ZA200406023B - New immunoeffector compounds - Google Patents
New immunoeffector compounds Download PDFInfo
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- ZA200406023B ZA200406023B ZA200406023A ZA200406023A ZA200406023B ZA 200406023 B ZA200406023 B ZA 200406023B ZA 200406023 A ZA200406023 A ZA 200406023A ZA 200406023 A ZA200406023 A ZA 200406023A ZA 200406023 B ZA200406023 B ZA 200406023B
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- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
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- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 125000004429 atom Chemical group 0.000 description 1
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-YPZZEJLDSA-N iodine-125 Chemical compound [125I] ZCYVEMRRCGMTRW-YPZZEJLDSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Attorney Docket No.: 14058-016200
This invention relates generally to immunoeffector compounds, their use in pharmaceutical compositions, and methods for their production and their use in prophylactic and/or therapeutic vaccination. More particularly, the present invention relates to novel compounds comprising 2-deoxy-2-amino-g-D-glucopyranose (glucosamine) glycosidically linked to a cyclic aminoalkyl (aglycon) group, and their use in pharmaceutical adjuvant systems.
Humoral immunity and cell-mediated immunity are the two major branches of the mammalian immune response. Humoral immunity involves the generation of antibodies to foreign antigens. Antibodies are produced by B-lymphocytes.
Cell-mediated immunity involves the activation of T-lymphocytes which either act upon infected cells bearing foreign antigens or stimulate other cells to act upon infected cells.
Both branches of the mammalian immune system are important in fighting disease. 70 Humoral immunity is the major line of defense against bacterial pathogens. In the case of viral disease, the induction of cytotoxic T lymphocytes (CTLs) appears to be crucial for protective immunity. Thus, an effective vaccine preferably stimulates both branches of the immune system to protect against disease.
Vaccines present foreign antigens from disease causing agents to a host so 75 that the host can mount a protective immune response. Often, vaccine antigens are killed or attenuated forms of the microbes which cause the disease. The presence of non- essential components and antigens in these killed or attenuated vaccines has encouraged considerable efforts to refine vaccine components including developing well-defined synthetic antigens using chemical and recombinant techniques. The refinement and simplification of microbial vaccines, however, has led to a concomitant loss in potency.
Low-molecular weight synthetic antigens, though devoid of potentially harmful B contaminants, are often not sufficiently immunogenic by themselves. These observations have led investigators to add immune system stimulators known as adjuvants to vaccine compositions to potentiate the activity of the vaccine components. * Immune adjuvants are compounds which, when administered to an individual or tested in vitro, increase the immune response to an antigen in a subject to which the antigen is administered, or enhance certain activities of cells from the immune system. A number of compounds exhibiting varying degrees of adjuvant activity have been prepared and tested (see, for example, Shimizu et al. 1985, Bulusu et al. 1992, Ikeda et al. 1993, Shimizu et al. 1994, Shimizu et al. 1995, Miyajima et al. 1996). However, these and other prior adjuvant systems often display toxic properties, are unstable and/or have unacceptably low immunostimulatory effects.
Presently, the only adjuvant licensed for human use in the United States is alum, a group of aluminum salts (e.g., aluminum hydroxide, aluminum phosphate) in which vaccine antigens are formulated. Particulate carriers like alum reportedly promote the uptake, processing and presentation of soluble antigens by macrophages. Alum, however, is not without side-effects and is unfortunately limited to humoral (antibody) immunity only.
The discovery and development of effective adjuvant systems is essential for improving the efficacy and safety of existing and future vaccines. Thus, there is a continual need for new and improved adjuvant systerns, particularly those that drive both effector arms of the immune system, to better facilitate the development of a next generation of synthetic vaccines. The present invention fulfills these and other needs.
