ZA200406025B

ZA200406025B - Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds

Info

Publication number: ZA200406025B
Application number: ZA200406025A
Authority: ZA
Inventors: Jory R Baldridge; David A Johnson; Christopher W Cluff
Original assignee: Corixa Corp
Priority date: 2004-07-28
Filing date: 2004-07-28
Publication date: 2006-06-28

Description

PATENT APPLICATION

PROPHYLACTIC AND THERAPEUTIC TREATMENT OF INFECTIOUS AND OTHER

‘ DISEASES WITH IMMUNOEFFECTOR COMPOUNDS "5 BACKGROUND OF THE INVENTION

The innate immune system coordinates the inflammatory response to pathogens by a system that discriminates between self and non-self via receptors that identify classes of molecules synthesized exclusively by microbes. These classes are sometimes referred to as pathogen associated molecular patterns (PAMPs) and include, for example, lipopolysaccharide (LPS), peptidoglycans, lipotechoic acids, and bacterial lipoproteins (BLPs). :

LPS, an abundant outer cell-wall constituent from gram-negative bacteria, is recognized by the innate immune system. Although the chemical structure of LPS has been known for some time, the molecular basis of recognition of LPS by serum proteins and/or cells is only now being elucidated. In a series of recent reports, a family of receptors, referred to as Toll-like receptors (TLRs), have been linked to the potent innate immune response to LPS and other microbial components. TLR are membrane proteins having a single transmembrane domain. The cytoplasmic domains are approximately 200 amino acids and share similarity with the cytoplasmic domain of the IL-1 receptor. The extracellular domains are relatively large (about 550-980 amino acids) and may contain multiple ligand- binding sites.

The importance of TLRs in the immune response to LPS has been specifically demonstrated for at least two Toll-like receptors, Tlr2 and TIr4. For example, transfection studies with embryonic kidney cells revealed that human Tir2 was sufficient to confer responsiveness to LPS (Yang et al., Nature 395 1284-288 (1998); Kirschning et al. J Exp Med. 11:2091-97 (1998)). A strong response by LPS appeared to require both the LPS-binding . protein (LBP) and CD14, which binds LPS with high affinity. Direct binding of LPS to Tlr2 was observed at a relatively low affinity, suggesting that accessory proteins may facilitate ) binding and/or activation of Tlr2 by LPS in vivo.

The importance of Tlr4 in the immune response to LPS was demonstrated in conjunction with positional cloning in /ps mutant mouse strains. Two mutant alleles of the mouse Ips gene have been identified, a semidominant allele that arose in the C3H/HeJ strain ‘ and a second, recessive allele that is present in the C57BL/1 0ScN and C57BL/10ScCr strains.

Mice that are homozygous for mutant alleles of Ips are sensitive to infection by Gram- negative bacteria and are resistant to LPS-induced septic shock. The Ips locus from these strains was cloned and it was demonstrated that the mutations altered the mouse Tlr4 gene in both instances (Portorak et al., Science 282:2085-2088 (1998); Qureshi et al., J Exp Med 4:615-625 (1999)). It was concluded from these reports that Tlr4 was required for a response to LPS.

The biologically active endotoxic sub-structural moiety of LPS is lipid-A, a phosphorylated, multiply fatty-acid-acylated glucosamine disaccharide that serves to anchor the entire structure in the outer membrane of Gram-negative bacteria. We previously reported that the toxic effects of lipid A could be ameliorated by selective chemical modification of lipid A to produce monophosphoryl lipid A compounds (MPL® immunostimulant; Corixa Corporation; Seattle, WA). Methods of making and using MPL® immunostimulant, and structurally like compounds, for vaccine adjuvant and other applications have been described (see, for example, U.S. Patent Nos. 4,436,727; 4,877,611, 4,866,034 and 4,912,094; 4,987,237; Johnson et al, J Med Chem 42:4640-4649 (1999);

Ulrich and Myers, in Vaccine Design: The Subunit and Adjuvant Approach; Powell and

Newman, Eds.; Plenum: New York, 495-524, 1995). In particular, these and other references demonstrated that MPL® immunostimulant and related compounds had significant adjuvant activities for enhancing humoral and/or cell-mediated immunity to the antigens, when used in vaccine formulations with protein and carbohydrate antigens.

