PH20 polypeptide variants, formulations and uses thereof
Modified PH20 hyaluronidase polypeptides, including modified polypeptides that exhibit increased stability and/or increased activity, are provided. Also provided are compositions and formulations and uses thereof.
1. A method for increasing delivery of a therapeutic agent to a subject, comprising administering to a subject a pharmaceutical composition comprising:
(a) a therapeutic agent; and
(b) a modified PH20 polypeptide comprising an amino acid sequence, wherein:
i. at least 95% of the residues of the amino acid sequence of the modified PH20 polypeptide are identical to the residues in an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 32-66 when the sequence of the modified PH20 polypeptide is aligned at positions corresponding to the sequence selected from the group consisting of SEQ ID NOs: 3 and 32-66 to maximize identical residues; and
ii. the amino acid sequence of the modified PH20 polypeptide comprises an amino acid modification at a position corresponding to position 320 with reference to amino acid positions set forth in SEQ ID NO: 3; and
iii. the modification at position 320 is a replacement selected from the group consisting of H, K, R and S.
2. The method of claim 1 , wherein the amino acid modification is at a position corresponding to position 320 with reference to amino acid positions set forth in SEQ ID NO: 3 is K.
3. The method of claim 2 , wherein at least 96% of the residues of the amino acid sequence of the modified PH20 polypeptide are identical to the residues in an amino acid sequence set forth in SEQ ID NO:35.
4. The method of claim 2 , wherein at least 95% of the residues of the amino acid sequence of the modified PH20 polypeptide are identical to the residues in an amino acid sequence set forth in SEQ ID NO:32.
5. The method of claim 1 , wherein the modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the hyaluronidase activity of the polypeptide set forth in SEQ ID NO: 3, measured under identical conditions.
6. The method of claim 1 , wherein the hyaluronidase activity of the modified PH20 polypeptide is at least 120% of the hyaluronidase activity of the PH20 polypeptide of SEQ ID NO: 3, measured under identical condition.
7. The method of claim 1 , wherein the therapeutic agent is a polypeptide, a protein, a nucleic acid, a drug, a small molecule, or an organic molecule.
8. The method of claim 1 , wherein the therapeutic agent is an antibody.
9. The method of claim 1 , wherein the therapeutic agent is a small molecule drug.
10. The method of claim 1 , wherein the pharmaceutical composition is administered to the patient parenterally.
11. The method of claim 1 , wherein the pharmaceutical composition is administered to the patient subcutaneously.