The compounds of the present invention are immunoeffector molecules which enhance humoral and cell-mediated immune responses to vaccine antigens. The compounds can generally be descrbed as belonging to the class of cyclic AGP compounds, where AGP stands for aminoalkyl glucosaminide phosphates. The term “cyclic AGP” means an azacycloalkyl or (azacycloalkyl)alkyl glucosaminide phosphate, _ wherein a 2-deoxy-2-amino-b-D-glucopyranose (glucosamine) is glycosidically linked to an azacycloalkyl or (azacycloalkyl)alkyl (aglycon) group. BN
The compounds of this invention comprise a 2-deoxy-2-amino-p-D- glucopyranose (glucosamine) glycosidically linked to an cyclic aminoalkyl (aglycon) group. The compounds are phosphorylated at the 4 or 6-position of the glucosamine ring and acylated with alkanoyloxytetradecanoyl residues on the aglycon nitrogen and the 2 and 3-positions of the glucosamine ring. The compounds of the subject invention are described generally by formula (I):
OR®
SA ”
X Yor Im
NH iy RS
Rfo—(+ 0 @D and pharmaceutically acceptable salts thereof, wherein X is —O- or -NH- and Y is -O- or —S-:R',R? and R are each independently a ( Co-Cia)acyl group, including saturated, unsaturated and branched acyl groups; R* is -H or _PO;R’R®, wherein R” and R® are each independently H or (C1-C4) aliphatic groups; R’ is -H, -CH; or -PO;R’R'?; wherein R® and R'° are each independently selected from —H and (C1-Cs)aliphatic groups; RSis independently selected from H, OH, (C1-Cs) oxyaliphatic groups, -PO;R''RY, -
OPO;R'RY -SO;R",-08O:R", -NR"R", SR", -CN, -NO, -CHO, -COR", and _CONR!R"?, wherein R'! and R'? are each independently selected from H and (Ci-
Ca)aliphatic groups; with the provisos that one of R? and R’ is a phosphorus-containing group and that when R* is -PO;R'R", R” is other than —PO;R°R'’, wherein “*'*” and _ «*# represent chiral centers; wherein n, m, p and g are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.
In some embodimentsof compounds of the present invention X and Y are each oxygen, R* is PO;R'R®, R’ and Rare H, and n, m, p, and q are integers from 0 to 3.
In a more preferred embodiment, R’ and R® are —H. In an even more preferred embodiment, n is 1, m is 2, and subscripts p and q are 0. In yet an even more preferred embodiment, Ry, Ra, and Rj are Co-Ci3 acyl groups, most preferably C10-Ci2 acyl groups.
In a still more preferred embodiment, #13 are in the R configuration, Y is in the equatorial position, and ** is in the § configuration. Particularly preferred are (N-[(R)-3- : tetradecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)- 3 tetradecanoyloxytetradecanoylamino]-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]- g-D- glucopyranoside, Formula an,
OH oA oe _)
NH o N o 0 o ] am (N-[(R)-3-dodecanoyloxytetradecanoy!]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O- phosphono-2-[(R)-3-dodecanoyloxytetradecanoylamino] -3-O-[(R)-3- dodecanoyloxytetradecanoyl]- g-D-glucopyranoside, Formula (III),
OH oA a) 0 N
NH 0 0 (0) jo] any) and (N-[(R)-3-decanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O- phosphono-2-[(R)-3-decanoyloxytetradecanoylamino]-3-O-[(R)-3- decanoyloxytetradecanoyl]- p-D-glucopyranoside, Formula av),
OH
0 0 N
NH 0 0 0 o 0 av - and their pharmaceutically acceptable salts.
The present invention also provides pharmaceutical compositions containing compounds of the general and specific formulas above. The pharmaceutical compositions can be combined with a variety of antigens and in a variety of formulations known to those of skill in the art.
The compounds of the present invention are also useful in methods of inducing an immune response in a subject. The method entails administering to the subject a therapeutically effective amount of one or more compounds of the present invention, preferably in a pharmaceutical composition that also contains a pharmaceutically acceptable carrier.
