Mutated Alkaline Phosphatase Polypeptides for Weekly HPP Dosing
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Solution Overview
Problem
Current enzyme replacement therapies for hypophosphatasia, such as Asfotase alfa, face challenges with compliance due to frequent injections and injection site reactions, necessitating improvements in dosing frequency and volume to enhance patient quality of life.
Innovation Solution
Development of recombinant alkaline phosphatase polypeptides with specific mutations that improve catalytic activity, stability, and pharmacokinetic properties, potentially combined with a bone-targeting moiety and an Fc region, to enhance treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If asfotase alfa is administered three to six times weekly, then bone mineralization and therapeutic benefits are improved, but injection site reactions and compliance challenges increase
Solution Approach 1:
The patent applies parameter changes by modifying the dosing frequency from three to six times weekly to once weekly, and by engineering mutated alkaline phosphatase polypeptides with altered pharmacokinetic properties including extended half-life and improved stability, thereby reducing injection site reactions while maintaining therapeutic efficacy
2Reliability
If asfotase alfa is administered subcutaneously three to six times weekly, then therapeutic effects are achieved, but dosing volume and treatment complexity increase
Solution Approach 1:
The patent changes the dosing frequency parameter from multiple times weekly to once weekly, and modifies the enzyme structure through mutations to achieve extended half-life, thereby simplifying the dosing regimen from complex multiple injections to a single weekly injection while maintaining therapeutic effectiveness
3Productivity
If alkaline phosphatase polypeptides are engineered with mutations, then catalytic activity and stability are improved, but protein structure complexity increases
Solution Approach 1:
The patent applies local quality by introducing specific point mutations at targeted amino acid positions within the alkaline phosphatase protein sequence, thereby improving catalytic activity and stability without globally complicating the overall protein structure, as evidenced by sequences showing 85-99% identity to wild-type
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The mutated alkaline phosphatase polypeptides demonstrate increased catalytic activity, improved temperature stability, and reduced dimerization, offering potential for less frequent dosing and enhanced bone mineralization, muscle strength, and motor function improvements in hypophosphatasia patients.
Implementation Method 1
The at least one mutation may improve catalytic activity relative to the naturally occurring alkaline phosphatase
Data Source
AI summary
Featured are polypeptides that include soluble alkaline phosphatases, mutants, fragments, fusion proteins thereof, and methods of use thereof, 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).