Methods and compositions for enhancing innate immunity and antibody dependent cellular cytotoxicity

• US 20050191342A1
• Filed: 10/12/2004
• Published: 09/01/2005
• Est. Priority Date: 10/11/2003
• Status: Abandoned Application

• Current Assignee: Tekmira Pharmaceuticals Corporation
• Original Assignee: Inex Pharmaceuticals Corporation
• Inventors: Brodsky, Irina, Raney, Sameersingh G., Sekirov, Laura, Tam, Ying K., Chikh, Ghania
• Application Number:
  US10/963,999
• Publication Number:
  US 20050191342A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3084 against tumour-associated gangliosides
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]

Abstract

Cationic liposomes with immunostimulatory nucleic acids are shown to stimulate the innate immune response, and synergistic combinations of such liposomal nucleic acids and therapeutic antibodies are provided to dramatically improve antibody dependent cellular cytotoxicity and target cell lysis.

Claims

1. A composition for stimulating an enhanced antibody dependent cellular cytotoxicity response in a subject, comprising a therapeutic antibody in combination with a cationic liposome comprising an immunostimulatory nucleic acid.

2. The composition according to claim 1, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one CpG dinucleotide.

3. The composition according to claim 2, wherein the cytosine in said CpG dinculeotide is methylated.

4. The composition according to claim 1, wherein said immunostimulatory nucleic acid comprises the nucleic acid sequence 5′

TAAZGTTGAGGGGCAT 3′

(ODN1m) (SEQ ID NO;

4).

5. The composition according to claim 1, wherein said immunostimulatory nucleic acid comprises the nucleic acid sequence 5′

TCCATGAZGTTCCTGAZGTT 3′

(ODN2m) SEQ ID NO;

32).

6. The composition according to claim 1, wherein said cationic liposome fully encapsulates said nucleic acid.

7. The composition according to claim 1, wherein said therapeutic antibody is an anti-CD20 monoclonal antibody.

8. The composition according to claim 7, wherein said anti-CD20 monoclonal antibody is Rituxan™

.

9. The composition according to claim 1, wherein said therapeutic antibody is an anti-Her2/neu antibody.

10. The composition according to claim 9, wherein said anti-Her2/neu antibody is Herceptin™

.

11. A mammalian NK cell activated ex vivo or in vivo by a cationic liposome comprising an immunostimulatory nucleic acid, wherein said activated NK cell is bound to the Fc portion of a therapeutic antibody directed to a tumor-associated antigen.

12. The composition according to claim 11, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

13. An improved method of inducing antibody dependent cellular cytotoxicity against a target cell in a mammalian subject, said method comprising:

a) activating the subject'"'"'s NK cells ex vivo or in vivo with a cationic liposome comprising an immunostimulatory nucleic acid; and

b) opsonizing said target cell in vivo with a therapeutic antibody directed against a target cell antigen;

wherein said activated NK cells bind to the Fc portion of said therapeutic antibody in vivo.

14. The method according to claim 13, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

15. The method according to claim 13, wherein said target cell is a tumor cell and said target cell antigen is a tumor-associated antigen.

16. A method of lysing tumor cells, comprising administering to a patient having said tumor cells a therapeutic antibody and a cationic liposome comprising an immunostimulatory nucleic acid, wherein said therapeutic antibody is directed to an antigen associated with said tumor cell and said cationic liposome mobilizes and activates patient NK cells in vivo for effectuating antibody dependent cellular cytotoxicity.

17. The method according to claim 16, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

18. The method according to claim 16, wherein said cationic liposome is administered prior to said therapeutic antibody.

19. An improved method of treating a cancer patient with monoclonal antibodies directed to tumor-associated antigens, the improvement comprising pre-treating said patient with a cationic liposome comprising an immunostimulatory nucleic acid, wherein said pretreatment results in the mobilization and activation of patient NK cells for effectuating antibody dependent cellular cytotoxicity.

20. The method according to claim 19, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

21. The method according to claim 19, wherein said cancer is lymphoma and said monoclonal antibody is rituximab.

22. The method according to claim 19, wherein said cancer is breast cancer and said therapeutic antibody is trastuzumab.

23. Means for lysing a target cell in a mammalian subject, comprising:

a) means for activating the subject'"'"'s NK cells; and

b) means for opsonizing said target cell;

wherein said activated NK cells bind to the opsonized cell in vivo.

24. Means according to claim 23, wherein said means for activating comprises an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

25. Means according to claim 23, wherein said means for opsonizing comprises an antibody directed to a surface membrane antigen on said target cell

26. Means according to claim 23, wherein said target cell is a tumor cell and said means for opsonizing binds to a tumor-associated antigen.

27. A kit suitable for lysing a target cell in a mammalian patient, comprising a therapeutic antibody directed to a target cell antigen and a cationic liposome comprising an immunostimulatory nucleic acid.

28. The kit according to claim 27, wherein said therapeutic antibody and said cationic liposome are provided in separate vials.

29. The kit according to claim 27, wherein said immunostimulatory nucleic acid is an oligodeoxynucleotide (ODN) having at least one methylated CpG dinucleotide.

30. The kit according to claim 27, wherein said target cell is a tumor cell and said target cell antigen is a tumor-associated antigen.