Methods to trigger, maintain and manipulate immune responses by targeted administration of biological response modifiers into lymphoid organs

• US 20060153844A1
• Filed: 12/29/2005
• Published: 07/13/2006
• Est. Priority Date: 12/29/2004
• Status: Abandoned Application

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Bot, Adrian Ion, Kundig, Thomas
• Application Number:
  US11/321,967
• Publication Number:
  US 20060153844A1
• Time in Patent Office: Days
• US Class Current: 424/144.100
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/035 Animal model for multifactorial diseases
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/555 characterised by a specific combination antigen/adjuvant
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/55583 Polysaccharides
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants

Abstract

The present invention includes use of a biological response modifier (BRM) to modulate an immune response in a subject while avoiding or limiting common side-effects associate with BRM use. The BRMs of the present invention can be injected into a secondary lymphatic organ of the subject or into an area of relatively high drainage into a secondary lymphatic organ of the subject. The modulated immune response can be general or antigen-specific.

Claims

1. A method of improving the therapeutic index of a BRM, the method comprising the step of:

administering a BRM to a secondary lymphoid organ of a subject in a lymphatically effective dose wherein the lymphatically effective dose avoids or reduces a BRM-related adverse clinical event as compared to use of a non-lymphatically effective dose of the BRM.

2. The method of claim 1 wherein the modulated immune response is antigen-specific.

3. The method of claim 1 wherein little or no BRM-related adverse clinical event results.

4. The method of claim 1 wherein a lymphatically effective dose is at least 10-fold less than the non-lymphatically effective dose.

5. The method of claim 2 comprising co-administration of the antigen with the BRM.

6. The method of claim 2 comprising administering the antigen proximal in time to the BRM

7. The method of claim 1 comprising administration to an identified area of relatively high lymphatic drainage.

8. The method of claim 2 comprising administering the antigen to an identified area of high lymphatic drainage that drains to the secondary lymphoid organ of the subject.

9. The method of claim 2 wherein the antigen is endogenously present in the secondary lymphoid organ of the subject.

10. The method of claim 1 comprising administration directly to a lymph node or lymph vessel.

11. The method of claim 2 wherein the modulated immune response comprises an increased response to the antigen.

12. The method of claim 2 wherein the modulated immune response comprises a decreased response to the antigen.

13. The method of claim 2 wherein the modulated immune response comprises a shift toward a humoral response to the antigen.

14. The method of claim 1 wherein the modulated immune response comprises a shift in relative proportions of individual antibody isotypes.

15. The method of claim 2 wherein the modulated immune response comprises a shift toward a cellular response to the antigen.

16. The method of claim 1 wherein the modulated immune response comprises a shift toward a T1 response.

17. The method of claim 1 wherein the modulated immune response comprises a shift toward a T2.

18. The method of claim 15 wherein the modulated immune response comprises a shift toward a CTL response to the antigen.

19. The method of claim 15 wherein the modulated immune response comprises a shift toward a T helper cell response to the antigen.

20. The method of claim 15 wherein the modulated immune response comprises a shift toward a T regulatory cell response to the antigen.

21. The method of claim 1 wherein the BRM comprises a cytokine or chemokine.

22. The method of claim 1 wherein the BRM comprises a toll-like receptor ligand.

23. The method of claim 22 wherein the BRM comprises ds RNA.

24. The method of claim 22 wherein the BRM comprises a DNA comprising a CpG sequence.

25. The method of claim 24 wherein the DNA comprises an oligonucleotide.

26. The method of claim 24 wherein the DNA comprises a plasmid.

27. The method of claim 22 wherein the toll-like receptor ligand is selected from the group consisting of peptidoglycan, LPS, LPS analogues, flagellin, lipoteichoic acid, an imidazoqionoline, imiquimode, resiquimod, microbial nucleic acids, CpG-containing oligonucleotides, double-stranded RNA, and polyI:

C.

28. The method of claim 1 wherein the BRM comprises a small molecule, antibody, or engineered soluble ligand that acts as an agonist or an antagonist specific for a target selected from the group consisting of cellular receptors, co-stimulatory receptors, cytokine receptors, chemokine receptors, signal transduction elements, and transcriptional regulators.

29. The method of claim 2 wherein the antigen comprises a tumor-associated antigen.

30. The method of claim 2 wherein the antigen comprises a microbial antigen.

31. The method of claim 30 wherein the microbial antigen is associated with a protist, fungi, bacterium, virus, or prion.

32. The method of claim 2 wherein the antigen comprises an allergen, a toxin, or toxoid.

33. The method of claim 2 wherein the antigen comprises a disease-matched antigen.

34. A method of modulating an antigen-specific immune response, the method comprising the step of:

administering a BRM to a secondary lymphoid organ of a subject in a dose sufficient to obtain a modulated immune response.

35. A method of modulating an immune response to an antigen comprising the step of:

co-administering a BRM and said antigen to a secondary lymphatic organ whereby the antigen-specific immune response is modulated, wherein the modulation does not consist essentially of an augmented CTL response.

36. A composition comprising a lymphatically effective dose of a BRM, wherein said lymphatically effective dose comprises an amount of a BRM that is relatively nontoxic and wherein said lymphatically effective dose is less than a non-lyphatically effective dose.

37. A composition comprising a lymphatically effective dose of a BRM, wherein said lymphatically effective dose comprises an amount of a BRM that is relatively non-toxic and wherein the amount of the BRM is insufficient to be a non-lyphatically effective dose.

38. A composition comprising a lymphatically effective dose of a BRM and an antigen, wherein said lymphatically effective dose comprises an amount of a said lymphatically effective dose comprises an amount of a BRM that is relatively non-toxic and wherein the amount of the BRM is insufficient to be a non-lyphatically effective dose.

39. A composition comprising a lymphatically effective dose of a BRM wherein said lymphatically effective dose of a BRM is at least ten-fold less than the corresponding non-lyphatically effective dose.