Modified Factor VIII Reducing NKT Cell Activation
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Solution Overview
Problem
Patients with hemophilia A often develop antibodies against factor VIII, leading to inhibitors that neutralize its function and increase clearance, making regular administration risky and costly, with current treatments like immune tolerance induction being unreliable and costly.
Innovation Solution
Development of factor VIII molecules with reduced immunogenicity by modifying amino acid sequences to eliminate CD1d binding motifs, thereby reducing activation of NKT cells and subsequent adaptive immune response, using methods such as amino acid substitution or deletion in specific positions to prevent binding to the CD1d molecule.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If regular factor VIII administration is used to treat hemophilia A, then coagulation function is restored, but immune response leading to inhibitor formation occurs
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of factor VIII to alter its immunogenic properties. Specifically, mutations are introduced to eliminate or modify NKT cell epitopes while preserving the coagulation activity of the protein, thereby changing the molecular parameters to reduce immune recognition.
Solution Approach 2:
The patent applies local quality by making targeted modifications to specific regions of the factor VIII molecule. Rather than altering the entire protein, only specific amino acid residues that constitute NKT cell epitopes are modified, leaving the rest of the molecule intact to maintain its therapeutic function.
2Reliability
If high doses of factor VIII are administered to induce immune tolerance, then inhibitor disappearance may occur, but treatment cost increases prohibitively
Solution Approach 1:
The patent applies preliminary action by pre-modifying the factor VIII molecule to reduce its immunogenicity before administration. By eliminating NKT cell epitopes in advance through amino acid mutations, the treatment prevents immune tolerance induction issues that would otherwise require expensive high-dose regimens, thereby reducing treatment cost while maintaining efficacy.
3Object-affected harmful factors
If factor VIII molecules are modified to reduce immunogenicity, then inhibitor production is minimized, but molecular structure is altered
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations to alter the molecular structure of factor VIII. These changes modify the NKT cell epitopes to reduce immunogenicity while carefully selecting mutations that preserve the overall molecular structure and coagulation function of the protein.
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 modified factor VIII molecules significantly reduce the capacity to activate NKT cells, minimizing the production of inhibitors and allowing for safer and more effective treatment of hemophilia A patients by preventing immune responses, thus enabling more reliable and cost-effective therapy.
Implementation Method 1
modifying amino acid sequences to eliminate CD1d binding motifs, thereby reducing activation of NKT cells and subsequent adaptive immune response, using methods such as amino acid substitution or deletion in specific positions
Implementation Method 2
prevent binding to the CD1d molecule
Data Source
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AI summary
The invention describes factor VIII molecules with reduced capacity to elicit activation of NKT cells for use in the treatment of congenital and/or acquired haemophilia A and in bleeding disorders. Said factor VIII molecule is obtainable by: a. identification of at least one NKT cell epitope wherein said epitope comprises hydrophobic aminoacid residues in position P1 and/or P7 b. modification of said epitope(s) by eliminating at least one hydrophobic aminoacid residue in position P1 and/or P7, substituting at least one hydrophobic aminoacid residue in position P1 and/or P7 with a non-hydrophobic residue, or adding a non-hydrophobic residue in position P1 and/or P7.