DRUG DELIVERY SYSTEMS USING FC FRAGMENTS

• US 20100303723A1
• Filed: 11/20/2007
• Published: 12/02/2010
• Est. Priority Date: 11/20/2006
• Status: Abandoned Application

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Inventors: Pridgen, Eric, Kuo, Timothy T., Farokhzad, Omid C., Langer, Robert S., Radovic-Moreno, Aleksandar Filip, Alexis, Frank
• Application Number:
  US12/515,465
• Publication Number:
  US 20100303723A1
• Time in Patent Office: Days
• US Class Current: 424/9.1
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 2319/035 containing a signal for targeting to the external surface of a cell, e.g. to the outer membrane of Gram negative bacteria, GPI- anchored eukaryote proteins
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Abstract

The present invention provides drug delivery systems comprising FcRn binding partners (e.g., FcRn binding partner, Fc fragment) associated with a particle or an agent to be delivered. Inventive drug delivery systems allow for binding to the FcRn receptor and transcytosis into and/or through a cell or cell layer. Inventive systems are useful for delivering therapeutic agents across the endothelium of blood vessels or the epithelium of an organ.

Claims

1. A particle comprising an agent encapsulated in a particle, wherein the particle is associated with an FcRn binding partner.

2. The particle of claim 1, wherein the FcRn binding partner is an IgG Fc fragment.

7. The particle of claim 2, wherein the IgG Fc fragment comprises an amino acid sequence that is at least 80% identical to any of SEQ ID NOs.:

1-6.

8. The particle of claim 2, wherein the IgG Fc fragment comprises at least about 20 contiguous amino acids of any of SEQ ID NOs.:

1-6.

14. The particle of claim 1, whereby the FcRn binding partner allows the particle to bind to FcRn receptor.

15. The particle of claim 1, whereby the FcRn binding partner allows the particle to bind to FcRn receptor of endothelial or epithelial cells.

16. The particle of claim 1, whereby the FcRn binding partner allows the particle to cross a cell layer by transcytosis.

17. The particle of claim 1, wherein the FcRn binding partner allows the particle to cross an epithelial or endothelial barrier by transcytosis.

18. The particle of claim 1, wherein the agent is a therapeutic, diagnostic, prognostic, or prophylactic agent.

19. The particle of claim 1, wherein the agent is a therapeutic agent.

20. The particle of claim 19, wherein the agent is selected from the group consisting of anti-atherosclerotic agents, cholesterol-lowering agents, thrombolytic agents, anti-platelet agents, and anti-proliferative agents.

26. The particle of claim 1, wherein the agent is selected from the group consisting of insulin, human growth hormone, erythropoietin, cytokines, interferons, antibodies, monoclonal antibodies, humanized antibodies, antibody fragments, protein C, thrombin, bone morphogenetic proteins, colony-stimulating factor, etanercept, and enzymes.

27. The particle of claim 1, wherein the particle is in a form suitable for oral administration or pulmonary administration.

29. The particle of claim 1, wherein the particle is a polymeric particle.

30. The particle of claim 29, wherein the polymeric particle comprises a polymer selected from the group consisting of polyalkylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polyfumarates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, poly(arylates), polycarbonates, polypropylene fumarates), polyhydroxyalkanoates, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polyorthocarbonates, polyvinyl pyrrolidone), polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), and poly(maleic anhydride).

32. The particle of claim 29, wherein the polymer is selected from the group consisting of polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), polyvalerolactone, poly(1,3-dioxan-2one), poly(sebacic anhydride), and polyethylene glycol.

34. The particle of claim 1, wherein the particle is a non-polymeric particle selected from the group consisting of a metal particle, a quantum dot, a ceramic particle, an inorganic particle, a bone particle, a liposome, a micelle, and a reverse micelle.

36. The particle of claim 1, wherein the FcRn binding partner is covalently attached to the particle.

38. The particle of claim 1, wherein the FcRn biding partner is covalently or non-covalently associated with the particle in a orientation-specific manner.

