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Qs-21 and il-12 as an adjuvant combination

a technology of il-12 and qs-21, which is applied in the field of heterodimeric cytokine, can solve the problems of local acute toxicity and inability to completely regulate all type 2 responses

Inactive Publication Date: 2008-05-15
WYETH HOLDINGS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In preferred embodiments of the invention, the IL-12 is present in an amount of from about 0.01 ng to about 50 μg. In other preferred embodiments, the QS-21 is present in an amount of from about 0.01 ng to about 50 μg. Preferably, the QS-21 and IL-12 produce a synergistic adjuvant effect. In one embodiment of the invention, the IL-12 is recombinant human IL-12. In one embodiment of the invention, the antigen is a viral antigen. In a preferred embodiment, the antigen is respiratory syncytial virus F protein or functional portion thereof. In another embodiment, the antigen is a bacterial antigen. In that embodiment, the preferred antigen is P4 protein, or functional portion thereof, from non-typable Haemophilus influenzae. In one embodiment, the immune response comprises a response selected from the group consisting of a humoral response, a cell-mediated response, or both a humoral and cell-mediated response.

Problems solved by technology

However, co-formulation with rIL-12 did not completely regulate all type 2 responses elicited by F / AlOH.
However, clinical data has implied that QS-21 in this formulation was associated with local acute toxicity immediately after injection.

Method used

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  • Qs-21 and il-12 as an adjuvant combination
  • Qs-21 and il-12 as an adjuvant combination
  • Qs-21 and il-12 as an adjuvant combination

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Systemic Humoral Immune Responses of BALB / c Mice Vaccinated with RSV F Protein Co-Formulated with QS-21 and Recombinant (r) IL-12

[0047]The purpose of these experiments was to determine if immunization with RSV F protein formulated with QS-21 and recombinant IL-12 could elicit functional serum antibody titers that were greater than those achieved after immunization with either adjuvant alone. In the experiments native F protein was purified by ion exchange chromatography from Vero cells (ATCC No. CCL 81) infected with the A2 strain of RSV. The protein was greater than 95% pure as estimated by SDS-PAGE and antigen capture ELISA. QS-21 and rIL-12 were obtained from Aquila BioPharmaceuticals, Inc. (Worcester, Mass.) and Genetics Institute (Cambridge, Mass.), respectively. Naive female BALB / c mice (8-10 weeks of age) were obtained from Charles River Laboratories (Wilmington, Me.) and vaccinated intramuscularly on weeks 0 and 4 with natural F protein (3 μg / dose). The vaccines were pre...

example 2

The Determination of Antigen Dependent Killer Activity in the Spleens of BALB / c Mice Vaccinated with F Protein of Coformulated with Qs-21 and rIL-12

[0051]The purpose of these experiments was to determine if immunization with F protein formulated with QS-21 and rIL-12 could elicit antigen dependent killer cell activities that were greater than those achieved after immunization with either adjuvant alone. In the experiments natural F protein was purified, and vaccines were prepared and administered to naive female BALB / c mice as described in Example 1. To determine the presence of antigen dependent killer cells, bulk splenocytes were collected 2 weeks after secondary immunization and cultured 6 days in the presence of syngenic RSV-infected stimulator cells. Thereafter the effector cells (serially diluted 3-fold in RPMI 1640 with 10% heat-inactivated fetal bovine sera) were tested against RSV-infected and control syngeneic target cells for antigen dependent killer cell activity in a st...

example 3

The Effect of an Adjuvant Comprised of QS-21 and rIL-12 on the Systemic Humoral Immune Responses Elicited by RSV G Protein, an Antigen Prone to Induce Th2 Helper T Cells

[0054]The purpose of this experiment was to determine the adjuvant properties of rIL-12 plus QS-21 on humoral immune responses elicited by viral antigens prone to induce Th2 helper T cell responses. To that end, the effect of rIL-12 on the immune responses induced by natural G protein co-formulated with a suboptimal dose (0.8 μg) of QS-21 was investigated. In the experiment naïve female BALB / c mice (7-10 weeks of age) were primed intramuscularly with 1 μg natural G protein. The protein was purified via immunoaffinity chromatography from Vero cells infected with the A2 strain RSV and was greater than 95% pure as estimated by SDS PAGE electrophoresis. The protein was prepared in PBS alone, admixed with a suboptimal dose (0.8 μg) of QS-21 or admixed with a suboptimal dose (0.8 μg) of QS-21 plus 10 fold ascending doses o...

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Abstract

Adjuvant compositions comprising an effective amount IL-12 and QS-21 are disclosed. Immunogenic, vaccine and pharmaceutical compositions comprising a mixture of antigen and an adjuvant composition comprising an effective amount of IL-12 and QS-21 are also disclosed. These compositions elicit functional cell-mediated and humoral immune responses against at least one antigen. Methods of using the disclosed compositions are also disclosed.

Description

BACKGROUND OF THE INVENTION[0001]IL-12 is a heterodimeric cytokine that is primarily produced by dendritic cells, macrophages and neutrophils and plays an essential role in the generation of type 1 immune responses and cell-mediated immunity (Brunda, J. Leukocyte Biol. 55:280-288 (1994); Scott and Trinchieri, Semin. Immunol. 9:285-291 (1997)). The results from several studies in a variety of animal models support the idea that rIL-12 has great promise as an adjuvant for prophylactic or therapeutic vaccines against infectious and metastatic diseases (Rodolfo and Colombo, Methods 19:114-120 (1999); Scott and Trinchieri, Semin. Immunol. 9:285-291 (1997)). Recently, it was reported that rIL-12 has the potential to serve as an adjuvant for natural F protein of RSV (Hancock et al. Viral Immunol. 13:57-72 (2000)). In BALB / c mice, the results suggested that rIL-12 enhanced the capacity of F protein, when adsorbed to aluminum hydroxide adjuvant (F / AlOH), to elicit T cell responses that were ...

Claims

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Application Information

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IPC IPC(8): A61K39/102A61K38/20A61K39/02A61K38/00A61K36/00A61K39/12A61K39/39A61P37/04
CPCA61K38/208A61K39/102A61K39/39A61K2039/55522A61K2039/55577A61K2039/55538A61K2300/00A61P37/04Y02A50/30
Inventor HANCOCK, GERALD E.
Owner WYETH HOLDINGS CORP
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