Alkaline phosphatase polypeptides and methods of use thereof
Inventors
Voegtli, Walter C. • Wu, Yuhong • MONTELEONE, Jonathan • MEZHEBOVSKY, Tatyana • Falcone, Eric • Guo, Yang
Assignees
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Publication Number
US-12083169-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Featured are pharmaceutical compositions that include a soluble alkaline phosphatase for treating bone mineralization disorders, such as hypophosphatasia (HPP), and symptoms thereof. The polypeptides include a soluble alkaline phosphatase (sALP) or fragment thereof, which is derived from a naturally occurring alkaline phosphatase (ALP).
Core Innovation
The invention relates to soluble alkaline phosphatase (sALP) therapies for bone mineralization disorders, including hypophosphatasia (HPP). The pharmaceutical compositions are based on an ALP201 class polypeptide architecture, including a polypeptide comprising the amino acid sequence of SEQ ID NO:5, and form a dimer linked by defined inter-polypeptide disulfide bonds.
The compositions include a pharmaceutically acceptable carrier comprising one or more of phosphate, proline, and sucrose. The disclosure further specifies the dimer as linked by a first disulfide bond between C494 of the first polypeptide and C494 of the second polypeptide, and a second disulfide bond between C497 of the first polypeptide and C497 of the second polypeptide. Optional formulation components can include polyoxyethylene(20) sorbitan monooleate (polysorbate 80).
The disclosure reports preclinical/PK/tox findings for ALP201, including improved PPi/PLP substrate turnover and improved bone mineralization and survival in Akp2GW(−/−) HPP mice with less frequent subcutaneous dosing intervals. It also states favorable pharmacokinetic properties, including longer half-life and higher bioavailability, as well as favorable toxicology outcomes including GLP toxicology NOAELs, and addresses immunogenicity considerations, including anti-drug antibodies (ADA).
Claims Coverage
The independent claim is directed to a pharmaceutical composition comprising a defined SEQ ID NO:5 dimer linked by two specific disulfide bonds (C494-C494 and C497-C497) and including a carrier comprising phosphate, proline, and sucrose. The claim coverage centers on two inventive features.
Defined SEQ ID NO:5 dimer linked by two inter-polypeptide disulfide bonds
A pharmaceutical composition comprising a dimer in which each polypeptide comprises the amino acid sequence of SEQ ID NO: 5, linked by a first disulfide bond between C494 of the first polypeptide and C494 of the second polypeptide and a second disulfide bond between C497 of the first polypeptide and C497 of the second polypeptide.
Pharmaceutically acceptable carrier comprising phosphate, proline, and sucrose
The pharmaceutical composition includes a pharmaceutically acceptable carrier comprising one or more of phosphate, proline, and sucrose.
Overall claim coverage is anchored to the defined structural form of the SEQ ID NO:5 dimer together with a carrier containing phosphate, proline, and sucrose. Dependent coverage adds formulation constraints such as optional polyoxyethylene(20) sorbitan monooleate, target pH, and TSAC, and extends to treatment of a bone mineralization disorder by administering a dose of the composition.
Stated Advantages
Improved PPi/PLP substrate turnover.
Improved bone mineralization and survival in Akp2GW(−/−) HPP mice.
Longer half-life and higher bioavailability.
Favorable GLP toxicology NOAELs.
Documented Applications
Therapies for bone mineralization disorders, including hypophosphatasia (HPP).
Treatment of a bone mineralization disorder by administering a dose of the composition.
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