Immunomodulating compositions and uses therefor
The present invention discloses immunomodulating compositions. More particularly, the present invention discloses compositions comprising an immune-modulating agent and a lectin-interactive agent, which are useful for stimulating and prolonging host immune cell responses. The compositions of the present invention are particularly useful in the treatment and/or prophylaxis of a range of conditions including pathogenic infections, autoimmune diseases, transplant rejection, graft versus host disease, allergies, inflammatory disease, as well as cancers and tumours.
1. A composition for modulating an immune response to a cancer or tumor antigen, comprising
a galectin interactive agent selected from the group consisting of an antibody that binds to galectin and a soluble, non-metabolizable β-galactoside in a form selected from the group consisting of monosaccharides, disaccharides, larger saccharides, synthetic carbohydrates, glycopeptides, N-acetyllactosamine derivatives, modified polysaccharides, starburst dendrimers and glycopolymers, and
an immune-stimulating agent selected from the group consisting of the target antigen, a part of the target antigen that elicits an immune response against the target antigen, an antigen-binding molecule that is immuno-interactive with the target antigen and an immune-modulating cell that modulates an immune response to the target antigen, wherein the immune-stimulating agent produces a greater immune response in the presence of the galectin interactive agent than in the absence of the galectin interactive agent.
2. A composition according to claim 1 , wherein the galectin interactive agent binds to a galectin expressed by the cancer or tumor.
3. A composition according to claim 1 , wherein the galectin-interactive agent interacts with a galectin selected from the group consisting of galectin-1, galectin-3 and galectin-9.
4. A composition according to claim 1 , wherein the β-galactoside is a synthetic carbohydrate comprising thiodigalactoside.
5. A composition according to claim 1 , wherein the β-galactoside is lactulose.
6. A composition according to claim 1 , wherein the β-galactoside is selected from the group consisting of methyl 2-acetamido-2-deoxy-4-O-(3-[3-carboxypropanamido]-3-deoxy-β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[{Z}-3-carboxypropenamido]-3-deoxy-β-D-galactopyranosyl)-) β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-benzamido-3-deoxy-(β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[2-carboxybenzamido]-3-deoxy- β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]-3-deoxy- β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[2-carboxy-3,4,5,6-tetrafluorobenzamido]-3-deoxy-(β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-methane-sulfonamido-3-deoxy-β-D-galactopyranosyl)- β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[4-nitrobenzenesulfonamido]-3-deoxy- β-D-galactopyranosyl)- β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-phenylaminocarbonylamino-3-deoxy-β-D-galactopyranosyl)-(β-D-glucopyranoside, methyl 2-acetamido2-deoxy-4-O-(2-aminoacetamido-3-deoxy-β-D-galactopyranosyl)-β-D-glucopyranoside, and methyl 2-acetamido-2-deoxy-4-O-(3-[{2S}-2-amino-3-carboxy-propanamido]-3-deoxy-β-D-galactopyranosyl)-β-D-glucopyranoside and thiodigalactoside.
7. A composition according to claim 1 , wherein the β-galactoside has a binding affinity for the galectin in the range from about 10 −3 to about 10 −9 M.
8. A composition according to claim 1 , comprising at least two different β-galactosides.
9. A composition according to claim 8 , wherein one of the β-galactosides is soluble so that it can diffuse readily through the body of an animal and wherein the other is a larger β-galactoside that is partially soluble so as to limit its diffusion from the site of delivery to the animal.
10. A composition according to claim 1 , wherein the cancer or tumor antigen is in a form selected from the group consisting of a peptide, a polypeptide, a nucleic acid molecule from which any of these is expressible and an antigen-presented by an antigen-presenting cell.
11. A composition according to claim 1 , wherein the cancer or tumor antigen is an antigen-presenting cell that stimulates an immune response.
12. A composition according to claim 11 , wherein the antigen-presenting cell is a cell to which an immune response is required and which has been optionally modified to enhance its antigen-presenting functions.
