Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same

a technology of haptencarrier and conjugate, which is applied in the field of drug abuse treatment, can solve the problems of cocaine abuse, drug abuse is an international problem, and the individual productivity loss is an extremely high risk, and achieves the effects of stimulating the production of anti-hapten antibodies, reducing expected pharmacological effects, and high anti-drug antibody titers

Inactive Publication Date: 2006-10-26
XENOVA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] The present invention overcomes the above mentioned drawbacks and provides methods for treating drug abuse. Using therapeutic compositions, in particular hapten-carrier conjugates, the present invention elicits an immune response in the form of anti-drug antibodies within the addict which upon subsequent exposure to the drug in a vaccinated individual neutralizes the drug so the expected pharmacological effects are diminished, if not eliminated. The present invention provides a therapeutic for drug addiction, particularly cocaine and nicotine addiction, based on vaccination of subjects with a drug/hapten-carrier conjugate, and more particularly, a cocaine-protein or nicotine-protein conjugate. Therapeutic compositions of the invention comprise at least one hapten and at least one T cell epitope-containing carrier which when conjugated to form a hapten-carrier conjugate is capable of stimula...

Problems solved by technology

There are a plethora of drugs, both legal and illegal, the abuse of which have become serious public policy issues affecting all strata of society with its obvious medical and social consequences.
Some users live in an extremely high risk population associated with poverty and illegal activity.
Other users who might classify themselves as recreational users are at risk due to (a) properties of the drug(s) which make them addictive, (b) a predisposition of the user to become a heavy user or (c) a combination of factors including personal circumstances, hardship, environment and accessibility.
Two especially problematic drugs of addiction are cocaine and nicotine.
The cumulative effects of cocaine-associated violent crime, loss in individual productivity, illness, and death is an international problem.
Additional factors contributing to the lack of successful treatment programs is that patterns of cocaine abuse have varied with time.
This behavior leads to addiction, and in some cases, to toxic consequences (Carroll et al., Pharm.
There are only very limited treatments for drugs of abuse and no effective long term treatments for cocaine addiction.
There has also been the use of drugs which potentiate dopaminergic transmission, such as bromocriptine, but the benefits of such drugs are limited in part by toxicity (Taylor et al.
New drugs aimed at replacing methadone for opioid addiction, such as buprenorphine, have also been used based on cross-interference with the dopaminergic system, however only limited clinical study information is available (Fudula et al.
Present therapies used to treat cocaine addicts have at least four major limitations leading to a very high rate of recidivism.
First, and perhaps most fundamentally, the contributing neurochemical events in cocaine abuse and addiction are complex (Carroll et al.
As a result, single acting neuropharmacological approaches, such as inhibition of dopamine uptake, do not appear to be sufficient to overcome addiction.
Second, the drugs currently used in cocaine addiction treatments have significant side-effects themselves, limiting their utility.
Third, drug therapy compliance is problematic among this patient population.
Fourth, because of the complex chemistries involved in pharmacological therapies, many of them may be incompatible wit...

Method used

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  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of PS-2

[0192] A solution of ecgonine methyl ester hydrocholoride (50 mg, 0.21 mmol), diisopropylethylamine (80 μl, 0.46 mmol) in DMF (3 ml) was treated with bromoacetyl bromide (22 μl, 0.25 mmol) and heated at 40° C. overnight. The solvents were removed under reduced pressure and the residue purified by silica gel flash chromatography (9:1 chloroform:methanol as the eluent), furnishing the bromo compound (67 mg, 96%) as a pale yellow powder (3β-(Bromoacetyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2β-carboxylic acid methyl ester).

