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: -- Brief as my previous speakers did most of this work

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

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

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 Circulation Drug 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 serum antibody levels

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

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

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 Brief as my previous speakers did most of this work

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

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

COCAINE Brief as my previous speakers did most of this work

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

Cocaine self-administration

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

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

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

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

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

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

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

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 6 months still study started (4 mos after last vacc)

Plasma Antibody (n=7) Titer Weeks 82 ug 360 ug 1400 1200 1000 800 600 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks

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 Brief as my previous speakers did most of this work

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

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% 200 mg: 33% Data from Nabi website Brief as my previous speakers did most of this work

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

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

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

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)

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

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

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

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

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