Synthetic mono- and disaccharide molecules which share structural similarities with MPL® immunostimulant, referred to as aminoalkyl glucosaminide phosphates (AGPs), have been described, see for example, U.S. Patent No. 6,113,918, U.S. . Patent No. 6,303,347, and WO 98/50399, published October 12, 1998. These compounds retain significant adjuvant characteristics when formulated with antigens in vaccine * 30 compositions and have similar or improved toxicity profiles when compared with monophosphoryl lipid A. These compounds have been described for use in combination with antigens in vaccine formulations (U.S. Patent No. 6,113,918) and in the absence of antigen, as monotherapies, WO 01/90129, published 29-Nov-2001.

Cyclic aminoalkyl glucosaminide phosphates or “cyclic AGPs” have been ' described in PCT Patent Application No. PCT/US01/24284. These cyclic AGPs are effective immunoeffector molecules which enhance humoral and cell-mediated immune responses to ' vaccine antigens. As used herein, 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.

The present invention provides monotherapies formulated and administered in the absence of exogenous antigens for the prophylactic and/or therapeutic treatment of plant “and animal diseases and conditions, such as infectious diseases, autoimmunity and allergies.

The monotherapies of the present invention comprise one or more cyclic AGPs. These and other aspects of the invention will become evident upon reference to the following detailed description and the attached drawings. :

SUMMARY OF THE INVENTION

In one aspect, the present invention provides methods for treating, ameliorating or substantially preventing a disease or condition in an animal by administering an effective amount of a compound having the formula (I):

OR® x v VN i Rlo—(+ © lo) : @ 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-Czo)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 (C;-Cs)aliphatic groups; R’ is -H, -CH; or -PO;R’R®, wherein

R® and R' are each independently selected from —H and (C;-Cs)aliphatic groups; RS is independently selected from H, OH, (Ci-C)oxyaliphatic groups, PO,R''R'?, -OPO:R''R", _SOR'. -0SO,R!!, -NR''R", SR}, -CN, -NOy, -CHO, -COR"!, and -CONR''R'?, wherein

R! and R'? are each independently selected from H and (C1-Cy)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 «xl-3» and “**” represent chiral centers; wherein the subscripts 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.

In some embodiments, the compounds of the present invention contain an --O- at X and Y, R* is PO;R'R®, R® and RS are H, and the subscripts n, m, p, and q are integers from 0 to 3. In a more preferred embodiment, R’ and R® are -H. In one embodiment, subscript n is 1, subscript m is 2, and subscripts p and q are 0. In other embodiments, Ry, Ra,

A and Rj; are (Ce-Cis) acyl, (Cs-Cra), or (Ce-Cg)acyl groups, in a particular embodiment are provided (Cs-Ci2)acyl groups. A further embodiment provides, #13 are in the R configuration,

Y is in the equatorial position, and ** is in the § configuration.

Illustrative embodiments include N-[(R)-3-tetradecanoyloxytetradecanoyl}- (S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3- tetradecanoyloxytetradecanoylamino]-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]- B-D- : glucopyranoside and pharmaceutically acceptable salts thereof; Formula II,

OH

‘N 0 NH 0 0 0] 0 o) 0 o an

N-[(R)-3 -dodecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-0O-phosphono-2- [(R)-3 _dodecanoyloxytetradecanoylamino}-3-O-[(R)-3-dodecanoyloxytetradecanoyl]- B-D- glucopyranoside and pharmaceutically acceptable salts thereof; Formula III,

OH

. ANS or L ‘N 0 NH 0 0 0) 0 0) 0 0 (III)

and N-[(R)-3-decanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-0O-phosphono- [(R)-3 _decanoyloxytetradecanoylamino]-3-O-[(R)-3-decanoyloxytetradecanoyl]- B-D- } glucopyranoside and pharmaceutically acceptable salts thereof, Formula IV.

OH

: 0 ‘N 0 NH 0 0 0 o o) o °

S

Iv)

In certain illustrative aspects of the invention, the above methods are employed in treating, ameliorating or substantially preventing infectious diseases, autoimmune diseases and allergies.

