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

• US 5,876,727 A
• Filed: 09/30/1996
• Issued: 03/02/1999
• Est. Priority Date: 03/31/1995
• Status: Expired due to Term

• Current Assignee: Xenova Ltd. (Celtic X Ltd.)
• Original Assignee: ImmuLogic Pharmaceutical Corp.
• Inventors: Gefter, Malcolm L., Fox, Barbara S., Greenstein, Julia L., Schad, Victoria C., Powers, Stephen P., Swain, Philip A., Exley, Mark A.
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Assistant Examiner(s): PONNALURI, PADMASHRI
• Application Number:
  US08/720,487
• Time in Patent Office: 883 Days
• Field of Search: 530/405, 530/409, 424/130.1, 424/175.1, 424/193.1, 424/194.1, 546/129, 546/130, 546/131, 546/132, 546/279.4, 514/343
• US Class Current: 424/193.1
• CPC Class Codes: A61K 2039/6037 Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
• CPC Class Codes: A61K 39/0013 Therapeutic immunisation against small organic molecules, e.g. cocaine, nicotine
• CPC Class Codes: A61K 47/6415 Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61K 47/646 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Hapten-carrier conjugates capable of eliciting anti-hapten antibodies in vivo are disclosed. Methods of preparing the hapten-carrier 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.

Claims

1. A nicotine hapten-carrier conjugate comprising the structure shown in FIG. 17b, wherein A, B, C, D, E and F are side chains of nicotine, which are independently selected from the group consisting of chemical moieties, said chemical moieties are identified by CJ reference number:

space="preserve" listing-type="tabular">______________________________________CJ 0 QCJ 1 (CH.sub.2).sub.n QCJ 1.1 CO.sub.2 QCJ 1.2 COQCJ 1.3 OCH.sub.3CJ 2 OCO(CH.sub.2).sub.n QCJ 2.1 OCOCH═

QCJ 2.2 OCOCH(O)CH.sub.2CJ 2.3 OCO(CH.sub.2).sub.n CH(O)CH.sub.2CJ 3 CO(CH.sub.2)nCOQCJ 3.1 CO(CH.sub.2).sub.n CNQCJ 4 OCO(CH.sub.2).sub.n COQCJ 4.1 OCO(CH.sub.2).sub.n CNQCJ 5 CH.sub.2 OCO(CH.sub.2).sub.n COQCJ 5.1 CH.sub.2 OCO(CH.sub.2).sub.n CNQCJ 6 CONH(CH.sub.2).sub.n QCJ 7 Y(CH.sub.2).sub.n QCJ 7.1 CH.sub.2 Y(CH.sub.2).sub.n QCJ 8 OCOCH(OH)CH.sub.2 QCJ 8.1 OCO(CH.sub.2).sub.n CH(OH)CH.sub.2 QCJ 9 OCOC.sub.6 H.sub.5CJ 10 See FIG. 2bCJ 11 YCO(CH.sub.2).sub.n COQ;

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wherein Y is sulfur (S), oxygen (O), or an amine (NH), wherein n is an integer from 3 to 20, and wherein Q is selected from the group consisting of;

H, OH, OCH3, CH2, CH3, COOH, halogens, activated esters, acyl halides, acyl azides, alkyl halides, N-maleimides, imino esters, isocyarlate, isothiocyanate, and a T cell epitope-containing carriers;

with the proviso that Q in at least one of A, B, C, D, E, or F comprises a carrier containing at least one T cell epitope said carrier selected from the group consisting of cholera toxin B (CTB), diphtheria toxin, tetanus toxoid, pertussis toxin, ricin B subunit, retrovirus nucleoprotein (retro NP), rabies ribonucleoprotein (Rabies RNP), Tobacco Mosaic Virus, and vesicular stomatitis vius nudeocapsid protein (VSV-N).

2. The nicotine hapten-carrier conjugate of claim 1 wherein at least two haptens are coupled to the carrier, and the haptens are the same.

3. The nicotine hapten-carrier conjugate of claim 1 wherein the carrier is multivalent.

4. The nicotine hapten-carrier conjugate of claim 1 wherein the T cell epitope-containing carrier comprises cholera toxin B (CTB).

8. A therapeutic composition comprising at least one conjugate of claim 1 and a pharmaceutically acceptable carrier.

9. The therapeutic composition of claim 8 further comprising an adjuvant.

10. The therapeutic composition of claim 9 wherein the adjuvant is alum, MF59 or RIBI adjuvant.

11. The therapeutic composition of claim 8 wherein the composition is soluble in an aqueous solution at a physiological acceptable pH.

12. A method of treating drug addiction to nicotine in manmmals comprising:

(a) administering a therapeutically effective amount of the therapeutic composition of claim 1 to a subject mammal; and

(b) monitoring the mammal for a desired therapeutic effect, wherein an increase of anti-drug antibodies is an indication of the desired therapeutic effect.

14. A method of treating drug addiction to nicotine in mammals comprising administering a therapeutically effective amount of the therapeutic composition of claim 8 to a mammal in need of treatment for drug addiction.

15. A method of treating drug addiction to nicotine in mammals comprising administering a therapeutically effective amount of a composition of claim 9 to a mammal in need of treatment for drug addiction.

16. The therapeutic composition of claim 8 wherein the composition is in suspension in an aqueous solution at a physiologically acceptable pH.

17. The method according to claim 12 wherein the administration is enteral or parenteral.

18. The method according to claim 17 wherein the administration is oral or intramuscular.

5. A nicotine hapten-carrier conjugate selected from the group consisting of PS-51, PS-52, PS-53, PS-54, PS-55 and PS-56 as depicted in FIG. 18.

6. The nicotine hapten-carrier conjugate of claim 5 wherein at least two haptens are coupled to the carrier, and the haptens are the same.

7. The nicotine hapten-carrier conjugate of claim 5 wherein the carrier is multivalent.

13. A method of treating drug addiction to nicotine in mammals comprising:

(a) administering a therapeutically effective amount of the therapeutic composition of claim 5 to a subject mammal; and

(b) monitoring the subject mammal for a desired therapeutic effect, wherein an increase of anti-drug antibodies is an indication of the desired therapeutic effect.