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Immunotherapies for the Treatment of Drug Dependence. Margaret Haney, Ph.D. Associate Professor of Clinical Neuroscience Columbia University New York State Psychiatric Institute Supported by National Institute of Drug Abuse. Outline. Drug Abuse Immunological strategies

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Immunotherapies for the Treatment of Drug Dependence

Margaret Haney, Ph.D.

Associate Professor of Clinical Neuroscience

Columbia University

New York State Psychiatric Institute

Supported by National Institute of Drug Abuse


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


Chronic Relapsing Disorder

  • 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


Pharmacotherapy

  • Cigarettes: Nicotine replacement, bupropion

  • Heroin: Methadone, naltrexone, buprenorphine

  • Alcohol: Naltrexone, acamprosate, disulfiram

  • Cocaine: --

  • Methamphetamine: --


Medications act at CNS

  • Mimic drug of abuseMethadone,Nicotine patch

  • Block drug of abuse Naltrexone

  • Decrease‘craving’ or withdrawalBupropion


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 (not binding to drug metabolites or other drugs or medications)


Blood/Brain Barrier (not binding to drug metabolites or other drugs or medications)

Blood/Brain Barrier

Pre-vaccine

Post-vaccine

Drug in Circulation

Drug in Circulation


  • Antibody response fades over time, so boosters needed to maintain serumantibody levels


  • Immunological Approaches vaccination, but drug bound to antibody, so not toxic

    • Passive Immunization: Administer monoclonal antibodies generated in vitro

    • Active Immunization:Vaccinate to generate antibodies

    • Catalytic Antibodies: Enhance drug metabolism


    Passive Immunization vaccination, but drug bound to antibody, so not toxic

    Pros: Precisely controlled dosing

    Immediate protection

    Cons: High doses needed

    Cost

    Drugs tested to date: Cocaine, nicotine, PCP


    Active Immunization vaccination, but drug bound to antibody, so not toxic

    Pros: Easy, relatively inexpensive

    Antibodies long-lasting (e.g., 3-6 months), a particular benefit in treating drug addiction

    Presence of abused drug does not interfere with immunological response, so vaccinations can occur while drug use is ongoing


    Active Immunization (cont’d) vaccination, but drug bound to antibody, so not toxic

    Cons: Takes time for antibodies to be generated (repeated vaccinations over about 2 months)

    Enormous individual variability in amount of antibody generated

    Surmountable

    Substitution

    Drugs tested to date: Cocaine, nicotine, methamphetamine


    Catalytic Antibodies vaccination, but drug bound to antibody, so not toxic

    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 vaccination, but drug bound to antibody, so not toxic


    Xenova Research Ltd: TA-CD vaccination, but drug bound to antibody, so not toxic

    • b subunit of recombinant cholera toxin: Highly immunogenic protein eliciting potent antibody response

    • Covalently linked to succinyl norcocaine

    • Aluminum hydroxide adjuvant


    Cocaine self-administration vaccination, but drug bound to antibody, so not toxic


    Cocaine Self-Administration in rats vaccination, but drug bound to antibody, so not toxic(Fox et al., 1996)

    Passive Immunization

    10

    Cocaine

    8

    6

    Infusions per hour

    Saline

    4

    Cocaine + Antibody

    2

    0

    baseline

    1

    2

    3

    4

    5

    Day



    Relapse depends on plasma antibody concentration

    • In humans, relapse to drug use can be triggered by low doses of abused druge.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


    Clinical Data: TA-CD depends on plasma antibody concentration

    • Phase II trial conducted at Yale School of Medicine

    • Cocaine-dependent outpatients (n=21): TA-CD (82, 360 mg) administered 3-5 times over 12 wks

      Data from Xenova website, Kosten et al., 2002


    Clinical Data: TA-CD (cont’d) depends on plasma antibody concentration

    • 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 monthsLevels 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 depends on plasma antibody concentration

    • 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 weeks 3 cocaine sessions/week, each testing one dose of smoked cocaine (0, 25, 50 mg)


    Cocaine sessions
    Cocaine Sessions depends on plasma antibody concentration

    MinuteEvent

    -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 depends on plasma antibody concentration

    • Data collection ongoing: 82 mg TA-CD (n=4)360 mg 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


    Plasma Antibody (n=7) depends on plasma antibody concentration

    1400

    82 ug

    360 ug

    1200

    1000

    800

    Titer

    600

    400

    200

    0

    0

    2

    4

    6

    8

    10

    12

    14

    16

    18

    20

    22

    24

    26

    Weeks


    Laboratory study: PET depends on plasma antibody concentration

    • 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 depends on plasma antibody concentration



    Animal Models: Vaccination immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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 immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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 immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • Nabi Biopharmaceuticals: Phase II trial (n=68)

    • Doses: 0, 50, 100, 200 mgVaccinate: Day 0, 28, 56 and 182

    • Well-toleratedStopped smoking placebo: 9%200 mg: 33%

      Data from Nabi website


    Additional Clinical Data immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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


    METHAMPHETAMINE immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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 of administration (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


    Overall Conclusions immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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


    Chronic Relapsing Disorder immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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)


    Binding Capacity immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    Surprising result is that immunotherapies appear effective even when amount of drug substantially exceeds calculated binding capacity of antibodiesex: nicotine vaccine reduced drug distribution to brain even when single nicotine doses exceeded estimated binding capacity by 67-fold


    Binding Capacity immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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


    Issues immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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 (cont’d) immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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


    Summary immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    • 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


    Acknowledgements immunotherapy since lower daily doses of nicotine are consumed (milligrams as opposed to grams of cocaine)

    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


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