The present invention, in other aspects, provides pharmaceutical compositions comprising one or more of the compounds described above in a suitable excipient, formulated and/or administered in the absence of exogenous antigen.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention broadly concerns prophylactic and therapeutic methods of treating certain diseases and other medical conditions by administration of an effective amount of one or more compounds described herein or a pharmaceutical composition comprising one or more such compounds. While certain of the cyclic AGP compounds have been described for use as adjuvants in combination with exogenously administered antigens in vaccine formulations, and for use in certain other applications, the present invention : provides novel therapeutic methods that employ the compounds preferably in monotherapeutic applications, i.e., in the absence of exogenously administered antigen.

In one aspect the present invention provides methods for treating, ameliorating and/or substantially preventing infectious diseases in eukaryotic subjects, particularly in animals, preferably in humans. Given the importance of TLR-mediated signalling in the innate immune response to microbial challenge, the ability to stimulate such pathways selectively and with minimal toxicity represents a powerful approach for prophylactic and/or therapeutic treatment modalities against a wide range of infectious agents.

The methods described herein are applicable against essentially any type of infectious agent, including bacteria, viruses, parasites, and fungi. Illustratively, the invention is useful for the prophylactic and/or therapeutic treatment of bacterial infections by species from Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida,

Staphylococci, Streptococci, Chlamydia, Mycoplasma, Bacillus, and numerous others.

Illustrative viral conditions that may be treated in accordance with the invention include those caused, for example, by Influenza viruses, Adenoviruses, parainfluenza viruses,

Rhinoviruses, respiratory syncytial viruses (RSVs), Herpes viruses, Cytomegaloviruses,

Hepatitis viruses, e.g., Hepatitis B and C viruses, and others. Illustrative fungi include, for example, Aspergillis, Candida albicans, Cryptococcus neoformans, Coccidioides immitus, and others.

In one illustrative embodiment, the invention provides methods for the treatment of subjects, particularly immunocompromised subjects, that have developed or are at risk for developing infections, such as nosocomial bacterial and viral infections. About 2 million of the 40 million individuals hospitalized every year develop nosocomial infection during their stay and about 1% of these, or about 400,000 patients, develop nosocomial } pneumonia, more than 7000 of which die. This makes nosocomial pneumonia the leading cause of death in hospital-acquired infections. Thus, this embodiment fills a significant need * 30 for effective prophylactic approaches in the treatment of nosocomial infections.

In a related embodiment, the present invention provides prophylactic treatments for immunocompromised patients, such as HIV-positive patients, who have developed or are at risk for developing pneumonia from either an opportunistic infection or ‘ from the reactivation of a suppressed or latent infection. In 1992, about 20,000 cases of

Pneumocystis carinii infections in AIDS patients were reported in the U.S. alone.

Additionally, 60-70% of all AIDS patients get P.carinii at some time during their illness.

Thus, the present invention in this embodiment provides effective prophylactic methods for this at-risk population.

In another related embodiment, the methods of the present invention are used for treating other patient populations that may be immunocompromised and/or at risk for developing infectious diseases, including, for example, patients with cystic fibrosis, chronic obstructive pulmonary disease and other immunocompromized and/or institutionalized patients.

In another aspect of the invention, the compounds described herein are employed in methods for treating, ameliorating or substantially preventing allergic disorders and conditions, such as sinusitis, chronic rhinosinusitus, asthma, atopic dermatitis and psoriasis. This approach is based at least in part on the ability of the compounds to activate the production of cytokines from target cells that can compete with stereotypic allergic-type cytokine responses characterized by IL-4 production or hyperresponsiveness to IL-4 activity.

Administration of certain of the compounds disclosed herein results in IFN-gamma and IL-12 expression from antigen processing and presenting cells, as well as other cells, resulting in down regulation of cytokines associated with allergic responses such as IL-4, 5, 6,10 and 13.

In another aspect of the invention, compounds are employed in methods for treating autoimmune diseases and conditions. The compounds for use in this embodiment will typically be selected from those capable of antagonizing, inhibiting or otherwise negatively modulating one or more Toll-like receptors, particularly Tlr2 and/or Tlr4, such that an autoimmune response associated with a given condition is ameliorated or substantially : prevented. Tlustratively, the methods provided by this embodiment can be used in the treatment of conditions such as inflammatory bowel disease, rheumatoid arthritis, chronic * 30 arthritis, multiple sclerosis and psoriasis.