The present invention also encompasses methods of treating a mammal suffering from or susceptible to a pathogenic infection, cancer or an autoimmune disorder. The method entails administering to the mammal a therapeutically effective amount of one or more compounds of the present invention, preferably in a pharmaceutical composition that also contains a pharmaceutically acceptable carrier. _ Still further, the present invention involves a method for treating diseases or conditions ameliorated by nitric oxide production in a subject. The method entails contacting the subject with an effective amount of a compound or compounds of the present invention, or with an effective amoutn of a composition containing one or more compounds of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the compounds of the present invention can be administered 48 hours prior to, up to, and during ischemia.
The term “acyl” refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, and pivaloyl. “(Cg-Ci4)acyl”, for instance, refers to an acyl group having from 9 to 14 carbons.
The term “aliphatic” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic, hydrocarbon moiety, 3 30 including a moiety that contains both cyclical and chain elements, which may be fully saturated or mono- or polyunsaturated, having the number of carbon atoms designated — (i.e. C;-Ca means one to four carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- ‘butyl, cyclopropyl, cyclopropylmethyl, methylene, ethylene, and n-butylene.An unsaturated alkyl group is one having one or more double bonds and/or triple bonds.
Examples of unsaturated aliphatic groups include vinyl, 2-propenyl, crotyl, - 2- (butadienyl), 1-propynyl and 3-propynyl.
The term “oxyaliphatic refers to those groups having an aliphatic group attached to the remainder of the molecule through an oxygen atom.
Each of the above terms (e.g., “alkyl,” “acyl”) are meant to include both substituted and unsubstituted forms of the indicatedmoiety.
Substituents for the aliphatic groups can be a variety of groups selected from: -OR’, =0, =S, =NR’, =N-OR’, -NR'R”, -SR’, -halogen, -SiR’R”R*”, -OC(O)R’, -
C(O)R’,-CO;R’,-CONR'R”, -OC(O)NR’R”, -NR”C(O)R’, NR’-C(O)NR"R’”, -
NR”C(0):R’, -NH-C(NH,)=NH, -NR’C(NH,)=NH, -NH-C(NH,)=NR’, -S(O)R’, -
S(0):R’, -S(0),NR’R”, -CN and -NO; in a number ranging from zero to (2m’+1), where m’ is the total number of carbon atoms in such radical. R’, R” and R™ each independently refer to hydrogen and unsubstituted (C;-Ca)aliphatic groups. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups such as haloalkyl (e.g., -CF3 and -CH,CF3) and the like.
The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
In compounds having multiple halogen substituents, the halogens may be the same or different.
The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by addition of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, Organic amino, or magnesium salt, or a similar salt.
When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by addition of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those — derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, SM, etal, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present — invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such g compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (CH), iodine-125 (**1) or carbon-14 (**C). Allisotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Introduction
In an effort to improve the safety of vaccines, manufacturers are avoiding whole cell killed vaccines, and producing recombinant or subunit vaccines. In the preparation of these safer vaccines extraneous bacterial or viral components are eliminated, while the minimal structures or epitopes deemed necessary for protective immunity remain. The safety of these vaccines is improved due to the elimination of extraneous bacterial or viral components which often times prove to be toxic and pyrogenic. However, the same components that result in toxicity provide nonspecific immunostimulation that make whole cell vaccines so effective. Without the additional immunostimulation the minimal structures and epitopes comprising recombinant and subunit vaccines are often poorly immunogenic.
A disaccharide molecule derived from the LPS of Salmonella minnesota
R595, MPL® immunostimulant (Corixa Corp.), has immunostimulant properties. MPL® immunostimulant, Monophosphoryl lipid A, is a structural derivative of lipid A (or LPS) and has an improved therapeutic index relative to lipid A (see U.S. Patent 4,987,237 for the structure of Monophosphoryl lipid A; U.S. Patent Nos. 4,436,727 and 4,436,728 for description of preparation of Monophosphoryl lipid A). Other useful immunostimulants include 3-de-O-acylated monophosphoryl lipid A (3D-MPL), which is described in U.S.
