Use of DR6 and p75 antagonists to promote survival of cells of the nervous system
View Patent ↗The present invention relates to Death Receptor-6 (DR6) proteins which are members of the tumor necrosis factor (TNF) receptor family, and have now been shown to be important for regulating apoptosis in cells of the nervous system. In addition, it has been discovered that p75 is a ligand for DR6. As a result, this invention relates to methods for inhibiting the interaction of DR6 and p75 using DR6 and/or p75 antagonists. In addition, the methods described herein include methods of promoting survival of cells of the nervous system using DR6 antagonists, optionally in combination with p75 antagonists, and methods of treating neurodegenerative conditions by the administration of a DR6 antagonists, optionally in combination with a p75 antagonist.
1. A method of inhibiting the binding of DR6 to p75 comprising contacting a DR6 polypeptide and/or p75 polypeptide with a DR6 antagonist under conditions wherein binding of DR6 to p75 is inhibited.
2. The method of claim 1 , wherein said contacting occurs in vitro.
3. The method of claim 1 , wherein said contacting occurs in vivo.
4. A method of treating a condition associated with oligodendrocyte death or lack of differentiation comprising administering a therapeutically effective amount of a DR6 antagonist, wherein said DR6 antagonist is an antibody or antigen-binding fragment thereof that can specifically bind to DR6 and inhibit the binding of DR6 to p75.
5. The method of claim 4 , wherein said DR6 antagonist is used in combination with a p75 antagonist.
6. The method of claim 4 , wherein said DR6 antibody or antigen-binding fragment thereof does not prevent binding of DR6 to APP.
7. The method of claim 4 , wherein the antibody or antigen-binding fragment binds to an epitope in amino acids 133-189 of SEQ ID NO:2.
8. The method of claim 4 , wherein said DR6 antagonist is administered by a route selected from the group consisting of topical administration, intraocular administration, intravitreal administration, parenteral administration, intrathecal administration, subdural administration, subcutaneous administration or via a capsule implant.
9. The method of claim 8 , wherein said route is parenteral administration.
10. A method of treating a condition associated with oligodendrocyte death or lack of differentiation comprising administering a therapeutically effective amount of a DR6 antagonist, wherein said DR6 antagonist comprises a DR6 antibody or antigen-binding fragment thereof, and wherein said DR6 antibody, or antigen-binding fragment thereof can specifically bind to the same DR6 epitope as a reference monoclonal Fab antibody fragment selected from the group consisting of M50-H01, M51-H09, M53-E04, M53-F04, M62-B02, M63-E10, M66-B03, M67-G02, M72-F03, and M73-C04 or a reference monoclonal antibody selected from the group consisting of 1P1D6.3, 1P2F2.1, and 1P5D10.2.
11. The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises
a heavy chain variable region (VH) comprising VH-CDR1, VH-CDR2, and VH-CDR3 regions comprising the amino acid sequences of SEQ ID NOs: 128, 129, and 130 respectively and
a light chain variable region (VL) comprising VL-CDR1, VL-CDR2, and VL-CDR3 regions comprising the amino acid sequences of SEQ ID NOs: 133, 134, and 135 respectively.
12. The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132.
13. The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127.
14. The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132 and a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127.