Claims

1. The use of one or more compounds having the formula: OR® RO © X YOUN) 0 NH ( R® 0 PN ‘ rio «1 0 R20 *2 R30—( +3 ty) and pharmaceutically acceptable salts thereof, in a method of making a medicament for use in a method for ameliorating or substantially preventing an infectious disease, autoimmune disease or allergic condition in a subject comprising contacting the subject with an effective amount of one or more of the compounds or pharmaceutically acceptable salts thereof, wherein X is a member selected from the group consisting of —O- and —~NH-; Y is a member selected from the group consisting of —O- and —S-; R', R? and R® are each members independently selected from the group consisting of (Cy-Cao)acyl; R* is a member selected from the group consisting of -H and —-PO;R'R®, wherein R’ and R® are each members independently selected from the group consisting of ~H and (C1-Cy)aliphatic groups; R’ is a member selected from the group consisting of —-H, -CHj and -PO;R°R'®, wherein R? and R'® are each members independently selected from the group consisting of — H and (C;-Cy)aliphatic groups; 33 Amended sheet 16/02/2006

RS is selected from H, OH, (C;-Cy)oxyaliphatic groups, -PO;R''R", -OPO;R''R"?, -SO;R", -OSOsR"!, -NR''R"%, -SR", -CN, -NO,, -CHO, -CO,R"", and -CONR''R"?, wherein R' and R'? are each independently selected from H and (C,-Cy)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 carl (c2> R “32 and okx represent chiral centers; wherein n, m, p and gq are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.

2. The use of claim 1, wherein X and Y are ~O-, R* is PO;R'R®, R® and R®are H, and n, m, p, and q are integers from 0 to 3.

3. The use of claim 2, wherein R” and R® are -H.

4, The use of claim 2, wherein n, m, p, and ¢ are from 0 to 2.

5. The use of claim 2, wherein nis 1, m is 2, and p and q are 0.

6. The use of claim 1, wherein Rj, R; and Rj; are each Cs-Cy4 acyl.

7. The use of claim 1, wherein R;, R,; and Rj are each C¢-Cy; acyl.

8. The use of claim 5, wherein Rj, R;, and Rj are each decanoyl residues.

9, The use of claim 5, wherein R;, R,, and Rj are each dodecanoyl residues.

10. The use of claim 5, wherein Rj, R,, and Rj are each tetradecanoyl residues.

11. The use of claim 5, wherein *', *> and ** are in the R configuration.

12. The use of claim 5, wherein Y is in the equatorial position.

13. The use of claim 5, wherein ** is in the S configuration. 34 Amended sheet 16/02/2006

14. The use of claim 5, wherein *!, *2, and ** are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the § configuration.

15. The use of claim 1, wherein the infectious disease is caused by a bacteria, a virus, a parasite, or a fungus.

16. The use of claim 15, wherein said bacteria is a gram negative bacteria, or a gram positive bacteria.

17. The use of claim 15, wherein the infectious disease is caused by a bacteria selected from the group consisting of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus, and Staphylococcus.

18. The use of claim 17, wherein the infectious disease is pneumonia.

19. The use of claim 18, wherein said pneumonia is nosocomial pneumonia.

20. The use of claim 19, wherein said pneumonia is in an HIV-positive patient.

21. The use of claim 1, wherein said infectious disease is a chronic infection.

22. The use of claim 21, wherein said chronic infection comprises chronic hepatitis, human papillomavirus, oral or vaginal candidiasis, periodontal disease or chronic rhinosinusitis due to fungal colonization.

23. The use of claim 1, wherein said allergic condition is selected from the group consisting of asthma, atopic dermatitis, seasonal allergic disorder and chronic rhinosinusitis.

24. The use of claim 1, wherein said autoimmune disease is selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, chronic arthritis, multiple sclerosis and psoriasis. Amended sheet 16/02/2006

25. Theuse of claim 1, wherein said compound is administered to said animal by a route selected from the group consisting of parenteral, oral, intravenous, infusion, intranasal, inhalation, transdermal and transmucosal.

