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