Patent No. 4,912,094. The compound can be safely administered to humans as doses up to at least 20 pg/kg, although increases in temperature, flu-like symptoms, increasing heart rate and modest decreases in blood pressure can occur in some patients at dose levels of > 10 pg/kg. Cell culture and animal evaluations confirm MPL® immunostimulant still retains some of the immunostimulatory activity of the parent LPS in that pyrogenicity and the ability to induce pro-inflammatory cytokines such as TNF and IL-8 remain, albeit at higher dose levels. Thus, the need for effective vaccine adjuvants is well recognized. Ideally, these adjuvants will boost the protective immune response without inducing unwanted toxicity and pyrogenicity.
In an effort to obtain an immunostimulant that has low pyrogenicity, synthetic molecules have been prepared which share structural similarities with the
MPL® jmmunostimulant. These novel molecules which are collectively called aminoalkyl glucosaminide phosphates (AGPs), consist of an acylated glucose moiety linked to an acylated aminoalkyl group (Johnson ez al. (1999) Bioorg. Med. Chem. Lett. 9: 2273-2278; PCT/W098/50399 and references therein). Each molecule possesses 6 fatty acid tails which is thought to be the optimal number for peak adjuvant activity. The substitution of different chemical moieties within the aminoalkyl structures was designed into the AGPs in anticipation of optimizing stability and solubility properties. Thus the AGPs can be broadly separated into several families based on the structure of their aminoalkyl groups. After initial biological evaluation, it became apparent that the aminoalkyl motifs could dramatically affect the pyrogenic properties of the AGPs (see
U.S. Patent Application Serial No. 09/074,720 filed May 7, 1998, and U.S. Patent Nos. 6,113,918 and 6,303,347). As part of the initial screening process of the synthetic adjuvant compounds, rabbit pyrogenicity data was determined. It was noted that several of the compounds did not elicit a fever response when administered i.v. at doses of 10 pg/kg. In general, these same compounds failed to induce detectable levels of inflammatory cytokines TNF-a or IL-1B in an ex vivo cytokine induction assay on human peripheral blood mononuclear cells. Here we report on studies of the adjuvant properties ofa class of AGPs which induce minimal activity in both the rabbit pyrogen test and the ex vivo cytokine assay.
Compounds and Compositions
The present invention provides compounds described generally by formula (D:
OR® : X YEA
N q rlo—+1 1 @® and pharmaceutically acceptable salts thereof, wherein X is —O- or —-NH- and Y is -O- or _S-; R', R?, and R® are each independently a (C-Ci4) acyl group, including saturated, unsaturated and branched acyl groups; R* is —H or —PO;R'R®, wherein R’ and R® are each independently H or (C1-Cy)aliphatic groups; R’is-H, -CHj or —PO;R°R'?, wherein R’ and R!° are each independently selected from —H and (C,-C,)aliphatic groups; RC is independently selected from H, OH, (Ci-Cs)oxyaliphatic groups, -POsR!'RY, -
OPO;R''R, -SOsR"?, -OSO:R", NR''R", -SR"!, -CN, -NO,, -CHO, -COR", and —
CONR!R'?, wherein R!! and R'? are each independently selected from H and (Cy-
Cs)aliphatic groups; with the provisos that one of R*and R® is a phosphorus-containing group and that when R* is —PO;R'R®, R’ is other than —PO;RR!®, wherein “*'”>” and «x*” represent chiral centers; wherein n, m, p and q are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.
Although the hexopyranoside in Formula I is shown in the gluco configuration, other glycosides are within the scope of the invention. For example glycopyranosides, including other hexopyranosides (e.g., allo, altro, manno, gulo, ido, galacto, talo), are within the scope of the invention.
In the general formula above, the configuration of the 3’-stereogenic -. — centers to which the normal fatty acyl residues are attached, denoted “*', «i? and «x», is R or S, but preferably R. The absolute stereochemistry of the carbon atoms of the cyclic aglycon unit to which R® and the glucosamine unit are attached, directly or indirectly (denoted “**”) can be R or S. In the general formula above, Y can be in the equatorial or axial position, but is preferably equatorial. All stereoisomers, enantiomers, diastereomers and mixtures thereof are considered to be within the scope of the present invention.
