Transcutaneous immunization without heterologous adjuvant

a technology of immunization and immunization site, which is applied in the direction of antibacterial agents, antibody medical ingredients, immunological disorders, etc., can solve the problems of similar redness and swelling, undesirable reaction, and secretion of intestinal fluid, so as to enhance immune response, promote skin hydration, and increase local concentration

Inactive Publication Date: 2006-01-05
ARMY GOVERNMENT OF THE UNITED STATES AS REPRESENTED BY THE SEC OF THE OFFICE OF THE COMMAND JUDGE ADVOCATE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0033] The invention may be practiced without perforation of the intact skin. But the invention may also include applying the formulation to skin with physical energy, electrical energy, sonic energy, or combinations thereof used to perforate the stratum corneum to reach the outer layer of the epidermis. Optionally, the formulation may include chemical penetration enhancers, viral particles, whole or intact cells, liposomes, proteosomes, chemical transfectants, materials to promote skin hydration, or combinations thereof. Hydrating the skin at the application site, increasing the local concentration, or recruiting antigen presenting cells to the application site may enhance the immune response.
[0034] A preferred embodiment of the formulation is to provide a single or unit dose for administration. Thist may simplify adm...

Problems solved by technology

These homologous proteins cause intestinal fluid secretion and massive diarrhea (Spangler, 1992), and are viewed as dangerous toxins.
Thus, one could have reasonably expected that CT would be extremely reactogenic when placed on the skin or inserted through the stratum corneum, and would cause similar redness and swelling.
Craig (1965) cautioned, “The absence of skin lesions in clinical cholera certainly does not preclude the possibility that the noxa responsible for gut damage could also have a deleterious effect upon the skin provided it is applied to skin in sufficient concentration.” The extreme reactogenicity of cholera toxin in the skin was used as a test for its toxicity and such prior art evidenced an expectation that cholera toxin would be reactogenic if applied to the skin, producing an undesirable reaction.
This lack of reactogenicity when cholera toxin w...

Method used

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  • Transcutaneous immunization without heterologous adjuvant
  • Transcutaneous immunization without heterologous adjuvant
  • Transcutaneous immunization without heterologous adjuvant

Examples

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example 1

[0186] BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized using 100 μl of immunization solution, which was comprised of liposomes prepared as described above by mixing with saline. The pre-formed liposomes were then diluted in either saline (“Liposomes” only group) or with CT in saline to yield an immunizing solution containing liposomes at 10 mM to 150 mM phospholipid with 100 μg CT per 100 μl of immunizing solution. CT was mixed in saline to make an immunizing solution containing 100 μg CT per 100 μg of solution for the group receiving CT alone. Solutions were vortexed for 10 seconds prior to immunization.

[0187] The mice were immunized transcutaneously at 0 and 3 weeks. Antibody levels were determined as described above for “ELISA IgG(H+L)” on serum collected three weeks after the boosting immunization, and compared against pre-immune sera. As shown in Table 1, the level of anti-CT antibodies induced b...

example 2

[0188] BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized at 0 and 3 weeks using 100 μl of immunization solution prepared as follows: BSA was mixed in saline to make an immunizing solution containing 200 μg BSA per 100 μl of saline for the group receiving BSA alone; BSA and CT were mixed in saline to make an immunizing solution containing 200 μg BSA and 100 μg CT per 100 μl of saline for the group receiving BSA and CT. Where liposomes were used, the liposomes were prepared as described above, and were first mixed with saline to form liposomes. They were then diluted in BSA or BSA and CT in saline to yield an immunizing solution containing liposomes at 50 mM phospholipid with 200 μg BSA per 100 μl of immunizing solution, or 200 μg BSA+100 μg CT per 100 μl of immunizing solution. Solutions were vortexed for 10 seconds prior to immunization.

