Claims
- 1. An isolated immunomodulatory polymer, comprising:
a polymer comprising a plurality of a repeating unit, with each repeating unit comprising a tetramer backbone having a structure —(S1—S2—S3—S4)—including, each independent of the others, a first subunit S1, a second subunit S2, a third subunit S3, and a fourth subunit S4, each tetramer backbone including a negatively charged moiety on the first subunit S1 and a free amino moiety on the fourth subunit S4.
- 2. The isolated immunomodulatory polymer of claim 1, wherein the plurality of a repeating unit is selected from the group consisting of: at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, and at least 20 repeating units.
- 3. The isolated immunomodulatory polymer of claim 2, wherein the repeating units of the plurality of a repeating unit are contiguous.
- 4. The isolated immunomodulatory polymer of claim 1, wherein the polymer consists essentially of a plurality of the repeating unit.
- 5. The isolated immunomodulatory polymer of claim 1, wherein the negatively charged moiety on the first subunit is selected from the group consisting of: carboxyl, phosphate, and phosphonate.
- 6. The isolated immunomodulatory polymer of claim 1, wherein the subunits are independently selected from the group consisting of: monosaccharide, disaccharide, amino acid, dipeptide, nucleotide, C5-18 cycloalkyl, C5-18 aryl, and combinations and analogs thereof
- 7. The isolated immunomodulatory polymer of claim 1, wherein the subunits are independently monosaccharides or analogs thereof.
- 8. The isolated immunomodulatory polymer of claim 1, wherein the subunits are independently amino acids or analogs thereof.
- 9. The isolated immunomodulatory polymer of claim 1, wherein the subunits are independently branched or unbranched.
- 10. The isolated immunomodulatory polymer of claim 1, wherein the subunits S3 are branched.
- 11. The isolated immunomodulatory polymer of claim 1, wherein the repeating unit is a pentamer.
- 12. The isolated immunomodulatory polymer of claim 1, wherein the repeating unit is a branched pentamer.
- 13. The isolated immunomodulatory polymer of claim 1, wherein the isolated immunomodulatory polymer is a naturally occurring polymer.
- 14. The isolated immunomodulatory polymer of claim 1, wherein the free amino moiety on the fourth subunit of one repeating unit is less than about 32 Å from a next-nearest free amino moiety on the fourth subunit of another unit.
- 15. A pharmaceutical preparation which activates immune cells, comprising:
an effective amount, for activating immune cells, of an isolated immunomodulatory polymer according to claim 1; and a pharmaceutically acceptable carrier.
- 16. A pharmaceutical preparation which activates immune cells, comprising:
an effective amount, for activating immune cells, of an isolated immunomodulatory polymer according to any of claims 2-14; and a pharmaceutically acceptable carrier.
- 17. An isolated immunomodulatory polysaccharide, comprising:
a polysaccharide comprising a plurality of a repeating unit, with each repeating unit comprising a tetrasaccharide backbone having a structure -(M1-M2-M3-M4)- including, each independent of the others, a first monosaccharide M1, a second monosaccharide M2, a third monosaccharide M3, and a fourth monosaccharide M4, each tetrasaccharide backbone including a negatively charged moiety on the first monosaccharide M1 and a free amino moiety on the fourth monosaccharide M4.
- 18. The immunomodulatory polysaccharide of claim 17, wherein the immunomodulatory polysaccharide is PS A2.
- 19. A pharmaceutical preparation which activates immune cells, comprising:
an effective amount, for activating immune cells, of an isolated immunomodulatory polysaccharide according to claim 17; and a pharmaceutically acceptable carrier.
- 20. An isolated immunomodulatory polysaccharide comprising PS A2.
- 21. A pharmaceutical preparation which activates immune cells, comprising:
an effective amount, for activating immune cells, of an isolated immunomodulatory polysaccharide according to claim 20; and a pharmaceutically acceptable carrier.
- 22. An isolated immunomodulatory polymer, comprising:
a polymer having a plurality of a repeating charge motif, wherein the repeating charge motif is a positive charge and a negative charge arranged along the polymer so that positive charges of consecutive charge motifs are separated by less than about 32 Å, wherein the polymer has a three-dimensional solution conformation in which a majority of the positive charges and the negative charges are solvent-accessible, said three-dimensional solution conformation having a plurality of docking sites, each docking site being about 10 Å wide and about 5 Å deep.
- 23. The isolated immunomodulatory polymer of claim 22, wherein the isolated immunomodulatory polymer is not selected from the group consisting of: PS A1, PS B, Salmonella typhi Vi antigen, Escherichia coli K5 antigen, Staphylococcus aureus type 5 capsular polysaccharide, Rhizobium meliloti exopolysaccharide II, group B streptococcus type III capsular polysaccharide, Pseudomonas aerugenosa Fisher immunotype 7O-antigen, Shigella sonnei Phase I lipopolysaccharide O-antigen, Streptococcus pneumoniae type I capsular polysaccharide, Streptococcus pneumoniae group antigen: C substance, and Trypanosoma cruzi lipopeptidophosphoglycan.
- 24. The isolated immunomodulatory polymer of claim 22, wherein the polymer comprises a plurality of a repeating unit.