In preferred embodiments, of the present invention, X and Y are —O-, Ris phosphono, RS and R® are H, and n, m, p, and q are integers of from 0 to 3, and more preferably 0 to 2. Most preferably the integer n is 1, the integer m is 2, and integers p and q are 0. In this preferred embodiment, the compounds of this invention are 2- pyrrolidinylmethyl g-D-glucosaminide 4-phosphates having the general formula v):
OH oro oR oo) © NH 0 !
Rlo—(+1 1 1 ™
In a preferred embodiment of the present invention, the configuration of the 3’-stereogenic centers (“*!3”) to which they are attached is R, Y is in the equatorial position, and the absolute stereochemistry of the pyrrolidine stereogenic center (“**”) is
S. ” 20 Particularly preferred embodiments are N-[(R)-3-tetradecanoyloxytetradecanoyl]- (S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3- a tetradecanoyloxytetradecanoylamino}-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]- B-D- glucopyranoside, and its pharmaceutically acceptable salts, depicted in formula (II):
OH
0 N
NH o 0 0) 0] 0} 0 o an (N-[(R)-3-dodecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O- phosphono-2-[(R)-3 -dodecanoyloxytetradecanoylamino]-3-O0-[(R)-3- dodecanoyloxytetradecanoyl]- p-D-glucopyranoside and pharmaceutically acceptable salts thereof: Formula (III),
OH lo] 0 NH o 0 .
P 0 ty)
and (N-[(R)-3-decanoyloxytetradecanoyl}-(S)-2-pyrrolidinylmethyl 2-deoxy-4-0O- phosphono-2-[(R)-3-decanoyloxytetradecanoylamino}-3-O-{(R)-3- decanoyloxytetradecanoyl]- 8-D-glucopyranoside and pharmaceutically acceptable salts thereof, Formula (IV),
OH
‘N iY NH 0 @) 0 0 0] 0 0 av)
Preparation of Compounds
The compounds of the present invention can be prepared using methods outlined in Johnson et al., Bioorg. Med. Chem. Lett. 9:2273-2278 (1999) and
PCT/W098/50399 and references therein. In general, the synthetic methods described in the above-noted references are broadly applicable to the preparation of compounds having different acyl groups and substitutions. One of skill in the art will appreciate that the convergent methods described therein can be modified to use alternate acylating agents, or can be initiated with commercially available materials having appropriate acyl groups attached.
Evaluation of Compounds
The compounds provided herein can be evaluated in a variety of assay formats to select a compound having a suitable pharmacophoric profile. For example,
U.S. Patent No. 6,013,640 describes animal models suitable for evaluating cardioprotective effects of compounds described herein. The examples below also provide assays for evaluating pyrogenicity of the subject compounds, and further assays for evaluating the proinflammatory effects of the compounds.
The present invention further provides pharmaceutical compositions comprising the compounds provided herein in admixture with one or more pharmaceutically acceptable carriers. Suitable carriers will depend on the condition being treated along with the route of administration. Accordingly, a discussion of the carriers is provided below in conjunction with the methods of use.
Pharmaceutical Compositions and Their Uses
In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the present invention and a pharmaceutically acceptable carrier. The compound is present in a therapeutically effective amount, which the amount of compound required to achieve the desired effect in terms of treating a disease, condition, or achieving a biological occurrence. The pharmaceutical compositions can act as an adjuvant when co-administered with an antigen.
Compositions of this invention include both compositions that are formulated for direct administration of the active compounds to patients without dilution, either in conjunction with a vaccine or other active agent, or alone, as well as more concentrated compositions of the compounds that may be formulated for later dilution, so 70 as to avoid shipment and/or storage of large amounts of diluent (e.g. water, saline or aqueous materials). In general, pharmaceutical compositions of this invention that are intended for direct or immediate administration to a subject (that is, without dilution) will contain one or more of the compounds, in a therapeutically effective amount. This amount will vary both based on the particular therapeutic compound or compounds and on the therapeutic effect desired. More concentrated compositions will contain amounts of the compound or compounds of the invention as may be appropriate for such compositions.