[0189] The antibodies were determined using “ELISA IgG(H+L)” as des...

example 3

[0190] BALB / c mice at 6 to 8 weeks of age were immunized transcutaneously as described above in groups of five mice. Mice were immunized at 0 and 3 weeks using 100 μl of immunization solution prepared as follows: LT was mixed in saline to make an immunizing solution containing 100 μg of LT per 100 μl of saline for the group receiving LT alone. Where liposomes were used, they were prepared as described above and first mixed with saline to form the liposomes. The pre-formed liposomes were then diluted in LT in saline to yield an immunizing solution containing liposomes at 50 mM phospholipid with 100 μg of LT per 100 μl of immunizing solution. Solutions were vortexed for 10 seconds prior to immunization.

[0191] The anti-LT antibodies were determined using ELISA as described above three weeks after the second immunization. The results are shown in Table 3. LT was clearly immunogenic both with and without liposomes, and no significant difference between the groups could be detected. LT a...

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Abstract

Transcutaneous immunization can deliver antigen to the immune system through the stratum corneum without physical or chemical penetration to the dermis layer of the skin. This delivery system induces an antigen-specific immune response without the use of a heterologous adjuvant. Although perforation of intact skin is not required, superficial penetration or micropenetration of the skin can act as an enhancer; similarly, hydration may enhance the immune response. This system can induce antigen-specific immune effectors after epicutaneous application of a formulation containing one or more antigens. The formulation may initiate processes such as antigen uptake, processing, and presentation; Langerhans cell activation, migration from the skin to other immune organs, and differentiation to mature dendritic cells; contacting antigen with lymphocytes bearing cognate antigen receptors on the cell surface and their stimulation; and combinations thereof. Systemic and/or regional immunity may be induced. Immune responses that provide prophylactic and/or therapeutic treatments are preferred. Antigenic activities in the formulation may be found in the same molecule, two or more different molecules dissociated from each other, or multiple molecules in a complex formed by covalent or non-covalent bonds. For antigens which are proteinaceous, they may be provided in the formulation as a polynucleotide for transcutaneous genetic immunization. Besides simple application of a dry or liquid formulation to the skin, patches and other medical devices may be used to deliver antigen for immunization.

Description

DESCRIPTION OF RELATED APPLICATIONS [0001] This application is a continuation in-part of U.S. appln. Ser. No. 08 / 896,085 (filed Jul. 17, 1997 and pending); U.S. application Ser. No. 09 / 157,395 (filed Sep. 21, 1998 and pending) which is a divisional of U.S. application Ser. No. 08 / 749,164 (filed Nov. 14, 1996, now U.S. Pat. No. 5,910,306); U.S. application Ser. No. 09 / 257,188 (filed Feb. 25, 1999 and pending); U.S. application Ser. No. 09 / 309,881 (filed May 11, 1999 and pending); and U.S. application Ser. No. 09 / 311,720 (filed May 14, 1999 and pending) which is a continuation in-part of PCT / US97 / 21324 (filed Nov. 14, 1997 designating the U.S., now abandoned). [0002] This application also claims priority benefit from provisional U.S. Appln. No. 60 / 090,169 (filed Jun. 22, 1998) and U.S. Appln. No. 60 / 128,370 (filed Apr. 8, 1999).[0003] All patent applications cited herein, as well as patents issued therefrom, are incorporated by reference in their entirety. BACKGROUND OF THE INVENTION ...

Claims

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Application Information

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IPC IPC(8): A61K39/00
CPCA61K39/0258C12N2760/20134A61K39/099A61K39/102A61K39/104A61K39/107A61K39/116A61K2039/54A61K2039/55555A61K39/008A61K39/015A61K39/05A61K39/12A61K2039/5252A61K2039/53A61K2039/545A61K2039/55505A61K2039/55522A61K2039/55533A61K2039/55544A61K2039/55561A61K2039/70C12N2740/16234C12N2760/16134C12N2760/16234A61K39/08A61P31/04A61P31/10A61P31/16A61P33/00A61P37/04Y02A50/30
Inventor GLENN, GREGORYALVING, CARL
Owner ARMY GOVERNMENT OF THE UNITED STATES AS REPRESENTED BY THE SEC OF THE OFFICE OF THE COMMAND JUDGE ADVOCATE
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