Inhibition of the Anti-FVIII Immune Response
The invention relates to a compound capable of inhibiting the endocytosis of FVIII (factor VIII) by immune system cells capable of endocytosing the antigen and to the therapeutic use of such a compound for the manufacture of a medicament for use in the treatment of hemophiliacs in order to reduce the immunogenicity of FVIII and/or increase the half-life of FVIII.
1 .- 28 . (canceled)
29 . Deglycosylated factor VIII or a fragment thereof for which the ability for interacting and the ability for endocytosited by cells which are capable of endocytosing an antigen are decreased or inhibited with respect to native factor VIII.
30 . Deglycosylated factor VIII or a fragment thereof according to claim 29 , for which the ability for interacting with the receptors present on the surface of the said cells which are capable of endocytosing an antigen is reduced or inhibited.
31 . Deglycosylated factor VIII or a fragment thereof according to claim 30 , for which the said receptors are receptors specific for mannose.
32 . Deglycosylated factor VII or a fragment thereof according to claim 31 , for which the said receptors are the mannose receptor CD206 or the DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin) receptor CD209.
33 . Deglycosylated factor VIII or a fragment thereof according to claim 29 , for which the said cells which are capable of endocytosing an antigen are antigen-presenting cells (APCs).
34 . Deglycosylated factor VIII or a fragment thereof according to claim 33 , for which the said antigen-presenting cells (APCs) are dendritic cells or B lymphocytes.
35 . Deglycosylated factor VIII or a fragment thereof according to claim 29 , for which the said cells which are capable of endocytosing an antigen are chosen from macrophages, endothelial cells, liver sinusoidal endothelial cells, liver Kupffer cells.
36 . Deglycosylated factor VIII or a fragment thereof according to claim 29 , for which the deglycosylation is obtained without the use of one or more enzymes chosen from the group consisting of a neuraminidase, a beta-galactosidase and an alpha-mannosidase.
37 . Deglycosylated factor VIII or a fragment thereof according to claim 29 , for which the deglycosylation is obtained by the action of a single enzyme of the endoglucosidase type.
38 . Deglycosylated factor VIII or a fragment thereof according to claim 37 , for which the said enzyme of the endoglucosidase type is an endo-beta-N-acetylglucosaminidase.
39 . Deglycosylated factor VIII or a fragment thereof according to claim 38 , for which the said endo-beta-N-acetylglucosaminidase has the ability to cut carbohydrate structures of the oligomannose type and of the hybrid type, and does not have the ability to cut carbohydrate structures of the complex type.
40 . Deglycosylated factor VIII or a fragment thereof according to claim 38 , for which the said endo-beta-N-acetylglucosaminidase is chosen from the group consisting of endo-beta-N-acetylglucosaminidase F1 and endo-beta-N-acetylglucosaminidase H.
41 . Deglycosylated factor VIII or a fragment thereof according to claim 40 , for which the said endo-beta-N-acetylglucosaminidase F1 is the endo-beta-N-acetylglucosaminidase F1 of Chryseobacterium ( Flavobacterium ) meningosepticum.
42 . Deglycosylated factor VIII or a fragment thereof according to claim 40 , for which the said endo-beta-N-acetylglucosaminidase H is the endo-beta-N-acetylglucosaminidase H of Streptomyces picatus.
43 . A pharmaceutical composition comprising a carrier and deglycosylated factor VIII or a fragment thereof according to claim 29 .
44 . A pharmaceutical composition comprising a carrier and an amount of deglycosylated factor VIII or a fragment thereof according to claim 29 effective to treat a hemophilic patient.
45 . A pharmaceutical composition comprising a carrier and an amount of deglycosylated factor VIII or a fragment thereof according to claim 29 effective to treat a patient afflicted with hemophilia of type A or B.
46 . A method for treating a hemophilic patient comprising administering to the patient the deglycosylated factor VIII or fragment thereof according to claim 29 .
47 . The method of claim 46 , wherein the factor VIII or fragment is administered in combination with exogenous factor VIII.
48 . A method for treating a patient afflicted with hemophilia of type A or B comprising administering to the patient the deglycosylated factor VIII or fragment thereof according to claim 29 .
49 . A method for treating a hemophilic patient comprising administering to the patient the deglycosylated factor VIII or fragment thereof according to claim 29 , wherein the factor VIII or fragment increases the half-life of an exogenous factor VIII in the hemophilic patient.
50 . A method for treating a hemophilic patient comprising administering to the patient the deglycosylated factor VIII or fragment thereof according to claim 29 , wherein the factor VIII or fragment reduces the immunogenicity of an exogenous factor VIII in the hemophilic patient.
51 . Pharmaceutical composition comprising the deglycosylated factor VIII or fragment thereof according to claim 29 and one or more pharmaceutically acceptable adjuvant(s) and/or excipient(s).
52 . A method for treating a hemophilic patient comprising administering to the patient a composition comprising mannan.
53 . A method for treating a patient afflicted with hemophilia of type A or B comprising administering to the patient a composition comprising mannan.
54 . A method for treating a hemophilic patient comprising administering to the patient a composition comprising mannan, wherein the composition increases the half-life of an exogenous factor VIII in a hemophilic patient.
55 . A method for treating a hemophilic patient comprising administering to the patient a composition comprising mannan, wherein the composition reduces the immunogenicity of an exogenous factor VIII in a hemophilic patient.
56 . The method according to claim 52 , wherein the composition comprising mannan also comprises (i) an exogenous factor VIII of the native type and/or (ii) a deglycosylated factor VIII or fragment thereof for which the ability for interacting and the ability for endocytosited by cells which are capable of endocytosing an antigen are decreased or inhibited with respect to native factor VIII
57 . The method according to claim 53 , wherein the composition comprising mannan also comprises (i) an exogenous factor VIII of the native type and/or (ii) a deglycosylated factor VIII or fragment thereof for which the ability for interacting and the ability for endocytosited by cells which are capable of endocytosing an antigen are decreased or inhibited with respect to native factor VIII
58 . The method according to claim 54 , wherein the composition comprising mannan also comprises (i) an exogenous factor VIII of the native type and/or (ii) a deglycosylated factor VIII or fragment thereof for which the ability for interacting and the ability for endocytosited by cells which are capable of endocytosing an antigen are decreased or inhibited with respect to native factor VIII
59 . The method according to claim 55 , wherein the composition comprising mannan also comprises (i) an exogenous factor VIII of the native type and/or (ii) a deglycosylated factor VIII or fragment thereof for which the ability for interacting and the ability for endocytosited by cells which are capable of endocytosing an antigen are decreased or inhibited with respect to native factor VIII