Antibodies Neutralizing TFPI Inhibition to Restore Thrombin Generation

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Solution Overview

Problem

Current treatments for bleeding disorders, such as hemophilia, face challenges due to the inhibitory effects of tissue factor pathway inhibitor (TFPI) on coagulation, leading to inadequate thrombin generation and prolonged bleeding.

Innovation Solution

Development of antibodies specifically binding to the N-terminal part of TFPI, which neutralize TFPI's inhibitory effects on the TF/FVIIa complex, thereby enhancing thrombin generation and coagulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TFPI inhibition is maintained to regulate coagulation, then coagulation is controlled, but thrombin generation becomes inadequate and bleeding occurs

Engineering Contradiction:

Improvecoagulation controlVSAvoidthrombin generation

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent converts the harmful inhibitory effect of TFPI on coagulation into a beneficial therapeutic effect by using antibodies to block TFPI's inhibition. The antibodies specifically bind to TFPI and prevent it from inhibiting the TF/FVIIa complex and FXa, thereby converting TFPI's harmful anticoagulant effect into a pro-coagulant therapeutic effect that restores normal thrombin generation in bleeding disorders

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent introduces antibodies as intermediary molecules that mediate between TFPI and the coagulation factors. These antibodies specifically bind to TFPI and act as a bridge to prevent TFPI from interacting with and inhibiting the TF/FVIIa complex and FXa, thereby restoring normal coagulation function without directly modifying the coagulation factors themselves

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If TFPI levels are elevated to inhibit coagulation, then coagulation is suppressed, but bleeding diathesis worsens

Engineering Contradiction:

Improvecoagulation suppressionVSAvoidhemostasis

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by using antibodies to preemptively block TFPI's inhibitory action before it can suppress coagulation. The antibodies are administered to patients with bleeding disorders to prevent TFPI from exerting its harmful anticoagulant effect, thereby maintaining adequate thrombin generation and preventing worsening of bleeding diathesis

Inventive Principle:

Principle #9Preliminary anti-action

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 normalize thrombin generation even under elevated TFPI levels, providing a therapeutic solution for bleeding disorders by blocking TFPI's inhibitory action, thus promoting effective hemostasis.

Implementation Method 1

antibodies specifically binding to the N-terminal part of TFPI, which neutralize TFPI's inhibitory effects on the TF/FVIIa complex

Methodology Applied

Scientific EffectAntibody-antigen binding:

Implementation Method 2

TFPI is a slow, tight-binding competitive inhibitor which regulates FX activation through inhibition of both FXa and the TF/FVIIa complex

Methodology Applied

Scientific EffectCompetitive inhibition:

Data Source

PatentUS10457743B2Antibodies recognizing the N-terminal part of tissue factor pathway inhibitor capable of eliciting pro-coagulant activity

Publication Date: 2019.10.29 NOVO NORDISK AS

AI summary

The present invention relates to an antibody that specifically binds to an epitope in the N-terminal part (residues 1 to 79) of tissue factor pathway inhibitor (TFPI). An antibody according to the invention may be capable of neutralising TFPI inhibition of the TF/FVIIa complex, even in the presence of elevated levels of TFPI. Such antibodies may find utility in the treatment of subjects with a coagulopathy, such as those with haemophilia A or B, with or without inhibitors.