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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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slide1

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

slide2

Outline

  • Drug Abuse
  • Immunological strategies
  • Latest clinical findings: Cocaine and nicotine
slide3

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
slide4

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
slide5

Pharmacotherapy

  • Cigarettes: Nicotine replacement, bupropion
  • Heroin: Methadone, naltrexone, buprenorphine
  • Alcohol: Naltrexone, acamprosate, disulfiram
  • Cocaine: --
  • Methamphetamine: --
slide6

Medications act at CNS

  • Mimic drug of abuseMethadone,Nicotine patch
  • Block drug of abuse Naltrexone
  • Decrease‘craving’ or withdrawalBupropion
slide7

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

slide8

Novel Approach: Target Drug rather than Brain

Immunotherapy blocks the effects of abused drugs peripherally, before they reach the brain

No CNS side effects

slide9

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
slide10

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
slide12

Blood/Brain Barrier

Blood/Brain Barrier

Pre-vaccine

Post-vaccine

Drug in Circulation

Drug in Circulation

slide13

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
slide14

Immunological Approaches

  • Passive Immunization: Administer monoclonal antibodies generated in vitro
  • Active Immunization:Vaccinate to generate antibodies
  • Catalytic Antibodies: Enhance drug metabolism
slide15

Passive Immunization

Pros: Precisely controlled dosing

Immediate protection

Cons: High doses needed

Cost

Drugs tested to date: Cocaine, nicotine, PCP

slide16

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 not interfere with immunological response, so vaccinations can occur while drug use is ongoing

slide17

Active Immunization (cont’d)

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

slide18

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

slide20

Xenova Research Ltd: TA-CD

  • b subunit of recombinant cholera toxin: Highly immunogenic protein eliciting potent antibody response
  • Covalently linked to succinyl norcocaine
  • Aluminum hydroxide adjuvant
slide22

Cocaine Self-Administration in rats(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

slide23

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
slide24

Relapse

  • 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
slide25

Clinical Data: TA-CD

  • 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

slide26

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 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
slide27

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

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

slide29

Preliminary Data

  • 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
slide30

Plasma Antibody (n=7)

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

slide31

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
slide33

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
slide34

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
slide35

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
slide36

Clinical Data: NicVAX

  • 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

slide37

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

slide38

METHAMPHETAMINE

  • 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
slide39

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
slide40

Chronic Relapsing Disorder

  • 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)
slide41

Binding Capacity

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

slide42

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
slide43

Issues

  • 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
slide44

Issues (cont’d)

  • 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
slide45

Summary

  • 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
slide46

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

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