with potential for
wide application
Immunotherapy will not guarantee drug abstinence,
but could increase the odds a motivated treatment
seeker would not relapse to pre-vaccine levels of
drug use
Summary
Acknowledgements
Richard Foltin, Ph.D. NIDA
Diana Martinez, M.D. Xenova Research Ltd.
Recent Reviews
1. Haney and Kosten (2004) Expert Review Vaccines 3: 11-18
2. Pentel (2004) New Treatments for Addiction National Academy of Sciences