[0193] To a solution of the bromo compound (17 mg, 0.053 mmol) in PBS (0.5 ml), thiolated BSA (15 mg) in PBS (0.5 ml) was added and stirring continued at ambient temperature for 3 days. The conjugate was purified by dialysis against PBS and then analyzed by mass spectral analysis.

example 2

Synthesis of PS-4

[0194] To a solution of ecgonine methyl ester (32 mg, 0.16 mmol) in DMF (2 ml), triethylamine (22 μl, 0.16 mmol), followed by succinic anhydride (16 mg, 0.16 mmol) was added and the solution heated at 35 C for 2 hours. The solvent was removed under reduced pressure and the residue purified by silica gel flash chromatography (9:1 chloroform:methanol as the eluent). This furnished the desired hemisuccinate (21 mg, 44%) as a white powder (3β-(Succinoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2β-carboxylic acid methyl ester).

[0195] To a solution of the hemisuccinate (2.4 mg, 7.69 μmol) in distilled water (0.5 ml) at 0° C., EDC (1.5 mg, 7.69 μmol) was added. After 10 minutes, BSA (2 mg in 0.5 ml PBS) and the solution allowed to warm to ambient temperature overnight. The conjugate was purified by dialysis against PBS and the degree of haptenation determined by mass spectral analysis.

example 3

Synthesis of PS-5

[0196] Method A

[0197] A solution of norcocaine hydrochloride (1 g, 3.07 mmol), triethylamine (0.86 ml, 6.14 mmol) in methylene chloride (20 ml) was treated with succinic anhydride (614 mg, 6.14 mmol) and the mixture heated at 45° C. overnight. The solvents were removed under reduced pressure and the residue purified using silica gel flash chromatography (2:1 chloroform:methanol as the eluent) This gave succinylated norcocaine (1.0 g, 84%) as a thick syrup (3β-(Benzoyloxy)-8-succinoyl-8-azabicyclo[3.2.1]octane-2β-carboxylic acid methyl ester).

[0198] To a solution of the acid (14 mg, 0.036 mmol) in distilled water (1 ml) at 0° C., EDC (10.4 mg, 0.055 mmol) was added. After 5 minutes a solution of BSA (14 mg) in PBS (1 ml) was added dropwise and the mixture allowed to warm to ambient temperature overnight. The conjugate was purified by dialysis against PBS and the degree of conjugation analyzed by mass spectral analysis.

[0199] Method B

[0200] To a solution of BSA (...

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Abstract

Hapten-carrier conjugates capable of eliciting anti-hapten antibodies in vivo by administering, in a therapeutic composition, are disclosed. Methods of preparing said conjugates and therapeutic compositions are also disclosed. Where the hapten is a drug of abuse, a therapeutic composition containing the hapten-carrier conjugate is particularly useful in the treatment of drug addiction, more particularly, cocaine addiction. Passive immunization using antibodies raised against conjugates of the instant invention is also disclosed. The therapeutic composition is suitable for co-therapy with other conventional drugs.

Description

REFERENCE TO RELATED APPLICATION [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 08 / 563,673 filed Nov. 28, 1995, which is a continuation-in-part of U.S. patent application Ser. No. 08 / 414,971 filed Mar. 30, 1995.FIELD OF THE INVENTION [0002] The present invention relates to treatment of drug abuse. More specifically, the present invention relates to methods of treating drug abuse using drug / hapten-carrier conjugates which elicit antibody responses and / or using the antibodies to the drug / hapten-carrier conjugates. BACKGROUND OF THE INVENTION [0003] The prevalence of drug use and abuse worldwide, especially in the United States, has reached epidemic levels. There are a plethora of drugs, both legal and illegal, the abuse of which have become serious public policy issues affecting all strata of society with its obvious medical and social consequences. Some users live in an extremely high risk population associated with poverty and illegal activity....

Claims

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Application Information

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IPC IPC(8): G01N33/53C12P21/04A61K39/395C07K14/47C07K16/18A61K47/48A61P25/30
CPCA61K39/0013C07K16/44A61K2039/6037A61K47/4833A61K47/646A61P25/30A61P25/34A61P37/04A61P39/00
Inventor SWAIN, PHILIP A.SCHAD, VICTORIA C.GREENSTEIN, JULIA L.EXLEY, MARK A.FOX, BARBARA S.POWERS, STEPHEN P.GEFTER, MALCOLM L.
Owner XENOVA
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