- 25. The isolated immunomodulatory polymer of claim 24, wherein the plurality of a repeating unit is selected from the group consisting of: at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, and at least 20 repeating units.
- 26. The isolated immunomodulatory polymer of claim 25, wherein the repeating units of the plurality of a repeating unit are contiguous.
- 27. The isolated immunomodulatory polymer of claim 24, wherein the polymer consists essentially of a plurality of the repeating unit.
- 28. The isolated immunomodulatory polymer of claim 22, wherein the positive charge of the charge motif is a free amino group.
- 29. The isolated immunomodulatory polymer of claim 22, wherein the three-dimensional solution conformation comprises a helix.
- 30. The isolated immunomodulatory polymer of claim 29, wherein the helix has a pitch of about 20 Å.
- 31. The isolated immunomodulatory polymer of claim 22, wherein the isolated immunomodulatory polymer is a mixed polymer.
- 32. The isolated immunomodulatory polymer of claim 22, wherein the docking site is at least about 10 Å long.
- 33. The isolated immunomodulatory polymer of claim 22, wherein the docking site includes a plurality of solvent-accessible charges.
- 34. The isolated immunomodulatory polymer of claim 22, wherein the docking site is constructed and arranged to bind, under physiologic conditions, an alpha helix of a polypeptide with an affinity of at least 10−3 M−1.
- 35. The isolated immunomodulatory polymer of claim 22, wherein the docking site is constructed and arranged to bind, under physiologic conditions, an alpha helix of a polypeptide with an affinity of at least 10−6 M−1.
- 36. The isolated immunomodulatory polymer of claim 22, wherein the docking site is constructed and arranged to bind, under physiologic conditions, an alpha helix of a polypeptide with an affinity of at least 10−9 M−1.
- 37. The isolated immunomodulatory polymer of claim 22, wherein the alpha helix of a polypeptide is an alpha helix of a major histocompatibility complex (MHC) molecule.
- 38. The isolated immunomodulatory polymer of claim 22, wherein the alpha helix of a polypeptide is an alpha helix of a T-cell antigen receptor.
- 39. A pharmaceutical preparation which activates immune cells, comprising:
an effective amount, for activating immune cells, of an isolated immunomodulatory polymer according to any of claims 22-38; and a pharmaceutically acceptable carrier.
- 40. A method for inducing protection against abscess formation associated with infection, comprising:
administering to a subject in need of such protection a pharmaceutical preparation according to any of claims 15, 19, and 21, in an effective amount to induce protection against abscess formation associated with infection.
- 41. A method for reducing surgical adhesion formation occurring at a surgical site, comprising:
administering to a subject in need of such reducing surgical adhesion formation a pharmaceutical preparation according to any of claims 15, 19, and 21, in an effective amount to reduce surgical adhesion formation.
- 42. A method for inducing interleukin 2 (IL-2) secretion, comprising:
administering to a subject in need of such IL-2 secretion a pharmaceutical preparation according to any of claims 15, 19, and 21, in an effective amount to induce IL-2 secretion.
- 43. A method for inducing interleukin 10 (IL-10) secretion, comprising: administering to a subject in need of such IL-10 secretion a pharmaceutical preparation according to any of claims 15, 19, and 21, in an effective amount to induce IL-10 secretion.
- 44. A system for selecting a candidate immunomodulatory polymer, comprising:
a prediction module having an input to receive an input signal specifying primary structure of a candidate immunomodulatory polymer, logic to generate a three-dimensional solution conformation of the candidate immunomodulatory polymer, and an output to output a polymer signal specifying the three-dimensional solution conformation of the candidate immunomodulatory polymer; and an analysis module having an input to receive the polymer signal, logic to select a candidate immunomodulatory polymer if its three-dimensional solution conformation generated by the prediction module includes (i) a plurality of repeating units, (ii) a plurality of solvent-accessible charges, and (iii) a plurality of docking sites wherein each docking site is about 10 Å wide and about 5 Å deep, and an output to output an output signal specifying a candidate immunomodulatory polymer if the candidate immunomodulatory polymer is selected by the analysis module.
- 45. A computer-implemented method for selecting a candidate immuno modulatory polymer, comprising:
receiving a signal specifying a primary structure of a candidate immunomodulatory polymer; generating a three-dimensional solution conformation of the candidate immunomodulatory polymer; selecting a candidate immunomodulatory polymer if the three-dimensional solution conformation of the candidate immunomodulatory polymer includes a plurality of repeating units, a plurality of solvent-accessible charges, and a plurality of docking sites, each docking site being about 10 Å wide and about 5 Å deep; and outputting an output signal specifying the candidate immunomodulatory polymer if the candidate immunomodulatory polymer is selected.
- 46. The method of claim 45, wherein the signal specifying a primary structure of a candidate immunomodulatory polymer specifies a plurality of candidate immunomodulatory polymers.
- 47. The method of claim 45, wherein the selected candidate immunomodulatory polymer is made up of repeating units.
- 48. The method of claim 47, wherein the repeating units are contiguous.
- 49. The method of claim 47, wherein the repeating units are separated by intervening sequence.
