Factor VIII Variants with Decreased Cellular Uptake
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Solution Overview
Problem
Current treatments for hemophilia A, which involve administering coagulation factor VIII (FVIII), often lead to the development of neutralizing antibodies, reducing treatment efficacy due to immune system recognition, and require frequent intravenous injections, causing inconvenience and pain, especially in children. Additionally, existing methods to prolong FVIII's circulatory half-life are limited by the redundancy of LRP binding sites and potential loss of coagulant activity.
Innovation Solution
Development of recombinant FVIII variants with specific substitutions in the C1 and C2 domains, such as K2092A and F2093A, which decrease cellular uptake and immunogenicity, combined with conjugation to half-life extending moieties like PEG, to maintain coagulant activity while reducing LRP binding and increasing circulatory half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FVIII is administered to treat hemophilia A, then coagulant activity is restored, but neutralizing antibodies are induced reducing treatment efficacy
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions in the C1 and C2 domains of FVIII. These localized modifications alter the surface properties at specific regions to reduce recognition by neutralizing antibodies while preserving overall coagulant function.
Solution Approach 2:
The patent employs parameter changes by modifying amino acid sequences through substitutions of positively charged residues with neutral or hydrophobic residues. This changes the electrostatic and hydrophobic parameters of the protein surface, reducing immunogenicity while maintaining structural integrity and function.
2Reliability
If traditional FVIII treatment is used, then coagulant activity is achieved, but frequent intravenous injections are required causing inconvenience and pain
Solution Approach 1:
The patent applies dynamics by conjugating FVIII with PEG polymers of varying molecular weights and configurations. This creates a dynamic system where the PEG-FVIII conjugate exhibits altered pharmacokinetics with prolonged circulatory half-life, reducing the frequency of administrations required to maintain therapeutic levels.
Solution Approach 2:
The patent employs composite materials by combining FVIII with polyethylene glycol (PEG) polymers to create PEGylated FVIII conjugates. This composite structure combines the coagulant function of FVIII with the pharmacokinetic benefits of PEG, resulting in prolonged circulation time and reduced injection frequency.
3Duration of action of stationary object
If LRP binding sites are modified to decrease cellular uptake, then circulatory half-life is prolonged, but coagulant activity may be lost
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions in the C1 and C2 domains of FVIII. These localized modifications alter the surface properties at specific regions to reduce recognition by neutralizing antibodies while preserving overall coagulant function.
Solution Approach 2:
The patent employs parameter changes by modifying amino acid sequences through substitutions of positively charged residues with neutral or hydrophobic residues. This changes the electrostatic and hydrophobic parameters of the protein surface, reducing immunogenicity while maintaining structural integrity and function.
Data Source
AI summary
The present invention relates to modified coagulation factors. In particular, the present invention relates to modied Factor VIII molecules having decreased cellular uptake.