Monoclonal antibody antagonists for treating medical problems associated with d-amphetamine-like drugs

• US 20030119083A1
• Filed: 09/26/2002
• Published: 06/26/2003
• Est. Priority Date: 04/20/2000
• Status: Active Grant

• Current Assignee: University of Arkansas for Medical Sciences (University of Kansas)
• Original Assignee: University of Arkansas for Medical Sciences (University of Kansas)
• Inventors: Carroll, Frank Ivy, Owens, Samuel M., Abraham, Philip
• Granted Patent: US 7,202,348 B2
• Time in Patent Office: Days
• US Class Current: 435/7.92
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 217/60 linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/55 Fab or Fab'

Abstract

The present invention provides synthetic immunochemical haptens for the generation of antibodies that are designed to recognize the common molecular features of d-methamphetamine-like abused stimulants with insignificant cross-reactivity to endogenous substrates (e.g. dopamine) or over-the-counter medications (e.g. 1-methamphetamine, pseudoephedrine, phenylpropanolamine and ephedrine). These monoclonal antibodies and their antigen binding fragments are useful in treatment plans for recovering addicts, in emergency room settings for rapidly reversing a drug overdose, in protection of fetuses from drug-abusing pregnant mothers or in a psychiatric setting to reduce the exacerbation of psychotic disorders caused by stimulant drugs.

Claims

5. An antigen binding fragment that specifically recognizes a stimulant drug of abuse or a metabolite thereof, wherein said drug of abuse or its metabolite is selected from the group consisting of d-methamphetamine, d-amphetamine, (+/−

) 3,4-methylenedioxymethamphetamine, (+/−

) 3,4-methylenedioxyamphetamine and structural-related analogs of these compounds.

6. The antigen binding fragment of claim 5, wherein said antigen binding fragment is of murine origin.

7. The antigen binding fragment of claim 5, wherein said antigen binding fragment is of human origin or contains portions of a human antibody.

10. A method of treating stimulant drug abuse or overdose, comprising the step of administering a pharmacological effective dose of the antigen binding fragment of claim 5 to a n individual in need of such treatment.

11. The method of claim 10, wherein said stimulant drug is selected from the group consisting of d-methamphetamine, d-amphetamine, (+/−

) 3,4-methylenedioxymethamphetamine, (+/−

) 3,4-methylenedioxyamphetamine and structural-related analogs of these compounds.

12. A substituted methamphetamine having the structure

1. A monoclonal antibody that specifically recognizes a stimulant drug of abuse or a metabolite thereof, wherein said drug of abuse or its metabolite is selected from the group consisting of d-methamphetamine, d-amphetamine, (+/−

) 3,4-methylenedioxymethamphetamine, (+/−

) 3,4-methylenedioxyamphetamine and structural-related analogs of these compounds.

2. The monoclonal antibody of claim 1, wherein said antibody is of murine origin.

3. The monoclonal antibody of claim 2, wherein said antibody is monoclonal antibody 6H8 or monoclonal antibody 6H4

4. The monoclonal antibody of claim 1, wherein said antibody is of human origin or contains portions of a human antibody.

8. A method of treating stimulant drug abuse or overdose, comprising the step of administering a pharmacological effective dose of the monoclonal antibody of claim 1 to an individual in need of such treatment.

9. The method of claim 8, wherein said stimulant drug is selected from the group consisting of d-methamphetamine, d-amphetamine, (+/−

) 3,4-methylenedioxymethamphetamine, (+/−

) 3,4-methylenedioxyamphetamine and structural-related analogs of these compounds.

13. The substituted methamphetamine of claim 12, wherein R is O(CH₂)_xCOOH, and x is 2 to 9.

14. The substituted methamphetamine of claim 13, wherein said methamphetamine is (S)- or (R)-3-(5′

-carboxypentyloxy) methamphetamine hydrochloride.

15. The substituted methamphetamine of claim 12, wherein R is OCH₂CH═

CH(CH₂)_xCOOH, and x is 1 to 6.

16. The substituted methamphetamine of claim 12, wherein R is OCH₂C≡

C(CH₂)_xCOOH, and x is 1 to 6.

17. The substituted methamphetamine of claim 12, wherein R is O(CH₂)_xO(CH₂)_yCOOH, and x is 2 to 4, y is 1 to 5.

18. The substituted methamphetamine of claim 12, wherein R is O(CH₂)_xNR₃(CH₂)_yCOOH, x is 2 to 3 and y is 1 to 5,.

19. The substituted methamphetamine of claim 12, wherein R is S(CH₂)_xCOOH, and x is 2 to 9.

20. The substituted methamphetamine of claim 12, wherein R is SCH₂CH═

CH(CH₂)_xCOOH, and x is 1 to 6.

21. The substituted methamphetamine of claim 12, wherein R is SCH₂C≡

C(CH₂)_xCOOH, and x is from 1 to 6.

22. The substituted methamphetamine of claim 12, wherein R is S(CH₂)_xO(CH₂)_yCOOH, and x is 2 to 4, y is 1 to 5.

23. The substituted methamphetamine of claim 12, wherein R is S(CH₂)_xNR₃(CH₂)_yCOOH, x is 2 to 3 and y is from 1 to 5.

24. The substituted methamphetamine of claim 12, wherein R is (CH₂)_xCOOH, and x is 3 to 8.

25. The substituted methamphetamine of claim 12, wherein R is (CH₂)_xCH═

CHCOOH, and x is 2 to 7.

26. The substituted methamphetamine of claim 12, wherein R is (CH₂)_xC═

CCOOH, and x is from 2 to 7.

27. The substituted methamphetamine of claim 12, wherein R is CH═

CH(CH₂)_xCOOH, and x is from 1 to 6.

28. The substituted methamphetamine of claim 12, wherein R is C≡

C(CH₂)_xCOOH, and x is from 1 to 6.

29. A method of generating a class-specific monoclonal antibody that recognizes methamphetamine-like stimulants, comprising the step of:

immunizing animals with the substituted methamphetamine of claim 12;

generating antibody-secreting hybridomas from the spleen cells of said animals; and

screening the specificity of the antibodies, wherein antibody showing cross-reactivity to methamphetamine-like stimulants indicates the generation of methamphetamine-like stimulants-specific antibody.

30. A method of generating a class-specific monoclonal antibody that recognizes methamphetamine-like stimulants, comprising the step of:

immunizing animals with the substituted methamphetamine of claim 14;

generating antibody-secreting hybridomas from the spleen cells of said animals; and

screening the specificity of the antibodies, wherein antibody showing cross-reactivity to methamphetamine-like stimulants indicates the generation of methamphetamine-like stimulants-specific antibody.

16-1. The substituted methamphetamine of claim 12, wherein R is OCH₂C≡

C(CH₂)_xCOOH, and x is 1 to 6.