- 50. The method of claim 45, wherein the selected candidate immunomodulatory polymer has a repeating charge motif, wherein the repeating charge motif is a positive charge and a negative charge arranged along the polymer so that positive charges of consecutive charge motifs are separated by less than about 32 Å.
- 51. The method of claim 45, wherein the selected candidate immunomodulatory polymer has a sugar backbone.
- 52. The method of claim 45, wherein the selected candidate immunomodulatory polymer is a polysaccharide.
- 53. The method of claim 45, wherein the selected candidate immunomodulatory polymer has a polypeptide backbone.
- 54. The method of claim 45, further comprising:
contacting a selected candidate immunomodulatory polymer with an immune cell under physiologic conditions in which the immune cell is normally not activated; and measuring an activation marker of the immune cell.
- 55. A system for designing a candidate immunomodulatory polymer, comprising:
a virtual subunit selection module having (a) an input to receive an input signal specifying a plurality of virtual subunits corresponding to chemical compounds, the plurality of virtual subunits including virtual subunits having positive charge, virtual subunits having negative charge, and virtual subunits having no charge, wherein each virtual subunit comprises a core and optionally at least one charged or neutral substituent attached to the core, (b) logic for selecting from the plurality of virtual subunits (i) a virtual subunit having positive charge, (ii) a virtual subunit having a negative charge, or (iii) both (i) and (ii), and (c) an output to output a selected virtual subunit signal; a conversion module having a first input to receive the selected virtual subunit signal and a second input to receive an input signal specifying at least one template, wherein the template is a three-dimensional solution phase representation of a reference immunomodulatory polymer having a plurality of repeating units, each unit comprising a charge motif provided by at least a first subunit having a positive charge and a second subunit having a negative charge, logic to convert (i) the subunit having the positive charge of the charge motif of the template with the virtual subunit having positive charge selected from the plurality of virtual subunits, (ii) the subunit having negative charge of the charge motif of the template with the virtual subunit having a negative charge selected from the plurality of virtual subunits, or (iii) both (i) and (ii), and an output to output a converted template signal specifying a primary structure of a candidate immunomodulatory polymer, a prediction module having an input to receive the converted template signal, logic to generate a three-dimensional solution conformation of the candidate immunomodulatory polymer, and an output to output a polymer signal specifying the three-dimensional solution conformation of the candidate immunomodulatory polymer; and a comparison module having a first input to receive the polymer signal, a second input to receive the input signal specifying at least one template, and a third input to receive an input signal specifying comparison criteria selected to measure similarity between the polymer signal and the template, logic to compare the polymer signal and the template according to the comparison criteria, and an output to output an output signal specifying the candidate immunomodulatory polymer if comparison of the polymer signal and the template meets the comparison criteria.
- 56. A computer-implemented method for designing a candidate immunomodulatory polymer, comprising:
receiving a signal specifying a plurality of virtual subunits corresponding to chemical compounds, the plurality of virtual subunits including virtual subunits having positive charge, virtual subunits having negative charge, and virtual subunits having no charge, wherein each virtual subunit comprises a core and optionally at least one charged or neutral substituent attached to the core; selecting from the plurality of virtual subunits (i) a virtual subunit having positive charge, (ii) a virtual subunit having a negative charge, or (iii) both (i) and (ii); receiving a signal specifying at least one template, wherein the template is a three-dimensional solution phase representation of a reference immunomodulatory polymer having a plurality of repeating units, each unit comprising a charge motif provided by at least a first subunit having a positive charge and a second subunit having a negative charge; generating a candidate immunomodulatory polymer having a primary structure by converting (i) the subunit having the positive charge of the charge motif of the template with the virtual subunit having positive charge selected from the plurality of virtual subunits, (ii) the subunit having negative charge of the charge motif of the template with the virtual subunit having a negative charge selected from the plurality of virtual subunits, or (iii) both (i) and (ii); generating a three-dimensional solution conformation of the candidate immunomodulatory polymer having a primary structure; receiving a signal specifying comparison criteria selected to measure similarity between the three-dimensional solution conformation of the candidate immunomodulatory polymer and the template; comparing the three-dimensional solution conformation of the candidate immunomodulatory polymer and the template according to the comparison criteria; and outputting a signal specifying the candidate immunomodulatory polymer if comparison of the three-dimensional solution conformation of the candidate immunomodulatory polymer and the template meets the comparison criteria.
- 57. The method of claim 56, wherein the reference immunomodulatory polymer is PS A2.
- 58. The method of claim 56, wherein the candidate immunomodulatory polymer comprises a polysaccharide.
- 59. The method of claim 56, wherein the candidate immunomodulatory polymer is a polysaccharide.
- 60. The method of claim 56, wherein the candidate immunomodulatory compound comprises a polypeptide.
- 61. The method of claim 56, wherein the candidate immunomodulatory compound is a polypeptide.
Priority Claims (1)
Number |
Date |
Country |
Kind |
60251747 |
Dec 2000 |
US |
|
RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional patent application Serial No. 60/251,747, filed on Dec. 5, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US01/47251 |
12/5/2001 |
WO |
|