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EP-3762716-B1 - A PROTEIN-BINDING PRODUCT, A DEVICE CONTANING SAID PROTEIN-BINDING PRODUCT AND A METHOD FOR EXTRACORPOREAL REDUCTION OF THE LEVEL OF PROTEIN IN BLOOD PLASMA

EP3762716B1EP 3762716 B1EP3762716 B1EP 3762716B1EP-3762716-B1

Inventors

  • NILSSON, KURT

Dates

Publication Date
20260506
Application Date
20190308

Claims (15)

  1. A protein-binding product comprising one or more porous polymer beads, wherein at least one ligand is bound to the surfaces of said polymer beads via a spacer (R), and wherein said at least one ligand is a derivative of Galβ1-3GlcNAcβ-O-, wherein the 3-OH group of Gal is substituted with one of the following groups: a) a 3-OR2 group where the R2 group contains an alkyl group or an aromatic group, b) a 3-OR2 group where the R2 group contains a D-galactosyl group or GalNAc group, c) a 3-NH-CO-R2 group where the R2 group contains an alkyl group or an aromatic group, d) a 3,5-dimethoxybenzamido group, and/or wherein said at least one ligand is Galβ1-3GalNAcβ-O-and/or a derivative thereof, wherein said derivative of said at least one ligand has a structure in which the 3-OH group of Gal is substituted with one of the groups a)-d) above, and/or wherein said at least one ligand is a derivative of Galβ1-4GlcNAcβ-O-, wherein the 3-OH group of Gal is substituted with one of the groups a)-d) above, except for b) where the R2 group contains a D-galactosyl group, wherein said at least one ligand has the ability to bind at least one galectin in human blood, and wherein said protein-binding product in addition comprises polymer beads having at least one covalently bound compound or ligand having the ability to bind at least one antibody in human blood.
  2. The protein-binding product according to claim 1, wherein said at least one antibody is a blood group A specific antibody, a blood group B specific antibody, or an autoantibody.
  3. The protein-binding product according to claim 2, wherein said autoantibody is anAChR (acetylcholine receptor) antibody or a MuSK (muscle-specific kinase) receptor antibody.
  4. The protein-binding product according to any one of the preceding claims, wherein said at least one ligand having the ability to specifically bind to galectins in human blood plasma preferably is galectin-1, galectin-3, and galectin-8.
  5. The protein-binding product according to any one of claims 1 and 2, wherein said ligand having the ability to bind at least one antibody is a blood group A and/or B antigen.
  6. The protein-binding product according to any one of the preceding claims, wherein the concentration of the ligand is in a range of 0.1-20 µmol per mL polymer, preferably 5-20 µmol per mL polymer.
  7. The protein-binding product according to any one of the preceding claims, wherein the concentration of the at least one ligand is in a range of 0.1-5 µmol per mL polymer.
  8. The protein-binding product according to any one of the preceding claims, wherein the spacer (R) is covalently bound to the surfaces of said porous polymer beads and is glycosidically bound to the ligand.
  9. The protein-binding product according to any one of the preceding claims, wherein the spacer is chosen from the group consisting of (CH 2 ) n NH-, (CH 2 ) n PhNH-, PhNH- and Ph(CH 2 ) n NH-, wherein Ph is a phenyl group and n is an integer, preferably wherein n is one of 1, 2, 3, 4, 5 or 6.
  10. The protein-binding product according to any one of the preceding claims, wherein said porous polymer beads are agarose or cross-linked agarose beads, hydroxymethacrylate beads or other porous plastic beads.
  11. Use of said protein-binding product according to any one of claims 1-10 for extracorporeal reduction of the levels of said at least one galectin, preferably galectin-1, galectin-3 and galectin-8; and the levels of said at least one antibody, preferably a blood group A specific antibody, a blood group B specific antibody, an autoantibody, more preferably an AChR (acetylcholine receptor) antibody and a MuSK (muscle-specific kinase) receptor antibody, in human blood plasma.
  12. A device containing said protein-binding product according to any one of claims 1-10, wherein said device is a column or a tubing.
  13. A method for extracorporeal reduction of the level of at least one galectin and at least one antibody in human blood plasma, said method comprising the steps of: a) passing the blood plasma through the device according to claim 12, b) allowing said at least one galactin and said at least one antibody, preferably a blood group A specific antibody, a blood group B specific antibody, an autoantibody, more preferably an AChR (acetylcholine receptor) antibody and a MuSK (muscle-specific kinase) receptor antibody; to bind to said at least one antibody-binding-ligand, c) allowing at least one blood plasma volume to pass through the device after passage of one blood plasma volume through the device, d) repeating step c) until the desired reduction of the level of said at least one galectin and said at least one antibody in the blood plasma is achieved.
  14. The method according to any of claims 13, wherein - the derivative of Galβ1-4GlcNAcβ-O- or a derivative thereof according to claim 1 is used as ligand when the level of galectin-3 is to be reduced.
  15. A method according to any of claims 13 and 14, wherein said method additionally comprises at least one of the following steps: measuring the levels of said at least one galectin and/or said at least one antibody during the treatment and calculating the reduction of the levels of galactose-binding proteins and/or at least one other protein.