For preparing pharmaceutical compositions, the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, a preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Solid forms of the compositions also can be prepared by spray-drying aqueous formulations of the active adjuvants (e.g. in the form of a salt) or by lyophilizing and milling with excipients.
Suitable carriers for the solid compositions of this invention include, for instance, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. In certain embodiments, the pharmaceutical compositions are formulated in a stable emulsion formulation (e.g., a water-in-oil emulsion or an oil-in-water emulsion)or an aqueous formulation that preferably comprise one or more surfactants. Suitable 95 surfactants well known to those skilled in the art may be used in such emulsions. In one embodiment, the composition is in the form of a micellar dispersion comprising at least one suitable surfactant. The surfactants useful in such micellar dispersions include phospholipids. Examples of phospholipids include: diacyl phosphatidyl glycerols, such as: dimyristoyl phosphatidyl glycerol (DPMG), dipalmitoyl phosphatidyl glycerol (DPPG), and distearoyl phosphatidyl glycerol (DSPG); diacyl phosphatidyl cholines, such as: dimyristoyl phosphatidylcholine (DPMC), dipalmitoy] phosphatidylcholine (DPPC), — and distearoyl phosphatidylcholine (DSPC); diacyl phosphatidic acids, such as: dimyristoyl phosphatidic acid (DPMA), dipalmitoyl phosphatidic acid (DPPA), and distearoyl phosphatidic acid (DSPA); and diacyl phosphatidyl ethanolamines such as:
dimyristoyl phosphatidyl ethanolamine (DPME), dipalmitoyl phosphatidyl ethanolamine (DPPE), and distearoyl phosphatidyl ethanolamine (DSPE). Other examples include, but are not limited to, derivatives of ethanolamine (such as phosphatidyl ethanolamine, as mentioned above, or cephalin), serine (such as phosphatidyl serine) and 3'-O-lysyl glycerol (such as 3'.0-lysyl-phosphatidylglycerol).
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. _ The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Thus, the adjuvant systems of the invention are particularly advantageous in making and using vaccine and other immunostimulant compositions to treat or prevent 75 diseases, such inducing active immunity towards antigens in mammals, preferably in humans. Vaccine preparation is a well developed art and general guidance in the preparation and formulation of vaccines is readily available from any of a variety of sources. One such example is New Trends and Developments in Vaccines, edited by
Voller et al., University Park Press, Baltimore, Md., U.S.A. 1978.
In one illustrative embodiment, the antigen in a vaccine composition of the invention is a peptide, polypeptide, or immunogenic portion thereof. An “immunogenic — portion,” as used herein is a portion of 2 protein that is recognized (i.e., specifically bound) by a B-cell and/or T-cell surface antigen receptor. Such immunogenic portions generally comprise at least 5 amino acid residuies, more preferably at least 10, and still more preferably at least 20 amino acid residues of an antigenic protein or a variant thereof. :
Tmmunogenic portions of antigen polypeptides may generally be identified using well known techniques, such as those summarized in Paul, Fundamental
Immunology, 31d ed., 243-247 (Raven Press, 1993) and references cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, antisera and/or T-cell lines or clones. As used herein, antisera and antibodies are "antigen-specific" if they specifically bind to an antigen (i.e., they react with the protein in an ELISA or other immunoassay, and do not react detectably with unrelated proteins). Such antisera and antibodies may be prepared as described herein, and using well known techniques. An immunogenic portion of a protein is a portion that reacts with such antisera and/or T-cells at a level that is not substantially less than the reactivity of the full length polypeptide (e.g., in an ELISA and/or T-cell reactivity assay). Such immunogenic portions may react within such assays at a level that is similar to or greater than the reactivity of the full length polypeptide. Such screens may generally be performed using methods well known to those of ordinary skill in the art, such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor
Laboratory, 1988. For example, a polypeptide may be immobilized on a solid support and contacted with patient sera to allow binding of antibodies within the sera to the immobilized polypeptide. Unbound sera may then be removed and bound antibodies detected using, for example, 1251.1abeled Protein A.
