Immunomodulatory compositions
Isolated immunomodulatory (e.g. immunostimulatory) polyhydroxlated pyrrolizidine compounds having the formula (I), wherein R is selected from the group comprising hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated acyl, alkyl (e.g. cycloalkyl), alkenyl, alkynyl and aryl groups, or a pharmaceutically acceptable salt or derivative thereof, are useful in therapy and prophylaxis, including increasing the Th1:Th2 response ratio, haemorestoration, alleviation of immuno-suppression, cytokine stimulation, treatment of proliferative disorders (e.g. cancer), vaccination, stimulation of the innate immune response and boosting of the activity of endogenous NK cells.
1. A vaccine comprising
(1) a polyhydroxylated pyrrolizidine compound of formula:
wherein R is selected from the group consisting of hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated acyl, alkyl, alkenyl, alkynyl, aryl groups, and a saccharide moiety,
or a pharmaceutically acceptable salt or acyl derivative thereof, wherein said acyl derivative is selected from the group consisting of aroyl, acetyl, propanoyl and butanoyl;
in combination with
(2) an antigen,
said pyrrolizidine compound being present in an amount sufficient to produce an adjuvant effect on vaccination.
2. A vaccine according to claim 1 wherein the pyrrolizidine compound has the formula:
wherein R is selected from the group consisting of hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated acyl, alkyl, alkenyl, alkynyl and aryl groups, or a pharmaceutically acceptable salt or acyl derivative thereof.
3. A vaccine according to claim 1 wherein the pyrrolizidine compound is an acyl derivative.
4. A vaccine according to claim 3 wherein the pyrrolizidine acyl derivative is chosen from the group consisting of a peracylated derivative, a derivative that is acylated at C-3 hydroxymethyl; a derivative that is acylated at C-6; and a derivative that is acylated at C-3 hydroxymethyl and C-6.
5. A vaccine according to claim 4 wherein the pyrrolizidine acyl derivative is acylated at C-6.
6. A vaccine according to claim 3 wherein the acyl derivative is an alkanoyl derivative selected from the group consisting of acetyl, propanoyl and butanoyl.
7. A vaccine according to claim 1 wherein R is a saccharide moiety.
8. A vaccine according to claim 7 wherein the saccharide moiety is a glucoside or arabinoside moiety.
9. A vaccine according to claim 1 wherein the pyrrolizidine compound is chosen from the group consisting of:
(a) 1R,2R,3R,6S,7S,7aR)-3-(hydroxymethyl)-1,2,6,7-tetrahydroxypyrrolizidine (casuarine), wherein R is hydrogen and having the formula:
(b) a casuarine glycoside;
(c) casuarine-6-α-D-glucoside of the formula:
(d) 6-O-butanoylcasuarine;
(e) 3,7-diepi-casuarine;
(f) 7-epi-casuarine;
(g) 3,6,7-triepi-casuarine;
(h) 6,7-diepi-casuarine;
(i) 3-epi-casuarine;
(j) 3,7-diepi-casuarine-6-α-D-glucoside;
(k) 7-epi-casuarine-6-α-D-glucoside;
(l) 3,6,7-triepi-casuarine-6-α-D-glucoside;
(m) 6,7-diepi-casuarine-6-α-D-glucoside;
(n) 3-epi-casuarine-6-α-D-glucoside, and
a pharmaceutically acceptable salt or acyl derivative of any of (a)-(n).
10. A vaccine according to claim 1 wherein the pyrrolizidine compound is chosen from the group consisting of:
or a pharmaceutically acceptable salt or aroyl, acetyl, propanoyl or butanoyl derivative thereof,
wherein R is selected from the group consisting of hydrogen, straight or branched, unsubstituted or substituted, saturated or unsaturated acyl, alkyl, alkenyl, alkynyl and aryl groups, and a saccharide moiety.
11. A vaccine according to claim 1 further comprising an additional therapeutic agent chosen from the group consisting of one or more of:
(a) an immunostimulant;
(b) a cytotoxic agent;
(c) an antimicrobial agent;
(d) an antiviral agent; and
(e) a primed dendritic cell.