Avidin dimers effective in increasing the concentration of radioactive biotin in pretargeted radioimmunotherapy

• US 7,807,133 B2
• Filed: 07/03/2008
• Issued: 10/05/2010
• Est. Priority Date: 03/08/2002
• Status: Expired due to Fees

• Current Assignee: Sigma-Tau Industrie Farmaceutiche Riunite SPA (Alfasigma S.p.A.)
• Original Assignee: Sigma-Tau Industrie Farmaceutiche Riunite SPA (Alfasigma S.p.A.)
• Inventors: Carlo Antonio, Nuzzolo, Ragnar, Lindstedt, Rita, De Santis
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US12/216,449
• Publication Number:
  US 20090010839A1
• Time in Patent Office: 824 Days
• Field of Search: 424/1.11, 424/1.49, 424/1.65, 424/1.73, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 424/78.01, 424/130, 424/1, 424/133.1, 424/134.1, 424/135.1, 424/136.1, 424/138.1, 424/141.1, 424/142.1, 424/143.1, 424/152.1, 424/155.1, 424/178.1, 536/1.11, 206/223, 206/569, 206/570
• US Class Current: 424/1.49
• CPC Class Codes: A61K 47/665 the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
• CPC Class Codes: A61K 47/6898 using avidin- or biotin-conjugated antibodies
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/30 from tumour cells

Abstract

Dimers of avidin and streptavidins (diavidins) are described wherein the linker is suberate, which in turn, is bound to different functional groups (—NH2 o-COOH) of avidin. As compared to avidin, the diavidins have shown the ability to increase the amount of labelled biotin on the target, when used in an in vitro pretargeting test using supported human tenascin, the biotinylated anti-tenascin monoclonal antibody (Mab-B), avidin/diavidin, and biotin-3H. The use of such diavidins is also described in cancer diagnosis and anticancer therapy based on the three-step pretargeted radioimmunotherapy procedure.

Claims

1. An avidin dimer, in which two molecules of avidin are bound via the —

NH₂ groups by crosslinking with disuccinimidyl suberate.

3. The avidin dimer of claim 1, wherein the avidin is streptavidin.

5. A pharmaceutical or diagnostic composition containing the avidin dimer of claim 1.

7. A method of manufacturing a pharmaceutical or diagnostic composition, the method comprising mixing the avidin dimer of claim 1 with a vehicle or excipient to prepare a pharmaceutical or diagnostic composition.

9. A kit for radiotherapy or diagnosis of tumours, the kit comprising a biotinylated antibody and the avidin dimer of claim 1.

10. The kit of claim 9 further comprising a biotinylated radiopharmaceutical.

11. The kit of claim 9, wherein the avidin is streptavidin.

15. A method of diagnosing or treating tumors in a subject with the avidin dimer of claim 1, the method comprising:

(a) administering a biotinylated antibody to the subject; and

(b) administering an effective amount of the avidin dimer to the subject.

17. A method of tumor diagnosis or therapy in a subject with the avidin dimer of claim 1, the method comprising:

(a) administering a biotinylated antibody specific for the tumors to the subject; and

(b) administering an effective amount of the avidin dimer to the subject.

19. A method pretargeting a biotinylated antibody with the avidin dimer of claim 1, the method comprising:

(a) binding the biotinylated antibody to antigen in vitro,

(b) binding avidin dimmers to the bound antibody in vitro, and

(c) binding radioactive biotin to the avidin dimers in vitro.

21. A method of treating tumors in a subject with the avidin dimer of claim 1, the method comprising:

(a) administering a biotinylated antibody to the subject,

(b) administering an effective amount of the avidin dimer to the subject, and

(c) administering radioactive biotin to the subject.

22. The method according to claim 21, wherein said antibody is an anti-tenascin antibody.

23. The method according to claim 22, wherein said anti-tenascin antibody is an anti-tenascin monoclonal antibody.

27. A pharmaceutical or diagnostic composition containing the streptavidin dimer of claim 3.

29. A method of manufacturing a pharmaceutical or diagnostic composition, the method comprising mixing the streptavidin dimer of claim 3 with a vehicle or excipient to prepare a pharmaceutical or diagnostic composition.

31. The method according to claim 21, wherein the avidin is streptavidin.

2. An avidin dimer, in which two molecules of avidin are bound via the —

COOH groups by crosslinking with polyethylene glycol diamine with a molecular weight of 3400.

4. The avidin dimer of claim 2, wherein the avidin is streptavidin.

6. A pharmaceutical or diagnostic composition containing the avidin dimer of claim 2.

8. A method of manufacturing a pharmaceutical or diagnostic composition, the method comprising mixing the avidin dimer of claim 2 with a vehicle or excipient to prepare a pharmaceutical or diagnostic composition.

12. A kit for radiotherapy or diagnosis of tumours, the kit comprising a biotinylated antibody and the avidin dimer of claim 2.

13. The kit of claim 12 further comprising a radiolabeled biotin.

14. The kit of claim 12, wherein the avidin is streptavidin.

16. A method of diagnosing or treating tumors in a subject with the avidin dimer of claim 2, the method comprising:

(a) administering a biotinylated antibody to the subject; and

(b) administering an effective amount of the avidin dimer to the subject.

18. A method of tumor diagnosis or therapy in a subject with the avidin dimer of claim 2, the method comprising:

(a) administering a biotinylated antibody specific for the tumors to the subject; and

(b) administering an effective amount of the avidin dimer to the subject.

20. A method pretargeting a biotinylated antibody with the avidin dimer of claim 2, the method comprising:

(a) binding the biotinylated antibody to antigen in vitro,

(b) binding avidin dimmers to the bound antibody in vitro, and

(c) binding radioactive biotin to the avidin dimers in vitro.

24. A method of treating tumors in a subject with the avidin dimer of claim 2, the method comprising:

(a) administering a biotinylated antibody to the subject,

(b) administering an effective amount of the avidin dimer to the subject, and

(c) administering radioactive biotin to the subject.

25. The method according to claim 24, wherein said antibody is an anti-tenascin antibody.

26. The method according to claim 25, wherein said anti-tenascin antibody is an anti-tenascin monoclonal antibody.

28. A pharmaceutical or diagnostic composition containing the streptavidin dimer of claim 4.

30. A method of manufacturing a pharmaceutical or diagnostic composition, the method comprising mixing the streptavidin dimer of claim 4 with a vehicle or excipient to prepare a pharmaceutical or diagnostic composition.

32. The method according to claim 24, wherein the avidin is streptavidin.