Anti-TMPRSS6 Antibodies for Hepcidin-Mediated Iron Overload Control
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Solution Overview
Problem
Current treatment options for iron overload disorders, such as hereditary hemochromatosis and secondary hemochromatosis, are limited and require lifelong management, with potential organ damage and associated diseases like diabetes as a result of excess iron storage.
Innovation Solution
Development of fully human antibodies and antigen-binding fragments that specifically target the transmembrane serine protease 6 (TMPRSS6) protein, inhibiting its protease activity and allosterically regulating its function to reduce iron overload by blocking the cleavage of hemojuvelin, thereby modulating hepcidin expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If iron chelation therapy or phlebotomy is used to treat iron overload disorders, then excess iron can be removed from the body, but treatment is required throughout the patient's lifetime and may still lead to organ damage
Solution Approach 1:
The patent applies preliminary action by targeting the upstream regulatory mechanism (TMPRSS6-hepcidin axis) before iron overload occurs. By administering anti-TMPRSS6 antibodies that block TMPRSS6 activity, hepcidin expression is upregulated in advance, preventing iron absorption at the source and avoiding the need for lifelong iron removal therapies
Solution Approach 2:
The patent uses the hepcidin protein as an intermediary mediator between the antibody therapy and iron metabolism regulation. The anti-TMPRSS6 antibodies indirectly regulate iron levels by modulating hepcidin expression, which then controls ferroportin activity and iron efflux, providing a more sustainable treatment approach compared to direct iron chelation
2Quantity of substance
If repeated blood transfusions are administered to treat anemia in thalassemia or myelodysplastic syndrome, then anemia symptoms are improved, but iron overload occurs as a complication
Solution Approach 1:
The patent implements a feedback mechanism by targeting the body's natural iron regulatory system. The anti-TMPRSS6 antibodies restore the physiological feedback loop where increased hepcidin levels (resulting from TMPRSS6 inhibition) automatically reduce iron absorption and increase iron sequestration, allowing the body to self-regulate iron levels even during repeated transfusions
Solution Approach 2:
Hepcidin serves as a protective intermediary that mediates between blood transfusion therapy and iron metabolism. By upregulating hepcidin through TMPRSS6 inhibition, the patent creates a buffer system that prevents transfused iron from accumulating in organs, thereby enabling continued transfusion therapy without iron overload complications
3Quantity of substance
If dietary restrictions are imposed to reduce iron intake, then iron absorption is decreased, but treatment compliance is difficult to maintain throughout a patient's lifetime
Solution Approach 1:
The patent applies self-service by enabling the body's own regulatory systems to control iron metabolism. The anti-TMPRSS6 antibodies trigger an endogenous response where the body automatically increases hepcidin production and iron excretion, eliminating the need for patients to actively comply with dietary restrictions or remember lifelong treatment protocols
Solution Approach 2:
The patent performs preliminary action by establishing sustained anti-TMPRSS6 antibody coverage that proactively prevents iron overload before it occurs. This upfront intervention creates long-lasting protection that reduces iron absorption at the molecular level, making lifestyle modifications unnecessary and simplifying patient management
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 antibodies effectively decrease serum iron levels, increase hepcidin levels, and enhance mature red blood cell production, providing a potential therapeutic approach to manage iron overload disorders without the need for lifelong interventions.
Implementation Method 1
binding of the antibody or antigen-binding fragment thereof to TMPRSS6 mediates allosteric inhibition of TMPRSS6
Implementation Method 2
the antibody or antigen-binding fragment thereof binds to the catalytic domain of TMPRSS6 but does not bind to the catalytic triad of TMPRSS6
Implementation Method 3
inhibiting its protease activity and allosterically regulating its function to reduce iron overload by blocking the cleavage of hemojuvelin, thereby modulating hepcidin expression
Data Source
AI summary
Provided herein are monoclonal antibodies that bind to the transmembrane serine protease 6 (TMPRSS6) protein, and methods of use thereof. In various embodiments of the disclosure, the antibodies are fully human antibodies that bind to TMPRSS6. In some embodiments, the antibodies disclosed herein are useful in a method for treating or preventing a disease, disorder or condition associated with TMPRSS6 in humans.