1. 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

2. Outline Drug Abuse Immunological strategies
Latest clinical findings: Cocaine and nicotine

3. 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

4. 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

5. Pharmacotherapy Cigarettes: Nicotine replacement, bupropion
Heroin: Methadone, naltrexone, buprenorphine
Alcohol: Naltrexone, acamprosate, disulfiram
Cocaine: --
Methamphetamine: --
Brief as my previous speakers did most of this work

6. Medications act at CNS Decrease ‘craving’ or withdrawal Bupropion
Mimic drug of abuse Methadone, Nicotine patch
Block drug of abuse Naltrexone
Decrease ‘craving’ or withdrawal Bupropion

7. Even effective medications do not work for many people
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
Brief as my previous speakers did most of this work

8. Novel Approach: Target Drug rather than Brain
Immunotherapy blocks the effects of abused drugs peripherally, before they reach the brain
No CNS side effects

9. 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

10. 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

11. Smoked cocaine produces comparable effects as IV cocaine

12. Pre-vaccine Post-vaccine
Blood/Brain Barrier
Blood/Brain Barrier
Drug in Circulation
Drug in Circulation

13. 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 serum antibody levels

14. Immunological Approaches
Passive Immunization: Administer monoclonal antibodies generated in vitro
Active Immunization: Vaccinate to generate antibodies
Catalytic Antibodies: Enhance drug metabolism
Brief as my previous speakers did most of this work

15. Passive Immunization Pros: Precisely controlled dosing
Immediate protection
Cons: High doses needed
Cost
Drugs tested to date: Cocaine, nicotine, PCP
Brief as my previous speakers did most of this work

16. Active Immunization Pros: Easy, relatively inexpensive
Antibodies long-lasting (e.g., 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
Brief as my previous speakers did most of this work

17. 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
Brief as my previous speakers did most of this work
Drugs tested to date: Cocaine, nicotine, methamphetamine

18. 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
Brief as my previous speakers did most of this work
Drugs tested to date: Cocaine

19. COCAINE
Brief as my previous speakers did most of this work

20. 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
Brief as my previous speakers did most of this work

21. Cocaine self-administration

22. Cocaine Self-Administration in rats (Fox et al., 1996)
Passive Immunization 10
Cocaine 8 6
Infusions per hour
Saline 4
Cocaine + Antibody 2
baseline 1 2 3 4 5
Day

23. 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

24. Relapse
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

25. 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
Brief as my previous speakers did most of this work

26. 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
Brief as my previous speakers did most of this work

27. 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)
Brief as my previous speakers did most of this work

28. 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
35 Mood Scales
50 Mood Scales

29. Preliminary Data
Data collection ongoing: 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
6 months still study started (4 mos after last vacc)

30. Plasma Antibody (n=7) Titer Weeks 82 ug 360 ug 1400 1200 1000 800 6002 4 6 8 10 12 14 16 18 20 22 24 26
Weeks

31. 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

32. NICOTINE

33. 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

34. Animal Models: Vaccination
nicotine distribution to the rat brain by %
nicotine self-administration
nicotine-induced drug seeking
blocks nicotine alleviation of withdrawal **may block relapse related to relief of withdrawal
Brief as my previous speakers did most of this work

35. Nicotine replacement
Vaccination most effective at blocking early distribution 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

36. Clinical Data: NicVAX Nabi Biopharmaceuticals: Phase II trial (n=68)
Doses: 0, 50, 100, 200 mg Vaccinate: Day 0, 28, 56 and 182
Well-tolerated Stopped smoking placebo: 9% mg: 33%
Data from Nabi website
Brief as my previous speakers did most of this work

37. 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

38. 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

39. 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

40. 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)

41. 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

42. 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

43. 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

44. 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

45. 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

46. Acknowledgements Richard Foltin, Ph.D. NIDA
Diana Martinez, M.D. Xenova Research Ltd.
Recent Reviews
1. Haney and Kosten (2004) Expert Review Vaccines : 11-18
2. Pentel (2004) New Treatments for Addiction National Academy of Sciences