Peptide and polypeptide antigens are prepared using any of a variety of well-known techniques. Recombinant polypeptides encoded by DNA sequences may be readily prepared from isolated DNA sequences using any of a variety of expression 75 vectors known to those of ordinary skill in the art. Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide. Suitable host cells include prokaryotes, yeast, and higher eukaryotic cells, such as mammalian cells and plant cells. Preferably, the host cells employed are E. coli, yeast or a mammalian cell line such as COS or CHO.
Portions and other variants of a protein antigen having less than about 100 — amino acids, and generally less than about 50 amino acids, may also be generated by synthetic means, using techniques well known to those of ordinary skill in the art. For example, such polypeptides may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See Merrifield, J. Am. Chem.
Soc. 85:2149-2146, 1963. Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Perkin Elmer/Applied BioSystems
Division (Foster City, CA), and may be operated according to the manufacturer's instructions.
Within certain specific embodiments, a polypeptide antigen used in the vaccine compositions of the invention may be a fusion protein that comprises two or more distinct polypeptides. A fusion partner may, for example, assist in providing T helper epitopes (an immunological fusion partner), preferably T helper epitopes recognized by humans, or may assist in expressing the protein (an expression enhancer) at higher yields than the native recombinant protein. Certain preferred fusion partners are both immunological and expression enhancing fusion partners. Other fusion partners may be selected so as to increase the solubility of the protein or to enable the protein to be targeted to desired intracellular compartments. Still further fusion partners include affinity tags, which facilitate purification of the protein.
Fusion proteins may generally be prepared using standard techniques, including chemical conjugation. Preferably, a fusion protein is expressed as a recombinant protein, allowing the production of increased levels, relative to a non-fused protein, in an expression system. Briefly, DNA sequences encoding the polypeptide components may be assembled separately, and ligated into an appropriate expression vector. The 3' end of the DNA sequence encoding one. polypeptide component is li gated, with or without a peptide linker, to the 5' end of a DNA sequence encoding the second polypeptide component so that the reading frames of the sequences are in phase. This permits translation into a single fusion protein that retains the biological activity of both component polypeptides.
A peptide linker sequence may be employed to separate the first and second polypeptide components by a distance sufficient to ensure that each polypeptide folds into its secondary and tertiary structures. Such a peptide linker sequence is incorporated into the fusion protein using standard techniques well known in the art.
Suitable peptide linker sequences may be chosen based on the following factors: (1) their | — ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide
Claims (1)
- WHAT IS CLAIMED IS:1 1. A compound having the formula: OR’ X YEA ° i ee rio—(t © ! ; 2 3 and pharmaceutically acceptable salts thereof, wherein X is a member 4 selected from the group consisting of —O- and ~-NH-; Y is a member selected from the group consisting of —O- and -S-; 6 R!, R? and R® are each members independently selected from the group 7 consisting of (Co-Cis)acyl; ) 8 R* is a member selected from the group consisting of -H and ~PO;R'R?, 9 wherein R” and R® are each members independently selected from the group consisting of ~H and (C;-Cs)aliphatic groups; 11 RS is a member selected from the group consisting of —H, -CH; and 12 -PO;R’R', wherein R® and R'° are each members independently selected from the group 13 consisting of —H and (C,-Ca)aliphatic groups; 14 RS is selected from H, OH, (Ci-C)oxyaliphatic groups, -PO;R’ RY, - OPO;R'R'Z -SOR', -0SO:R', -NR''R", -SR"!, -CN, -NO,, -CHO, COR", and 16 -CONR!'R'?, wherein R' and R' are each independently selected from H and (Cy- 17 Ca)aliphatic groups, with the provisos that one of R* and R® is a phosphorus-containing 18 group and that when R* is -PO;R’R’, R’ is other than —POR’R, 19 wherein “*1”, «x2» «kd anq «k*” represent chiral centers; : wherein n, m, p and g are each independently an integer from 0 to 6, with 21 the proviso that the sum of p and m is from 0 to 6.1 2. The compound of claim 1, wherein X and Y are -O-, R* is 2 PO,R'R®, R® and R®are H, and mn, m, p, and q are integers from 0 to2.1 3. The compound of claim 2, wherein R’ and R® are -H.1 4. The compound of claim 3, wherein n is 1, m is 2, and p and g are 0. 