Monoclonal Antibody Binding VWF D4 Domain to Manage Bleeding Risk
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Solution Overview
Problem
There is a need for a treatment that specifically targets excessive degradation of high molecular weight von Willebrand factor (VWF) multimers, particularly in conditions like acquired von Willebrand syndrome associated with circulatory assist devices, without fully inhibiting ADAMTS13-mediated degradation to avoid thrombotic thrombocytopenic purpura-like symptoms.
Innovation Solution
A monoclonal antibody specifically binding to the D4 domain of VWF, competing with ADAMTS13 for binding sites and partially inhibiting ADAMTS13-mediated degradation of VWF, thereby reducing excessive proteolysis while maintaining some activity to prevent bleeding episodes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ADAMTS13-mediated degradation of VWF is fully inhibited, then excessive bleeding is prevented, but thrombotic thrombocytopenic purpura-like symptoms occur
Solution Approach 1:
The patent applies partial inhibition of ADAMTS13-mediated VWF degradation rather than complete inhibition. The antibody reduces excessive proteolysis of VWF multimers while maintaining some ADAMTS13 activity, creating a therapeutic window that prevents bleeding episodes without causing thrombotic complications. This partial action approach resolves the contradiction by achieving sufficient protection against bleeding while avoiding the harmful thrombotic effects of complete inhibition.
2Reliability
If high molecular weight VWF multimers are preserved, then hemostatic function is improved, but excessive thrombus growth risk increases
Solution Approach 1:
The patent changes the parameter of VWF multimer size distribution by selectively preserving high molecular weight multimers through partial inhibition of ADAMTS13-mediated degradation. This parameter change improves hemostatic function while the controlled nature of the inhibition prevents complete preservation that would lead to excessive thrombus growth, thus resolving the contradiction between hemostatic efficacy and thrombotic risk.
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 diminishes VWF proteolysis, preventing excessive bleeding in patients with conditions like aortic stenosis or ventricular assist devices, while avoiding the risk of thrombotic complications by allowing partial ADAMTS13 activity, thus providing a therapeutic window for safe use.
Implementation Method 1
A monoclonal antibody specifically binding to the D4 domain of VWF, competing with ADAMTS13 for binding sites and partially inhibiting ADAMTS13-mediated degradation of VWF
Data Source
AI summary
The invention relates to an isolated monoclonal antibody that specifically binds to the D4 domain of VWF, competes for binding to VWF D4 domain with ADAMTS13 and partially inhibits ADAMTS 13-mediated degradation of VWF. More particularly, the invention relates to an isolated monoclonal antibody comprising a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 3 for H-CDR1, SEQ ID NO: 4 for H-CDR2 and SEQ ID NO: 5 for H-CDR3 and a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 7 for L-CDR1, SEQ ID NO: 8 for L-CDR2 and SEQ ID NO: 9 for L-CDR3. Antibodies of the invention are presented to be useful in for the prevention or the treatment of bleeding episodes, such as bleeding episodes occurring in patients with aortic stenosis or patients with ventricular assist devices (VAD).