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Aqueous immunologic adjuvant compositions of monophosphoryl lipid a

A monophosphoryl lipid and composition technology, applied in the direction of drug combination, sugar derivatives, sugar derivatives, etc., can solve the problems of reducing the effectiveness of ingredients, stimulating the mucosal surface, inflammation, etc.

Inactive Publication Date: 2007-07-18
CORIXA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the presence of solvents may further complicate vaccine formulation and, in some cases, reduce the effectiveness of its ingredients
Additionally, solvents may irritate mucosal surfaces or cause inflammation at the injection site

Method used

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  • Aqueous immunologic adjuvant compositions of monophosphoryl lipid a
  • Aqueous immunologic adjuvant compositions of monophosphoryl lipid a
  • Aqueous immunologic adjuvant compositions of monophosphoryl lipid a

Examples

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preparation example Construction

[0018] The modified 3D-MLA used in the present invention is prepared by base hydrolysis of MLA under conditions that result in the loss of a single fatty acid at position 3 of the lipid A backbone. In alkaline media, the β-hydroxymyristyl fatty acid at position 3 is unusually unstable. Lipid A can be completely 3-deacylated only by mild alkali treatment. The other lipid A ester bonds require some more intense conditions before hydrolysis occurs so as to selectively deacylate the moiety at position 3 without significantly affecting the rest of the molecule. The reason for the unusual sensitivity of ester-linked β-hydroxymyristyl fatty acids at position 3 to alkaline media is currently unknown.

[0019] Although basic hydrolysis methods are known, it is important to choose conditions that do not cause further hydrolysis other than hydrolyzing the ester bond of the β-hydroxymyristyl group at position 3. Typically hydrolysis can be carried out in aqueous or organic media. In th...

Embodiment 1

[0029] Example 1 - Preparation of Aqueous Formulations of Attenuated Lipid A Derivatives

[0030] According to the present invention, water for injection contained 1000 μg / ml of the attenuated lipid A form of 3D-MLA from Salmonella minnesota R595 (RiBi ImmunoChem Research, Inc., Hamilton, Montana 59840) and 118 μg / ml of 1,2-bis An aqueous formulation of 3-O-deacylated monophosphoryl lipid A (3D-MLA / AF) of palmitoyl-sn-glycero-3-phosphocholine (DPPC) was prepared as follows:

[0031] DPPC was dissolved in ethanol to a concentration of 4 mg / ml and swirled to clarify. Add 2.7 ml of DPPC solution to the vial containing 100 mg lyophilized 3D-MLA and swirl gently to wet the 3D-MLA. Gently blow filtered nitrogen into the vial to remove ethanol. Water for injection (91.7ml) was added to the vial, then the vial was stoppered, sealed and suspended in a Labline 9303 water bath ultrasonicator. The suspension was sonicated at 60°C for 10 minutes until clear. The resulting aqueous form...

Embodiment 2

[0032] Example 2 - Stimulation of antibody responses

[0033] Mice immunized with tetanus toxoid (TT) in the aqueous formulation of the present invention produce tetanus toxoid-specific antibodies. After immunization, TT-specific total IgG titers and IgG isotype (2a, 2b, 1) titers in mouse sera were determined by enzyme-linked immunosorbent assay (ELISA).

[0034] Female ICR mice were immunized with a dose of vaccine containing 0.1 μg tetanus toxoid (TT) + 50 μg 3D-MLA / AF or 0.1 μg TT with saline. 3D-MLA / AF was prepared according to Example 1. Vaccines were administered subcutaneously on days 0 and 21. Sera were collected 14 days after the second immunization and assayed by standard ELISA technique to report tetanus toxoid-specific antibody IgG 1 , IgG 2a and IgG 2b Relative amounts of isotypes and total IgG.

[0035] Figure 1 shows the titers of tetanus toxoid-specific antibodies produced by 3D-MLA / AF. 3D-MLA / AF stimulates IgG antibody production in immunized animals...

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Abstract

An aqueous adjuvant composition comprising an attenuated lipid A derivative and a surfactant or surfactants enhances the immunological response in a warm blooded animal to a protein antigen. Attenuated lipid A derivatives useful according to the subject invention include monophosphoryl lipid A and 3-O-deacylated monophosphoryl lipid A. A surfactant or mixtures of surfactants are dissolved in a solvant. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine is a preferred surfactant. The dissolved surfactant is added to an attenuated lipid A derivative to obtain a mixture. The molar ratio of attenuated lipid A derivative to surfactant in the mixture is about 4:1. The solvent is evaporated and water is added to the resulting film. The suspension is sonicated in a 60 DEG C water bath until it becomes clear. Animals administered the adjuvant formulation exhibited increased antibody responses to a given antigen as well as displayed enhanced lymphocyte proliferative and cytotoxic T-lymphocyte responses. Intranasal administration of the aqueous adjuvant composition and an antigen stimulates the production of serum and mucosal secreted IgA.

Description

[0001] This application is a divisional application of the Chinese invention patent application "aqueous immune adjuvant composition of monophosphoryl lipid A" filed on April 1, 1998 with application number 98804685.7. [0002] Cross References to Related Applications [0003] This application is a continuation-in-part of co-pending patent application serial number 08 / 831,073 filed April 1,1997. technical field [0004] The present invention relates to aqueous formulations of attenuated lipid A (ALD) and surfactants and methods for their preparation. Background of the invention [0005] Compounds Monophosphoryl Lipid A (MLA) and 3-O-Deacylated Monophosphoryl Lipid A (3D-MLA) are lipid A derivatives of attenuated bacterial lipopolysaccharide (LPS). LPS and lipid A are potent immunostimulants that induce humoral antibody responses and cell-mediated immune responses in patients administered these compounds. However, lipid A and LPS can also exhibit toxic side effects such as ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/39A61P31/12A61P31/16A61P43/00A61P31/00C07H13/06
CPCA61K2039/55572C07H13/06A61K39/39A61P31/00A61P31/12A61P31/16A61P37/00A61P43/00
Inventor R·T·克莱恩
Owner CORIXA CORP
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