21 5. The compound of claim 1 wherein Ry, Ry; and Rj are each Ci-Ci2 2 acyl1 6. The compound of claim 4 wherein R;, R;, and Rj; are each 2 decanoyl residues.1 7. The compound of claim 4 wherein R;, Ry, and Rj are each 2 dodecanoyl residues.1 8. The compound of claim 4, wherein *', *2 and *3 are in the R 2 configuration.1 9. A pharmaceutical composition comprising a pharmaceutically 2 acceptable carrier and a compound of any of claims 1-8. 3 1 10. The pharmaceutical composition according to claim 9 comprising a 2 therapeutically effective amount of a compound of any of claims 1-8. 1 11. The pharmaceutical composition of claims 9 or 10, wherein the 2 pharmaceutical composition further comprises at least one antigen. 3 1 12. The pharmaceutical composition of claim 11, wherein the antigen 9 is derived from the group consisting of Herpes Simplex Virus type 1, Herpes Simplex 3 virus type 2, Human cytomegalovirus, HIV, Hepatitis A, B, C or E, Respiratory Syncytial 4 virus, human papilloma virus, Influenza virus, Tuberculosis, Leishmaniasis, T.Cruzi, Ehrlichia, Candida, Salmonella, Neisseria, Borrelia, Chlamydia, Bordetella, Plasmodium 6 and Toxoplasma. 1 13. The pharmaceutical composition of claim 11, wherein the antigen 2 is a human tumor antigen.Lf14. The pharmaceutical composition of claim 13, wherein the tumor antigen is derived from a prostate, colon, breast, ovarian, pancreatic, brain, head and neck, melanoma, leukemia or lymphoma cancer.15. The pharmaceutical composition of claim 13, wherein the antigen is a self antigen.16. The pharmaceutical composition of claim 15, wherein the self antigen is an antigen associated with an autoimmune disease.17. The pharmaccutical composition of claim 16, wherein the autoimmune disease is type 1 diabetes, multiple sclerosis, myasthenia gravis, rheumatoid arthritis or psoriasis.18. The pharmaceutical composition of any of claims 10-17, in an aqueous formulation.19. The pharmaceutical composition of claim 18, wherein the aqueous formulation comprises one or more surfactants.20. The pharmaceutical composition of any of claims 10-17, in an emulsion formulation.21. The pharmaceutical composition of any of claims 10-17, in a solid formulation.22. A compound of any of claims 1-8 or a composition of any of claims 9-21 for use in a method of inducing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound or the composition.23. A compound of any of claims 1-8 or a composition of any of claims 9-21 for use in a method of treating a mammal suffering from or susceptible 44 Amended sheet: 11 July 2006.. t to a pathogenic infection, cancer or an autoimmune disorder comprising administering to the mammal a therapeutically effective amount of the compound or the composition.24. A compound of any of claims 1-8 or a composition of any of claims 9-21 for use in a method of treating diseases or conditions ameliorated by nitric oxide production in a subject comprising contacting said subject with an effective amount of the compound or the composition.25. Use of a compound of any of claims 1-8 or a composition of any of claims 9-21 in the manufacture of a medicament for use in a method of inducing an immune response in a subject.26. Use of a compound of any of claims 1-8 or a composition of any of claims 9-21 in the manufacture of a medicament for use in a method of treating a mammal suffering from or susceptible to a pathogenic infection, cancer or an autoimmune disorder.27. Use of a compound of any of claims 1-8 or a composition of any of claims 9-21 in the manufacture of a medicament for use in a method of treating diseases or conditions ameliorated by nitric oxide production in a subject.28. A compound of claim 1 as specifically described herein.29. A pharmaceutical composition of claim 9 substantially as herein described with reference to any one of Examples 1 to 3. 45 Amended sheet: 11 July 2006
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