13. A composition according to claim 11 , wherein the antigen-presenting cell is modified by culturing the cell in the presence of a type II interferon (IFN) and optionally at least one type I IFN for a time and under conditions sufficient to enhance the antigen-presenting function of the cell and washing the cell to remove the IFN.
14. A composition according to claim 11 , wherein the antigen-presenting cell is modified by introducing a construct into the cell from which one or more IFNs selected from a type II IFN and a type I IFN are expressible.
15. A composition according to claim 11 , wherein the antigen-presenting cell is an allogeneic antigen-presenting cell or cell line that shares major and/or minor histocompatability antigens to a recipient of the composition.
16. A composition according to claim 1 , wherein the cancer or tumor antigen is an immune effector cell selected from the group consisting of T lymphocytes and B lymphocytes.
17. A composition according to claim 16 , wherein the T lymphocytes are selected from the group consisting of cytolytic T lymphocytes helper T lymphocytes and T regulatory cells.
18. A composition according to claim 1 , wherein the immune stimulating agent is an antigen-binding molecule, which binds to or otherwise interacts with the target antigen so as to reduce its level or functional activity.
19. A composition according to claim 1 , further comprising one or more immunoregulatory molecules selected from the group consisting of co-stimulatory molecules, cytokines and co-inhibitory molecules.
20. A composition according to claim 19 , wherein the co-stimulatory molecules are selected from the group consisting of B7-1, B7-2, B7-3, ICAM-1 and ICAM-2.
21. A composition according to claim 19 , wherein the cytokines are selected from the group consisting of interferons, granulocyte/macrophage-colony stimulating factor (GM-CSF), interleukin-10 and tumor necrosis factor α (TNF-α).
22. A composition according to claim 19 , wherein the co-inhibitory molecules are selected from the group consisting of OX-2 and programmed death-1 ligand (PD-1L).
23. A composition according to claim 19 , wherein the immunoregulatory molecule (s) is/are provided in soluble form.
24. A composition according to claim 19 , wherein the immunoregulatory molecule (s) is/are produced intracellularly from an expression construct or vector.
25. A composition according to claim 1 , further comprising an adjuvant.
26. A composition according to claim 1 , further comprising a pharmaceutically acceptable carrier.
27. A method for modulating an immune response to a cancer or tumor antigen in a subject, comprising administering to the subject a composition according to claim 1 .
28. A method according to claim 27 , wherein the galectin interactive agent and the immune-stimulating agent are administered sequentially, separately or simultaneously.
29. A method according to claim 27 , which is used for the treatment of a disease or condition associated with the presence or aberrant expression of the cancer or tumor antigen in a subject.
30. A method according to claim 29 , wherein the disease or condition is treated by using a composition that stimulates or otherwise enhances an immune response to the cancer or tumor antigen.
31. A method according to claim 29 , wherein the disease or condition is selected from the group consisting of a pathogenic infection, a disease characterized by immunodeficiency and a cancer or tumor.
32. A method according to claim 29 , wherein the disease or condition is treated by using a composition that elicits a tolerogenic response to the cancer or tumor antigen.
33. A method according to claim 29 , wherein the disease or condition is selected from the group consisting of transplant rejection, graft versus host disease, allergies, parasitic diseases, inflammatory diseases and autoimmune diseases.
34. A composition according to claim 1 , wherein the β-galactoside is selected from the group consisting of methyl 2-acetamido-2-deoxy-4-O-(3-benzamido-3-deoxy-β-D-galactopyranosyl)β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-(3-[2-carboxy-benzamido]-3-deoxy-β-D-galactopyranosyl)-β-D-glucopyranoside, methyl 2-acetamido-2-deoxy-4-μ-(3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]-3-deoxy-β-D-galactopyranosyl)-β-D-glucopyranoside, and methyl 2-acetamido-2-deoxy-4-O-(3-[2-carboxy-3,4,5,6-tetrafluorobenzamido]-3-deoxy-β-D-galactopyranosyl)-D-glucopyranoside.