Lefty polypeptides and derivatives thereof
AssigneeAcceleron Pharma Inc.
InventorsJohn Knopf, Jasbir Seehra, Ravindra Kumar
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Abstract
The disclosure relates to Lefty derivatives and the uses of Lefty polypeptides as antagonists of the function of certain ligands such as Nodal, GDF-8 (Myostatin), and GDF-11. These derivatives may be fused to other functional heterologous proteins such as IgG, especially the Fc portion of IgG. According to the disclosure, Lefty polypeptides are useful in the treatment of a variety of disorders, including, for example, neuronal diseases, muscle and bone conditions, and metabolic disorders.
Claims33
A recombinant Lefty derivative polypeptide comprising an amino acid sequence as set forth in the formula:
- W-A-X-B-Y,
- wherein A consists essentially of an amino acid sequence at least 85% identical to the sequence of Region 2 of SEQ ID NO:
- 1;
- wherein B consists essentially of an amino acid sequence at least 85% identical to the sequence of Region 4 of SEQ ID NO:
- 1;
- wherein X consists of zero, one or more than one amino acid;
- wherein W consists of zero, one or more than one amino acid;
- wherein Y consists of zero, one or more than one amino acid;
- wherein the recombinant Lefty derivative polypeptide binds to one or more of Nodal, myostatin and GDF-11;
- wherein the recombinant Lefty derivative polypeptide is not a wild-type Lefty polypeptide;
- wherein the recombinant Lefty derivative polypeptide comprises an amino acid sequence that is at least 95% identical to a human Lefty polypeptide sequence selected from the group consisting of amino acids 78-353 of SEQ ID NO:
- 1 and amino acids 78-353 of SEQ ID NO:2;
- and
- wherein the recombinant Lefty derivative polypeptide comprises one or more mutations within the RXXR cleavage sequence corresponding to amino acid residues 132-135 of SEQ ID NO:
- 1 or 2 so as to prevent cleavage at the mutated sequence.
An isolated Lefty polypeptide complex comprising:
- a) a first Lefty polypeptide;
- and
- b) a second Lefty polypeptide,
- wherein the first and second Lefty polypeptides are associated to form a complex, wherein the complex binds to a TGF-β family member selected from the group consisting of:
- myostatin, Nodal and GDF-11, and wherein at least one of the Lefty polypeptides of the complex comprises one or more mutations within the RXXR cleavage sequence corresponding to amino acid residues 132-135 of SEQ ID NO:1 or 2 so as to prevent cleavage at the mutated sequence.
A recombinant Lefty derivative polypeptide comprising an amino acid sequence as set forth in the formula:
- W-A-X-B-Y;
- wherein the Lefty derivative polypeptide comprises an amino acid sequence that is at least 85% identical to a human Lefty polypeptide sequence selected from the group consisting of:
- SEQ ID NO:1 and SEQ ID NO:2;
- wherein A is selected from the group consisting of:
- CRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGT (SEQ ID NO:
- 5) and CRQEMYIDLQGMKWAENWVLEPPGFLAYECVGT (SEQ ID NO:
- 7);
- wherein B is selected from the group consisting of:
- CIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKC (SEQ ID NO:
- 6) and CIASETDSLPMIVSIKEGGRTRPQVVSLPNMRVQKC (SEQ ID NO:
- 8);
- wherein X consists of zero, one or more than one amino acid;
- wherein W consists of zero, one or more than one amino acid;
- wherein Y consists of zero, one or more than one amino acid;
- wherein the recombinant, Lefty derivative polypeptide binds to one or more of Nodal, myostatin and GDF-11;
- wherein the recombinant Lefty derivative polypeptide is not a wild-type Lefty polypeptide;
- and
- wherein the recombinant Lefty derivative polypeptide comprises one or more mutations within the RXXR cleavage sequence corresponding to amino acid residues 132-135 of SEQ ID NO:
- 1 or 2 so as to prevent cleavage at the mutated sequence.
Dependencies are inferred from the claim text.