ALK1 receptor and ligand antagonist and uses thereof
AssigneeAcceleron Pharma Inc.
InventorsAsya Grinberg, John Knopf, Robert Scott Pearsall, Ravindra Kumar, Jasbir Seehra
Life of this patent
Estimating the term…
Abstract
In certain aspects, the present disclosure relates to the insight that a polypeptide comprising a ligand-binding portion of the extracellular domain of activin-like kinase I (ALK1) polypeptide may be used to inhibit angiogenesis in vivo, particularly in mammals suffering angiogenesis-related disorders. The disclosure also identifies ligands for ALK1 and demonstrates that such ligands have pro-angiogenic activity, and antibodies that inhibit receptor-ligand interaction.
Claims92
An ALK1-Fc fusion protein comprising:
- a polypeptide having an amino acid sequence that is at least 97% identical to the sequence of amino acids 22-118 of SEQ ID NO:1, which polypeptide is fused to an Fc portion of an immunoglobulin, and wherein the ALK1-Fc fusion protein binds to GDF5, GDF7 and BMP9 with a KD of less than 1×10−7 M and binds to TGFβ-1 with a KD of greater than 1×10−6.
The ALK1-Fc fusion protein, wherein the Fc portion is an Fc portion of a human IgG1.
An ALK1-Fc fusion protein comprising the amino acid sequence of SEQ ID NO:
- 3.
An ALK1-Fc fusion protein that is produced by expression of the nucleic acid of SEQ ID NO:4 in a mammalian cell line.
An antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10.
A method of inhibiting angiogenesis in a mammal, the method comprising, administering to the mammal an effective amount of an ALK1 ECD protein.
A method of inhibiting angiogenesis in a mammal, the method comprising, administering to the mammal an effective amount of an antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10.
An antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6 and GDF7.
An antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of BMP9 and BMP10.
A method of inhibiting angiogenesis in a mammal, the method comprising, administering to the mammal an effective amount of an antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10.
44-48. (canceled)
A method of inhibiting angiogenesis in a mammal, the method comprising, administering to the mammal an effective amount of a DAN protein.
50-56. (canceled)
A method for treating rheumatoid arthritis in a mammal, the method comprising, administering to a mammal that has rheumatoid arthritis an effective amount of an agent selected from the group consisting of:
- (a) an ALK1 ECD protein;
- (b) an antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10;
- (c) an antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10;
- and
- (d) a DAN polypeptide.
A method for treating a tumor in a mammal, the method comprising, administering to a mammal that has a tumor an effective amount of an agent selected from the group consisting of:
- (a) an ALK1 ECD protein;
- (b) an antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10;
- (c) an antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10;
- and
- (d) a DAN poly'peptide.
An ophthalmic pharmaceutical formulation comprising an agent selected from the group consisting of:
- (a) an ALK1 ECD protein;
- (b) an antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10;
- (c) an antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10;
- and
- (d) a DAN polypeptide.
A method of treating an angiogenesis related disease of the eye comprising administering systemically or to said eye a pharmaceutical formulation comprising:
- an effective amount of an agent selected from the group consisting of:
- (a) an ALK1 ECD protein;
- (b) an antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10;
- (c) an antibody that binds to an ALK1 polypeptide consisting of amino acids 22-118 of SEQ ID NO:1 and inhibits the binding of at least one ALK1 ligand selected from the group consisting of:
- GDF5, GDF6, GDF7, BMP9 and BMP10;
- and
- (d) a DAN polypeptide.
Dependencies are inferred from the claim text.