Humanized Tissue Factor Antibody for Selective Oncogenic Signaling Inhibition
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Solution Overview
Problem
Current therapeutic candidates for cancer treatment that target tissue factor (TF) often interfere with both oncogenic and procoagulant functions of TF, making it challenging to block TF-mediated signaling without affecting hemostasis.
Innovation Solution
Development of a human-adapted antibody that binds to human TF, retaining the binding epitope of the murine antibody 10H10, which does not compete with TF for FVIIa binding, thereby not blocking the procoagulant activity of the TF-VIIa complex but inhibiting TF-VIIa mediated signaling and downstream oncogenic effects like cytokine IL-8 release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic candidates target tissue factor to block oncogenic functions, then cancer treatment efficacy is improved, but procoagulant functions are also inhibited leading to hemostasis disruption
Solution Approach 1:
The antibody is engineered to target a specific epitope on tissue factor that is spatially segregated from the FVIIa binding site. This segmentation allows the antibody to block oncogenic signaling functions while leaving the procoagulant pathway intact, as the two functional regions on TF are distinct and non-overlapping
Solution Approach 2:
The therapeutic antibody exhibits localized specificity by binding to a particular region of tissue factor (the epitope recognized by 10H10) that is responsible for oncogenic signaling. This local quality ensures that only the harmful oncogenic functions are inhibited while the beneficial hemostatic functions remain unaffected
2Object-affected harmful factors
If antibodies block TF-VIIa complex formation, then oncogenic signaling is inhibited, but coagulation activity is also reduced
Solution Approach 1:
The antibody selectively extracts or removes the oncogenic signaling function from the tissue factor system by blocking the TF-VIIa mediated signaling pathway. The antibody binds to TF in a way that prevents signaling without interfering with the coagulation cascade, effectively taking out only the harmful function while preserving the beneficial one
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 antibody effectively blocks TF-VIIa mediated signaling without interfering with coagulation, providing a therapeutic option for cancer treatment by targeting oncogenic functions of TF without affecting hemostasis.
Implementation Method 1
an isolated antibody which binds to human tissue factor wherein the antibody comprises a heavy chain variable region of SEQ ID NO:139 and a light chain variable region of SEQ ID NO:23
Data Source
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AI summary
The invention relates to a humanized form of an antibody capable of preventing tissue factor (coagulation factor F3) signaling but which does not interfere with Factor VII binding or FX binding to tissue factor and does not prolong coagulation time. The antibody of the invention is useful in treating conditions, such as tumor progression, in which the associated cells express tissue factor and tissue factor signaling occurs.