Ticagrelor-Binding Antibody Reversal for Perioperative Bleeding
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Solution Overview
Problem
There are no approved effective therapies to mitigate ticagrelor-induced platelet inhibition, which increases the risk of bleeding in patients, particularly during surgeries or invasive procedures, and current reversal agents are not suitable for rapid use during such events.
Innovation Solution
Administering an antibody or antigen-binding fragment, such as bentracimab, that binds to ticagrelor or its metabolite, comprising specific CDR sequences, to rapidly reverse platelet inhibition and enhance hemostasis during surgeries or invasive procedures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ticagrelor is administered to prevent thrombotic events, then efficacy in preventing myocardial infarction and stroke is improved, but the risk of spontaneous bleeding and blood loss increases
Solution Approach 1:
Bentracimab serves as an intermediary substance that binds to ticagrelor and its active metabolite, preventing them from binding to the P2Y12 receptor on platelets. This mediator approach allows the reversal of ticagrelor's antiplatelet effects without requiring breakdown of the drug itself, enabling rapid control of bleeding while the patient remains on ticagrelor therapy for cardiovascular protection
2Reliability
If ticagrelor is used in dual antiplatelet therapy to prevent recurrent thrombotic events, then protection against myocardial infarction and stroke is improved, but the risk of major or life-threatening bleeding increases
Solution Approach 1:
Bentracimab acts as a reversible intermediary that temporarily sequesters ticagrelor and its metabolite, allowing dual antiplatelet therapy to be paused during acute bleeding events without permanently discontinuing the protective regimen. This enables safe interruption of the harmful effect while preserving the ability to resume therapy when bleeding is controlled
Solution Approach 2:
The invention changes the pharmacokinetic parameters of ticagrelor by introducing bentracimab binding, which increases the apparent clearance of active ticagrelor from circulation. This parameter change temporarily reduces platelet inhibition to acceptable levels during bleeding events, allowing dynamic adjustment of antiplatelet effect intensity
3Reliability
If ticagrelor is administered to reduce stent thrombosis, then protection against thrombotic events is improved, but blood loss during surgery increases
Solution Approach 1:
Bentracimab can be administered prior to scheduled surgery in patients on ticagrelor, preemptively reversing the antiplatelet effect before the surgical procedure begins. This preliminary action ensures adequate hemostasis during surgery while maintaining ticagrelor therapy continuity, preventing both excessive blood loss and stent thrombosis risk
Solution Approach 2:
Bentracimab serves as a temporary intermediary that blocks ticagrelor-P2Y12 receptor interaction specifically during the surgical window, allowing normal hemostasis during surgery while the patient remains protected against stent thrombosis before and after the procedure
4Reliability
If ticagrelor is used to prevent recurrent cardiovascular events, then clinical outcomes are improved, but there are limited treatment options for reversing P2Y12 inhibition
Solution Approach 1:
Bentracimab introduces a new therapeutic class (ticagrelor-binding antibody fragment) as a reversal agent, expanding the arsenal of available treatments for ticagrelor-induced bleeding. This intermediary approach complements existing reversal strategies for other antiplatelet agents, providing targeted reversal specifically for P2Y12 inhibition by ticagrelor and its metabolite
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 or antigen-binding fragment effectively reduces P2Y12 reaction units (PRU) inhibition by 78-56% within 4 hours, significantly reducing the risk of severe bleeding and mortality in patients, even in fragile populations.
Implementation Method 1
Bentracimab, also known as PB2452, is an intravenously delivered monoclonal antibody fragment (Fab) that binds to ticagrelor and intended to reverse its antiplatelet effects. The transient binding of ticagrelor to the P2Y12 receptor allows anti-ticagrelor agents, such as bentracimab, a human Fab fragment that binds to ticagrelor, to bind to free ticagrelor, thereby preventing ticagrelor's activation of the receptor and removing ticagrelor from circulation.
Data Source
AI summary
Herein is provided a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering to said patient during surgery, in a perioperative setting, or during an invasive procedure an antibody or antigen-binding fragment thereof that binds to ticagrelor. Also provided is a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering an antibody or antigen-binding fragment thereof that binds to ticagrelor, wherein the patient is elderly, has underlying cardiac or pulmonary or metabolic disease, optionally wherein the patient has a minimum percent inhibition of P2Y12 reaction units (PRU) over 4 hours after starting administration of the antibody or antigen-binding fragment thereof that is less than the percent inhibition of PRU before administration.