Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1999-10-25
2001-07-17
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S001110, C435S005000, C514S110000, C514S075000, C514S137000
Reexamination Certificate
active
06261573
ABSTRACT:
This application relates to the field of polymers for biomedical applications, and in particular describes polymers in combination with amphiphilic compounds that are useful as immunoadjuvants.
BACKGROUND
A wide variety of antigens stimulate the production of antibodies in animals and confer protection against subsequent infection. However, some antigens are unable to stimulate an effective immune response.
The immunogenicity of a relatively weak antigen is often enhanced by the simultaneous administration of the antigen with an adjuvant, a substance that is not immunogenic when administered alone, but will induce a state of mucosal and/or systemic immunity when combined with the antigen. Unfortunately, many immunoadjuvants, such as Freund's Complete Adjuvant, are toxic and are therefore only useful for animal research purposes, not human vaccinations.
Ionically cross-linkable water soluble polymers, poly[di(carboxylatophenoxy)phosphazene]s (PCPPs) have been developed (Allcock, H. R. and S. Swan,
Macromolecules,
22:75-79 (1989)). In the soluble state, PCPP has been demonstrated to have adjuvant activity (U.S. Pat. No. 5,494,673) and has enhanced the immunogenicity of various antigens (Payne, L. G. et al.,
Vaccine,
16:92-98(1998)). Generally, the addition of PCPP to antigen preparations has enhanced functional hemagglutination inhibition (HAI) antibody response and has enhanced IgM, IgG, and IgG1 ELISA antibody titers over the levels elicited by vaccine alone. PCPP as an adjuvant has been demonstrated to be as efficient as or to outperform complete Freund's adjuvant. The immunogenicity of antigens as diverse as tetanus toxoid, hepatitis B surface antigen,
Hemophilus influenzae
type b polyribosribotolphosphate, herpes simplex virus type 2 glycoprotein D and HIV env has been dramatically enhanced in the presence of soluble PCPP (Payne, L. G. et al.,
Modulation of the Immune Response to Vaccine Antigens,
Lars Haaheim, ed, Geneva (1997); Lu, Y. et al.,
J. AIDS Human Retrovirol.,
12:99-106 (1996)).
SUMMARY OF THE INVENTION
The present invention provides a composition and method for inducing an effective immune response against an antigen, comprising an antigen and an adjuvant composition that includes (i) at least one water soluble polymer and (ii) at least one amphiphilic compound.
In a preferred embodiment, the water soluble polymer is a polyelectrolyte. The at least one water soluble polymer may or may not function as an adjuvant in the absence of the amphiphilic compound.
In a preferred embodiment, the at least one polymer has adjuvant properties in the absence of an amphiphilic compound.
The use of a combination of a water soluble polymer and an amphiphilic compound provides an improved adjuvant in that the combination provides an unexpected improvement over the use of either component in the absence of the other component.
For example, the use of such a combination can increase the humoral response to an antigen as compared to the use of either component alone.
In addition, the combination can provide a cytotoxic T lymphocyte (CTL) response to an antigen that is not present when using the antigen alone or the antigen with one of the two components of the composition of the invention in the absence of the other component and/or in the case where the antigen does generate a CTL response, the combination of the invention can improve such CTL response.
Although not bound to any particular theory or mechanism of action, it is believed that the unexpected beneficial immune response generated by the combination of the present invention may be due to a modification of the polymer component by the amphiphilic compound.
In another aspect the invention provides a method of inducing or enhancing an immunoprotective response to an immunological challenge in a host which comprises administering to said host an antigen and an adjuvant composition that includes (i) at least one water soluble polymer and (ii) at least one amphiphilic compound.
DETAILED DESCRIPTION OF THE INVENTION
The polymer portion of the adjuvant composition of the present invention is a water soluble polymer. The term water soluble means that the polymer is at least partially soluble in water (typically to an extent of at least 0.001% by weight), an aqueous buffered salt solution or aqueous alcohol solution. The polymer is preferably biodegradable and exhibits minimal toxicity when administered to animals including humans. The term polymer as used herein includes both homopolymers and copolymers.