39. The particle of claim 1, wherein the FcRn binding partner is non-covalently associated with the particle through any association selected from the group consisting of affinity interactions, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, and dipole-dipole interactions.

40. The particle of claim 1, wherein the particle is less than 1000 nm in diameter.

79. The particle of claim 1, wherein the particle is associated with a binding partner of an adhesion molecule.

80. The particle of claim 79, wherein the adhesion molecule is selected from the group consisting of selectins, integrins, immunoglobulin superfamily members, and cadherins.

81. The particle of claim 79, wherein the adhesion molecule is selected from the group consisting of ICAM-I, ICAM-2, VCAM-I, E-selectin, and P-selectin.

100. A method of administering a particle, the method comprising step of:

administering a particle of claim 1 to a subject in need thereof.

101. The method of claim 100, wherein the step of administering comprises administering the particle orally, intravascularly, or via inhalation.

108. A method of preparing the particle of claim 1, the method comprising steps of:

providing a particle comprising an agent to be delivered encapsulated in a polymeric matrix;

providing an FcRn binding partner; and

attaching the FcRn binding partner to the surface of the particle.

109. The method of claim 108, wherein the step of attaching comprises covalently attaching the FcRn binding partner to the surface of the particle.

3-6. -6. (canceled)

9-13. -13. (canceled)

21-25. -25. (canceled)

28. (canceled)

31. (canceled)

33. (canceled)

35. (canceled)

37. (canceled)

41-46. -46. (canceled)

47. A conjugate for drug delivery comprising a therapeutic, diagnostic, prognostic, or prophylactic an agent associated with an IgG Fc fragment FcRn binding partner, wherein the IgG Fc fragment comprises an amino acid sequence that is at least 80% identical to any of SEQ ID NOs.:

1-6 or comprises at least about 20 contiguous amino acids of any of SEQ ID NOs.;

1-6.

66. The conjugate of claim 47, wherein the agent is selected from the group consisting of anti-atherosclerotic agents, cholesterol-lowering agents, thrombolytic agents, anti-platelet agents, anti-coagulants, and anti-proliferative agents.

72. The conjugate of claim 47, wherein the agent is selected from the group consisting of insulin, human growth hormone, interferons, antibodies, monoclonal antibodies, humanized antibodies, antibody fragments, protein C, thrombin, bone morphogenetic proteins, colony-stimulating factor, etanercept, and enzymes.

73. The conjugate of claim 47, wherein the particle is in a form suitable for oral or pulmonary administration.

75. The conjugate of claim 47, wherein the FcRn binding partner is covalently attached to the agent.

76. The conjugate of claim 47, wherein the FcRn binding partner is non-covalently associated with the agent through any association selected from the group consisting of affinity interactions, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, and dipole-dipole interactions.

78. The conjugate of claim 47, wherein the FcRn biding partner is covalently or non-covalently associated with the agent in a orientation-specific manner.

86. The conjugate of claim 47, wherein the conjugate is encapsulated in a polymeric particle, wherein the particle is associated with a binding partner of an adhesion molecule.

87. The conjugate of claim 86, wherein the adhesion molecule is selected from the group consisting of selectins, integrins, immunoglobulin superfamily members, and cadherins.

88. The conjugate of claim 86, wherein the adhesion molecule is selected from the group consisting of ICAM-I, ICAM-2, VCAM-I, E-selectin, and P-selectin.

110. A method of preparing the conjugate of claim 47, the method comprising steps of:

providing an agent to be delivered;

providing an FcRn binding partner; and

associating the FcRn binding partner to the agent.

111. The method of claim 110, wherein the step of associating comprises covalently attaching the FcRn binding partner to the agent.

48-65. -65. (canceled)

67-71. -71. (canceled)

74. (canceled)

77. (canceled)

82-85. -85. (canceled)

89-94. -94. (canceled)

95. A pharmaceutical composition comprising an agent associated with an FcRn binding partner.

96-99. -99. (canceled)

102-107. -107. (canceled)