Method of inducing a CTL response

• US 6,994,851 B1
• Filed: 07/10/1998
• Issued: 02/07/2006
• Est. Priority Date: 07/10/1997
• Status: Expired due to Fees

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Kundig, Thomas M., Simard, John L.
• Primary Examiner(s): Chan, Christina
• Assistant Examiner(s): HUYNH, PHUONG N
• Application Number:
  US09/380,534
• Time in Patent Office: 2,769 Days
• Field of Search: 604/500, 604/502, 604/506, 604/507, 604/508, 604/511, 604/522, 604/93.01, 604/131, 6048901-8921, 128/898, 424/184.1, 424/185.1, 424/186.1, 424/192.1, 424/204.1, 424/93.7, 424/190.1, 424/199.1, 424/200.1, 424/534, 435/5, 435/6, 435/320, 435/7.23, 435/7.24, 435/7.92, 435/236, 435/252, 435/325, 514/44, 530/300, 530/350, 530/351, 536/23.5
• US Class Current: 424/93.7
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2039/572 cytotoxic response
• 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 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4615 Dendritic cells
• CPC Class Codes: A61K 39/4622 Antigen presenting cells
• CPC Class Codes: A61K 39/4632 T-cell receptors [TCR]; antibody T-cell receptor constructs
• CPC Class Codes: A61K 39/464838 Viral antigens
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2710/16034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/10022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2760/10034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

A method of inducing a cytotoxic T-lymphocyte (CTL) response to an antigen is disclosed. The method involves delivering the antigen to the lymphatic system of an animal regularly over a sustained period of time using, e.g., an osmotic pump. The method is advantageous over prior art methods for inducing a CTL response in that it does not require repetitive immunizations or the use of adjuvants. The method of the present invention can be used for the induction of CTLs in tumor or infectious disease immunotherapy.

Claims

1. A method of obtaining a sustained CTL response in a mammal, which method comprises:

delivering an antigen directly to a lymph node or a lymph vessel of the mammal at a level sufficient to induce an antigen-specific CTL response in the mammal; and

maintaining the antigen in the mammal'"'"'s lymphatic system over time sufficient to sustain the antigen-specific CTL response.

2. The method of claim 1, wherein the antigen is provided in the form of a polypeptide.

3. The method of claim 1, wherein the antigen is provided as a component of a microorganism.

4. The method of claim 1, wherein the antigen is provided in the form of a nucleic acid encoding the antigen.

5. The method of claim 4, wherein the nucleic acid encoding the antigen comprises a plasmid, a vector, or a recombinant viral vector.

6. The method of claim 1, wherein the antigen is maintained by sustained, delivery of the antigen.

7. The method of claim in 1, wherein the antigen is a diseased matched antigen.

8. A method of obtaining a sustained effector CTL response in a mammal, which method comprises:

selecting an antigen suitable for a sustained CTL response in the mammal;

delivering the antigen to a lymphatic system of the mammal on a sustained basis over a period time at a level sufficient to induce and sustain a sustained antigen-specific effector CTL response in the mammal.

9. The method of claim 8, further comprising detecting the sustained antigen-specific effector CTL response in the mammal, wherein the detecting comprises an assay selected from the group consisting of a cytokine assay, a chromium release assay, an antiviral protection assay, virus titer, an immunofluorescence assay, a tumor growth inhibition assay, tumor size reduction, a CTL a say, inhibition of tumor metastasis, increase in life expectancy, infectious disease recovery, inflammatory reaction assay, and observation of the health of the mammal.

10. The method of claim 8, wherein the delivery step further comprises delivering a cytokine, adjuvant, or potentiator.

11. A method of obtaining a sustained CTL response in a mammal, which method comprises:

selecting an antigen that is capable of inducing CTL in a mammal;

delivering the antigen to the mammal at a level sufficient to induce an antigen-specific CTL response in the mammal, wherein the antigen is delivered to an area of high lymphatic drainage in the mammal; and

maintaining the antigen in the mammal'"'"'s lymphatic system sufficient to sustain the antigen-specific CTL response for a period of time that is substantially co-extensive with the desired duration of the CTL response.

12. A method of a sustained effector CTL response in a mammal, which method comprises:

delivering an antigen to a lymphatic system of the mammal on a sustained basis over a period time at a level sufficient to induce a sustained antigen-specific effector CTL response in the mammal; and

detecting the sustained effector CTL response in the mammal.

13. The method of claim 12, wherein the detection step comprises an assay selected from the group consisting of a cytokine assay, a chromium release assay, an antiviral protection assay, viral titer, an immunofluorescence assay, a tumor growth inhibition assay, tumor size reduction, a CTL assay, inhibition of tumor metastasis, increase in life expectancy, infectious disease recovery, inflammatory reaction assay, and observation of the health of the mammal.

14. The method of claim 12, wherein the antigen is a patient-matched antigen.

15. The method of claim 12, wherein delivering the antigen to the lymphatic system of the mammal on a sustained basis over a period of time comprises repeated exposure of the antigen to the mammal'"'"'s lymphatic system.

16. A method of obtaining effector CTL response in a mammal, which method comprises:

delivering an antigen in an acellular composition directly to an area of high lymphatic drainage in the mammal on a sustained basis over a period time at a level sufficient to induce a sustained effector antigen-specific CTL response in the mammal.

17. The method of claim 16, wherein the antigen in the acellular composition is provided in the form of a nucleic acid encoding a polypeptide antigen.

18. The method of claim 16, wherein the antigen is derived as a bolus in a single dose, and wherein the single dose is sufficient to maintain the antigen in the mammal'"'"'s lymphatic system over time sufficient to sustain the CTL response.

19. The method of claim 16, wherein the sustained CTL response is detectable by a CTL assay.

20. The method of claim 16, further comprising selecting an antigen in an acellular composition for delivery that is suitable for a sustained CTL response.