26. The use of one or more compounds having the formula: OR’ RO © X Y n sok Jn 0 NH RS 0 ’N a Rlo—+1 0 R20 *2 R30 *3 @ and pharmaceutically acceptable salts thereof, in a method of making a medicament for use in a method for prophylactic treatment of a bacterial or viral infection in a subject comprising contacting the subject with an effective amount of one or more of the compounds or pharmaceutically acceptable salts thereof, wherein X is a member selected from the group consisting of —O- and ~NH-; Y 1s a member selected from the group consisting of —O- and —S-; R', R? and R? are each members independently selected from the group consisting of (Co-Cao)acyl; R* is a member selected from the group consisting of -H and -PO;R'R?, wherein R” and R® are each members independently selected from the group consisting of —-H and (C;-Cy)aliphatic groups; 36 Amended sheet 16/02/2006

R? is a member selected from the group consisting of —H, -CHj; and -PO;R’R'®, wherein R’ and R'? are each members independently selected from the group consisting of —H and (C;-Cy)aliphatic groups; R® is selected from H, OH, (C,-C4)oxyaliphatic groups, -PO;R''R'?, - OPO;R''R'?, -SO;R", -0SO;R", -NR''R'?, -SR!!, -CN, -NO,, -CHO, -CO,R'!, and -CONR''R'?, wherein R'! and R'? are each independently selected from H and (C;- C)aliphatic groups, with the provisos that one of R* and R® is a phosphorus-containing group and that when R* is -PO;RR®, R’ is other than -PO;R°R!?; - wherein «*!7, «2» , Ck and orn” 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.

27. The use of claim 26, wherein X and Y are —O-, R*is PO;R'R®, R° and R® are H, and n, m, p, and q are integers from 0 to 3.

28. The use of claim 27, wherein R” and R® are —H.

29. The use of claim 27, wherein »n, m, p, and gq are from 0 to 2.

30. The use of claim 28, wherein n is 1, m is 2, and p and q are 0.

31. The use of claim 26, wherein R;, R; and Rj are each C¢-Cy4 acyl.

32. The use of claim 26, wherein R;, Ry; and Rj are each C¢-C;; acyl.

33. The use of claim 30, wherein Ry, Ry, and R; are each decanoyl residues.

34. The use of claim 30, wherein Rj, R,, and R; are each dodecanoyl residues.

35. The use of claim 30, wherein Rj, R;, and Rj are each tetradecanoyl residues.

36. The use of claim 30, wherein *', ** and ** are in the R configuration. 37 Amended sheet 16/02/2006

37. The use of claim 30, wherein Y is in the equatorial position.

38. The use of claim 30, wherein ** is in the § configuration.

39. The use of claim 30, wherein *!, *? | and ** are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the S configuration.

40. The use of claim 26, wherein the infection is caused by a bacteria, a virus, a parasite, or a fungus.

41. The use of claim 40, wherein said bacteria is a gram negative bacteria, or a gram positive bacteria.

42. The use of claim 40, wherein the infection is caused by a bacteria selected from the group consisting of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus, and Staphylococcus.

43. The use of claim 42, wherein the infection is pneumonia.

44. The use of claim 43, wherein said pneumonia is nosocomial pneumonia.

45. A composition formulated and administered in the absence of exogenous antigen comprising one or more compounds having the formula: 38 Amended sheet 16/02/2006

OR® x v Ue 0 NH eS RS RIO—(+1 © lo) " ; @D and pharmaceutically acceptable salts thereof, wherein X is a member selected from the group consisting of —~O- and -NH-; Y is a member selected from the group consisting of —O- and -S-; R!, R? and R? are each members independently selected from the group consisting of (C2-Cao)acyl; R* is a member selected from the group consisting of -H and ~PO;RRS, wherein R’ and R® are each members independently selected from the group consisting of —-H and (Ci-Cy)aliphatic groups; R® is a member selected from the group consisting of —H, -CHj and -PO;R’R", wherein R® and R'? are each members independently selected from the group consisting of —~H and (C,-Cy)aliphatic groups; R® is selected from H, OH, (C,-Cy)oxyaliphatic groups, -POsR''R"?, - OPO;R''R', -SO3R', -OSO;R", -NR''R", -SR'!, -CN, -NO,, -CHO, -CO,R"?, and -CONR'"R", wherein R!' and R'? are each independently selected from H and (C;- Cg)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'Y wherein coxls x2» , “iI” and ok represent chiral centers; 39 : Amended sheet 16/02/2006 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; in combination with a pharmaceutically acceptable carrier.

46. The composition of claim 45, wherein X and Y are —O-, R* is PO;R'R®, R’ and R® are H, and n, m, p, and q are integers from 0 to 3.

