FVIII Peptides for Haemophilia A Tolerance Induction
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Solution Overview
Problem
Current methods for treating haemophilia A and acquired haemophilia are hindered by the formation of factor VIII inhibitor antibodies, which are difficult to manage and often lead to severe bleeding complications, with existing treatments having significant shortcomings in efficacy and safety.
Innovation Solution
The use of peptides derived from factor VIII, specifically immunodominant regions that induce tolerance to factor VIII, such as sequences PRCLTRYYSSFVNME and DNIMVTFRNQASRPY, to prevent or reduce the formation of factor VIII inhibitor antibodies by pre-tolerising patients, thereby suppressing the immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If factor VIII replacement therapy is administered to treat haemophilia A, then the bleeding symptoms are improved, but factor VIII inhibitor antibodies are formed which neutralise the procoagulant function
Solution Approach 1:
The patent applies preliminary action by administering FVIII-derived peptides before full factor VIII replacement therapy to pre-tolerise the patient's immune system. This preliminary exposure to peptide epitopes conditions the immune system to accept subsequent full FVIII therapy without mounting an inhibitory antibody response, thereby preventing the harmful alloimmune reaction before it occurs
Solution Approach 2:
The patent segments the full factor VIII protein into smaller peptide fragments (epitopes) that contain the immunodominant regions recognized by T cells. These segmented peptides are administered first to induce tolerance to specific immunogenic regions, allowing the full FVIII protein to be administered later without triggering inhibitor formation
2Reliability
If immune tolerance induction using desensitization technique is used to treat patients with inhibitor antibodies, then some patients achieve tolerance, but about 30% of patients fail to respond and the treatment is long-term
Solution Approach 1:
The patent extracts the immunodominant T-cell epitopes from the full factor VIII protein structure. By identifying and isolating these specific peptide sequences that are most likely to trigger inhibitor formation, the treatment can target these specific regions with peptides, making the tolerance induction more efficient and effective compared to administering whole FVIII in desensitization protocols
Solution Approach 2:
The patent changes the parameters of the antigen presentation by using processed peptide fragments rather than intact FVIII protein. This parameter change in antigen form (from whole protein to processed peptides) enhances the ability to induce tolerance by directly presenting T-cell epitopes in a tolerogenic context, improving treatment response rates
3Quantity of substance
If CD4+ T cells recognize FVIII peptides presented on APC surface, then the immune response is activated, but this leads to B cells synthesizing antibodies that neutralise factor VIII
Solution Approach 1:
The patent converts the harmful immune recognition process into a beneficial tolerogenic response. By administering FVIII-derived peptides in a tolerogenic regimen, the same T-cell recognition pathway that normally leads to harmful antibody production is redirected to induce tolerance and suppressor T cell responses, thereby converting the immune system's harmful reactivity into a protective tolerant state
Data Source
Figure 1a~1b
Figure 1c
Figure 2a~2b
AI summary
The present invention provides a peptide comprising a core residue sequence derivable from human FVIII which peptide is capable of binding to an MHC class II molecule without further antigen processing. The present invention also relates to the use of such peptides for the prevention or suppression of inhibitor antibody formation in haemophilia A and/or acquired haemophilia.