Methods and compositions for enhancing the immunostimulatory effect of interleukin-12

• US 6,375,944 B1
• Filed: 09/13/1999
• Issued: 04/23/2002
• Est. Priority Date: 09/25/1998
• Status: Expired due to Term

• Current Assignee: The Wistar Institute, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: The Wistar Institute, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Lee, William M. F., Koblish, Holly, Trinchieri, Giorgio
• Primary Examiner(s): Mertz, Prema
• Assistant Examiner(s): Prasad, Sarada C
• Application Number:
  US09/395,038
• Time in Patent Office: 953 Days
• Field of Search: 424/201.1, 424/203.1, 424/234.1, 424/85.2, 530/350
• US Class Current: 424/85.2
• CPC Class Codes: A61K 2039/55511 Organic adjuvants
• CPC Class Codes: A61K 2039/55538 IL-12
• 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 38/208 IL-12
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• 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

Methods for enhancing the therapeutic and adjuvant use of IL-12 by reducing unwanted transient immunosuppression caused by IL-12 or by high doses thereof involve co-administering IL-12 with an effective amount of an agent that inhibits or neutralizes nitric oxide (NO) in vivo. Enhanced vaccine therapy involves co-administering the IL-12 adjuvant, a selected vaccine antigen and the NO inhibiting/neutralizing agent. Additionally, the toxicity of IL-12 treatment may be reduced by co-administering IL-12 with an effective amount of the NO inhibiting or neutralizing agent. A therapeutic composition characterized by reduced toxicity in mammals contains IL-12, preferably a low dose thereof, and an NO inhibiting or neutralizing agent in a pharmaceutically acceptable carrier. A vaccine composition contains an effective adjuvanting amount of IL-12, an effective amount of an NO inhibiting or neutralizing agent, and an effective protective amount of a vaccine antigen in a pharmaceutically acceptable carrier.

Claims

1. A method for enhancing the adjuvant effect of IL-12 comprising:

co-administering to a mammalian patient said IL-12, a vaccine antigen, and an effective amount of at least one agent selected from the group consisting of a nitric oxide inhibiting agent and a nitric oxide neutralizing agent.

2. The method according to claim 1 wherein said agent is an agent that inhibits or reduces the synthesis of nitric oxide in vivo.

3. The method according to claim 1 wherein said agent is an agent that breaks down, absorbs, metabolizes or eliminates nitric oxide in vivo.

4. The method according to claim 1 wherein said co-administration comprises simultaneously administering said agent with said IL-12 and said antigen.

5. The method according to claim 1 wherein said co-administration comprises sequentially administering said agent, said IL-12 and said antigen, in any order.

6. The method according to claim 3 wherein said co-administration comprises administering said IL-12 before said agent.

7. The method according to claim 2 wherein said agent inhibiting nitric oxide generation is an inhibitor of nitric oxide synthase.

8. The method according to claim 7 wherein said agent is specific for inducible nitric oxide synthase.

9. The method according to claim 2 wherein said agent is selected from the group consisting of L-N^G monomethyl arginine (L-NMMA), L-N^G nitroarginine (L-NORAG), L-N^G nitroarginine methylester (L-NAME), L-N^G nitroarginine p-nitroanilide (L-NAPNA), L-N^G aminoarginine (L-NAA), L-N^G cyclopropylarginine, L-N^G allylarginine, asymmetric L-N^GN^G dimethylarginine (L-ADMA), L-N^ω

iminoethyl ornithine (L-NIO), 7-nitro indazole (7-NI), 2,7 dinitro indazole, 3-bromo 7-nitro indazole, aminoguanidine, N,N′

-diaminoguanidine, dimethylguanidine, diphenyleneiodonium, iodoniumdiphenyl, di-2-thienyliodonium, chlorpromazine, trifluoperazine, pimozide, clozapine, calmidazolium, 2,4 diamino-6-hydroxypyrimidine, methotrexate, N-acetyl-5-hydroxytryptamine, miconazole, ketoconazole, clotrimazole, imidazole, 1-, 2- and 4-phenylimidazole, methylene blue, NO, carbon monoxide, ebselen, phencyclidine, and antineoplastic agents (doxorubicin, aclarubicin).

10. The method according to claim 9 wherein said agent is L-NAME.

11. The method according to claim 9 wherein said agent is L-NMMA.

12. The method according to claim 3 wherein said agent is a nitric oxide scavenger.

13. The method according to claim 12 wherein said scavenger is selected from the group consisting of N-acetyl cysteine, pyrrolidine dithiocarbamate, and hemoglobin.

14. The method according to claim 1 wherein said vaccine antigen is a mammalian tumor cell antigen.

15. The method according to claim 1 wherein said vaccine antigen is a pathogenic antigen selected from the group consisting of bacterial antigens, viral antigens, and parasitic antigens.

16. An adjuvant composition comprising an effective adjuvanting amount of IL-12 and an effective amount of at least one agent selected from the group consisting of a nitric oxide inhibiting agent and a nitric oxide neutralizing agent, in a pharmaceutically acceptable carrier.

17. A vaccine composition comprising an effective adjuvanting amount of IL-12, an effective amount of at least one agent selected from the group consisting of a nitric oxide inhibiting agent and a nitric oxide neutralizing agent, and an effective protective amount of a vaccine antigen in a pharmaceutically acceptable carrier.

18. A method of preparing an adjuvant composition comprising combining in a pharmaceutically acceptable carrier an effective amount of a vaccine antigen, and an effective adjuvanting amount of IL-12 and an effective amount of at least one agent selected from the group consisting of a nitric oxide inhibiting agent and a nitric oxide neutralizing agent.