47. The composition of claim 46, wherein R’ and R® are —H.

48. The composition of claim 46, wherein n, m, p, and g are from 0 to 2.

49. The composition of claim 47, wherein n is 1, m is 2, and p and q are 0.

50. The composition of claim 45, wherein R;, R; and Rj are each C4-Cy4 acyl.

51. The composition of claim 45, wherein Ry, R;; and Rj are each C4-C;; acyl.

52. The composition of claim 49, wherein Rj, R;, and Rj are each decanoyl residues.

53. The composition of claim 49, wherein R;, R,, and Rj are each dodecanoyl residues.

54. The composition of claim 49, wherein Ri, R,, and R; are each tetradecanoyl residues.

55. The composition of claim 49, wherein #1 *2 , and *3 are in the R configuration.

56. The composition of claim 49, wherein Y is in the equatorial position.

57. The composition of claim 49, wherein ** is in the S configuration. 40 : Amended sheet 16/02/2006

58. The composition of claim 49, wherein *!, ** | and *° are in the R configuration, wherein Y is in the equatorial position, and wherein ** is in the S configuration.

59. The composition of claim 45, further comprising one or more surfactants.

60. The composition of claim 59, wherein said one or more surfactants is selected from the group consisting of dimyristoyl phosphatidyl glycerol (DPMG), dipalmitoyl phosphatidyl glycerol (DPPQG), distearoyl phosphatidyl glycerol (DSPG), dimyristoyl phosphatidylcholine (DPMC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC); dimyristoyl phosphatidic acid (DPMA), dipalmitoyl phosphatidic acid (DPPA), distearoyl phosphatidic acid (DSPA); dimyristoyl phosphatidyl ethanolamine (DPME), dipalmitoyl phosphatidyl ethanolamine (DPPE) and distearoyl phosphatidyl ethanolamine (DSPE).

61. The composition of any one of claims 45 to 60 for use in ameliorating or substantially preventing an infectious disease, autoimmune disease or allergic condition in a subject.

62. The composition of any one of claims 45 to 60 for use in a method for prophylactic treatment of a bacterial or viral infection in a subject.

63. The composition of either one of claims 61 or 62, wherein the infectious disease or infection is caused by a bacteria, a virus, a parasite, or a fungus.

64. The composition of claim 63, wherein said bacteria is a gram negative bacteria, or a gram positive bacteria.

65. The composition of either one of claims 61 or 62, wherein the infectious disease or infection is caused by a bacteria selected from the group consisting of Pseudomonas, Escherichia, Klebsiella, Enterobacter, Proteus, Serratia, Candida, Bacillus, and Staphylococcus. 41 Amended sheet 16/02/2006

E IL EA

66. The composition of claim 65, wherein the infectious disease or infection is pneumonia.

67. The composition of claim 66, wherein said pneumonia is nosocomial pneumonia.

68. The composition of claim 67, wherein said pneumonia is in an HIV-positive patient.

69. The composition of claim 61, wherein said infectious disease is a chronic infection.

70. The composition of claim 69, wherein said chronic infection comprises chronic hepatitis, human papillomavirus, oral or vaginal candidiasis, periodontal disease or chronic rhinosinusitis due to fungal colonization.

71. The composition of claim 61, wherein said allergic condition is selected from the group consisting of asthma, atopic dermatitis, seasonal allergic disorder and chronic rhinosinusitis.

72. The composition of claim 61, wherein said autoimmune disease is selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, chronic arthritis, multiple sclerosis and psoriasis.

73. The use of a cyclic AGP in a method of making a medicament for use in a method for ameliorating or substantially preventing an infectious disease, autoimmune disease or allergic condition in a subject comprising contacting the subject with an effective amount of the cyclic AGP.

74. The use of claim 73 wherein said cyclic AGP is N-[(R)-3- dodecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3- dodecanoyloxy-tetradecanoylamino]-3-O-[(R)-3-dodecanoyloxytetradecanoyl]- g-D- glucopyranoside or a pharmaceuticaly acceptable salt thereof. 42 Amended sheet 16/02/2006 se

75. The use of claim 73 wherein said cyclic AGP is N-[(R)-3- : decanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3- decanoyloxytetradecanoylamino]-3-0-[(R)-3-decanoyloxytetradecanoyl]- p-D- glucopyranoside or a pharmaceutically acceptable salt thereof.

76. The composition of claim 45, substantially as herein described with reference to any one of the illustrative examples. 43 Amended sheet 16/02/2006