Compositions comprising natriuretic peptides and methods of use thereof

摘要

The present invention provides methods, compositions, and kits for the treatment of disorders associated with overactivation of FGFR3, such as achondroplasia; bone or cartilage disorders; or vascular smooth muscle disorders, or for the elongation of bone. In some embodiments, the present invention provides polypeptides having a natriuretic peptide fused to an Fc domain of an immunoglobulin. Such polypeptides can be administered to subjects, e.g., subcutaneously, to treat a disorder associated with overactivation of FGFR3, a bone or cartilage disorder, or a vascular smooth muscle disorder, or to elongate bone. The invention also features nucleic acid molecules encoding such polypeptides and the use of the nucleic acid molecules for treating disorders associated with overactivation of FGFR3, bone or cartilage disorders, or vascular smooth muscle disorders, or for elongating bone.

主权项

1. An isolated polypeptide comprising the structure X-Fc-Y-NP-Z or the structure X-NP-Y-Fc-Z, wherein NP is a natriuretic peptide that is an agonist of natriuretic peptide receptor B (NPR-B), wherein said NP comprises the structure: [N-terminal extension]-[short segment]-[ring domain]-[C-terminal extension], wherein each of said N-terminal extension, short segment, and C-terminal extension is, independently, absent or is an amino acid sequence of at least one amino acid, and wherein said NP comprises amino acids 6-22 of SEQ ID NO: 126, wherein the amino-acid at position 17 is not Met, and wherein:
(i) each of X and Z is, independently, absent or is an amino acid sequence of at least one amino acid; and (ii) the amino acid sequence of Y comprises [(Gly)4(Ser)]n(Gly)p or (Gly)p[(Ser)(Gly)4]n, wherein n is between 1and 10 and p is between 0 and 4, or wherein the amino acid sequence of Y comprises the amino acid sequence of any one of SEQ ID NOs: 304-313, 322-333, or 337-389.