Preferred natural water soluble polymers include alginate, gelatin, pectin, and collagen. Preferred synthetic water soluble polymers include poly(acrylamide), poly(methacrylamide), poly(vinyl acetate), poly(N-vinyl pyrrolidone), poly(hydroxyethylmethacrylate). poly(ethylene glycol), polyvinylamines, poly(vinylpyridine), poly(vinyl alcohols)and polyphosphazene.
In a preferred embodiment, the at least one polymer is a polyelectrolyte. The polyelectrolyte may be a polymer with anionic and/or cationic pendant groups.
As representative examples of anionic monomer units that form an anionic polymer there may be mentioned acrylic acid, methacrylic acid, styrenesulfonic acid, vinyl sulfonic acid, styrene carboxylic acid, maleic acid, 2-acrylamido-2-methylpropanesulfonic acid, 4-methylacryloyloxyethyl trimellitate, L-glutamic acid, L-aspartic acid, metaphosphoric acid, a phosphazene with a pendant anionic group(s), e.g. di(carboxylatophenoxy)phosphazene, or a salt thereof.
As representative examples of monomeric units that form cationic polymers, there may be mentioned ethyleneimine, vinylamine, 4-vinylpyridine, N,N-dimethylaminoethylmethacrylate, dimethylvinylbenzylamine, L-lysine, L-arginine and salts thereof.
In a preferred embodiment, the polymer is a water soluble polyphosphazene polyelectrolyte. Phosphazene is biodegradable and exhibits minimal toxicity when administered to animals, such as humans. Polyphosphazenes are polymers with backbones consisting of alternating phosphorus and nitrogen, separated by alternating single and double bonds. See U.S. Pat. No. 5,494,673 for representative examples of polyphosphazenes suitable for use in the present invention.
The other component of the adjuvant composition of the invention is an amphiphilic compound. The amphiphilic compound may or may not function as an adjuvant in the absence of the water soluble polymer.
The term amphiphilic compound as known in the art means that the compound includes both a hydrophobic portion and a hydrophilic portion.
Amphiphilic compounds suitable for producing the adjuvant of the present invention include dimyristoyl phosphatidylcholine, dimethyldioctadecylammonium bromide, N,N-dioctadecyl-N′,N′-bis(2-hydroxyethyl)propanediamine, N-(2-Deoxy-2-L-leucylamino-&bgr;-D-glucopyranosyl)-N-octadecydodecanoylamide hydroacetate, dimyristoyl phosphatidylglycerol, N-acetylglucosaminyl-N-acetylmuramyl-L-Ala-D-isoGlu-L-Ala-glycerol dipalmitate, sorbitan trioleate, deoxycholic acid sodium salt, dicetyl phosphate, mono-palmitoyl-rac-glycerol, N-acetylglucosaminyl-N-acetylmuramyl-L-Ala-D-isoGlu-L-Ala-dipalmitoxy propylamide, octadecyl tyrosine hydrochloride, D-murapalmitine, 3-O-desacyl-4′-monophosphoryl lipid A, mannide oleate, 1a,25-dihydroxyvitamin D
3
, phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, sphingosine (D-4-sphingenine, ceramides, sphingomyelin, galactosylceramide, GM
2
(ganglioside), salts of fatty acids including oleic acid, palmitic acid, capric acid, lauric acid, myristic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, linoleic acid, linolenic acid, arachidonic acid, and the like.
In one aspect, the adjuvant can be prepared by mixing the water soluble polymer and the amphiphilic compound at room temperature. Antigen is then added to the adjuvant combination. Alternatively, the antigen is first mixed with one of the adjuvant components, and then the second adjuvant component is added. Preferably the immunogenic composit
Andrainov Alexander K.
Jenkins Sharon A.
Loebelenz Jean R.
Roberts Bryan E.
AVANT Immunotherapeutics, Inc.
Lillie Raymond J.
Olstein Elliot M.
Salimi Ali R.
LandOfFree
Immunoadjuvants does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Immunoadjuvants, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Immunoadjuvants will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2542125