Description

Technical Field of the Invention The present invention relates to a protein-binding product comprising porous polymer beads, a device containing said protein-binding product and a method for extracorporeal elimination of at least one galactose-binding protein and optionally at least one other protein in blood plasma. Background An example of galactose binding proteins in blood plasma is a group of proteins called galectins. Galectins are a class of proteins that bind specifically to β-galactoside sugars. These proteins have been associated with a range of diseases. E. g. increased levels of galectins in blood have been detected in humans suffering from inflammatory conditions, autoimmune diseases and cancer. A range of galactoside derivatives, e. g. galactose compounds modified with aliphatic and or aromatic compounds, have been proposed as injectable compounds which potentially can inhibit the galectin activity. Walser P J et al (2005) "Ligand interactions of the Coprinopsis cinerea galectins", Fungal Genetics and Biology, page 293-305, discloses ligand interactions of the galectins of a mushroom, Coprinopsis cinerea. US2002/146814 relates to an apparatus for containing a biologically active saccharide covalently bound by at least one spacer to a cross linked matrix. WO2013/062479 relates to a method for extracorporeal elimination of components in whole blood or blood plasma in a treatment device containing an adsorbent. The adsorbent comprise a matrix to which a ligand is covalently bound. However, since galectins are important in the normal cell and tissue activities, the injection of the galactoside derivatives may lead to unfavourable side effects. A long-term use of these drugs might lead to more or less toxic effects. It is also difficult to assess the concentration of these injected or otherwise administered organic compounds in the different body parts, and thus to ascertain the inhibition effect achieved at the desired sites of galectin action. Summary of the Invention An object of the present invention is to overcome the drawbacks and disadvantages disclosed above. This object is achieved by providing a protein-binding product comprising porous polymer beads, a device containing said protein-binding product and a method for extracorporeal elimination of at least one galactose-binding protein and optionally at least one other protein in blood plasma. The present invention refers to a product as defined in independent claim 1, more precisely to a protein-binding product comprising one or more porous polymer beads, wherein at least one ligand is bound to the surfaces of said polymer beads via a spacer (R), and wherein said at least one ligand is a derivative of Galβ1-3GlcNAcβ-O-, wherein the 3-OH group of Gal is substituted with one of the following groups: a) a 3-OR2 group where the R2 group contains an alkyl group or an aromatic group,b) a 3-OR2 group where the R2 group contains a D-galactosyl group or GalNAc group,c) a 3-NH-CO-R2 group where the R2 group contains an alkyl group or an aromatic group,d) a 3,5-dimethoxybenzamido group, and/or wherein said at least one ligand is Galβ1-3GalNAcβ-O-and/or a derivative thereof, wherein said derivative of said at least one ligand has a structure in which the 3-OH group of Gal is substituted with one of the groups a)-d) above, and/orwherein said at least one ligand is a derivative of Galβ1-4GlcNAcβ-O-, wherein the 3-OH group of Gal is substituted with one of the groups a)-d) above, except for b) where the R2 group contains a D-galactosyl group,wherein said at least one ligand has the ability to bind at least one galectin in human blood, and wherein said protein-binding product in addition comprises polymer beads having at least one covalently bound compound or ligand having the ability to bind at least one antibody in human blood. The present invention refers also to a method as defined in independent claim 13, more precisely to a method for extracorporeal reduction of the level of at least one galectin and at least one antibody in blood plasma, said method comprising the steps of: a) passing the blood plasma through the device according to claim 12,b) allowing said at least one galactin, and said at least one antibody, preferably a blood group A specific antibody, a blood group B specific antibody, an autoantibody, more preferably an AChR (acetylcholine receptor) antibody and a MuSK (muscle-specific kinase) receptor antibody; to bind to said at least one antibody-binding-ligand,c) allowing at least one blood plasma volume to pass through the device after passage of one blood plasma volume through the device,d) repeating step c) until the desired reduction of the level of said at least one galectin and said at least one antibody in the blood plasma is achieved. Disclosed but not claimed is also a method, more precisely a method for extracorporeal reduction of the level of at least one galactose-binding protein and optionally at least one other protein in b