Selective Inhibitory KIR Agonists for NK Cell Rejection Avoidance

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Solution Overview

Problem

Current methods for allogeneic transplantation and cell therapy face challenges in avoiding immune rejection due to HLA mismatch, with existing substances like Lirilumab and Pan2D binding to both inhibitory and activating KIR receptors, potentially enhancing NK cell cytocidal activity, and techniques such as universal cell expression of HLA-E being ineffective against NK cells with low NKG2A expression.

Innovation Solution

Development of specific agonist binders that selectively target inhibitory KIR receptors, such as KIR2DL2, KIR2DL3, and KIR3DL1, while avoiding activating KIR receptors, using monoclonal antibodies or antigen-binding fragments with defined amino acid sequences to inhibit NK cell cytocidal activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing substances like Lirilumab and Pan2D are used to bind to KIR receptors, then NK cell activity can be modulated, but they bind to both inhibitory and activating KIR receptors which may enhance NK cell cytocidal activity and cause immune rejection

Engineering Contradiction:

Improveimmune rejection avoidanceVSAvoidNK cell cytocidal activity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the KIR receptor binding function by developing agonist binders that selectively target only inhibitory KIR receptors (KIR2DL2, KIR2DL3, KIR3DL1) while excluding activating KIR receptors. This selective segmentation allows modulation of NK cell activity without triggering cytocidal responses, resolving the contradiction between immune rejection avoidance and harmful NK cell activity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The agonist binders exhibit local quality by displaying different binding affinities to different KIR receptor types. The binders are designed with specific molecular characteristics that enable high affinity binding to inhibitory KIR receptors while having low or no affinity for activating KIR receptors, thus achieving selective immunomodulation without enhancing cytocidal activity.

Inventive Principle:

Principle #3Local quality

2Reliability

If HLA-E is expressed to avoid immune rejection through NKG2A recognition, then autologous cells can inhibit NK cell cytocidal activity, but this approach is ineffective against NK cells with low NKG2A expression

Engineering Contradiction:

Improveimmune rejection avoidanceVSAvoideffectiveness against diverse NK cell populations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The agonist binders provide universal protection against immune rejection by targeting inhibitory KIR receptors that are expressed on a broad spectrum of NK cell populations, including those with low or absent NKG2A expression. This multi-functional approach ensures effectiveness across diverse NK cell types, overcoming the limitation of HLA-E/NKG2A-specific approaches.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If personalized stem cells or stem cell bank with various HLAs are prepared to match patients, then immune rejection can be avoided, but the process is time-consuming, technically difficult, and expensive

Engineering Contradiction:

Improveimmune rejection avoidanceVSAvoidcell culture and characterization time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The invention extracts the essential function of HLA matching by using agonist binders that directly target inhibitory KIR receptors on NK cells. This approach removes the need for time-consuming HLA typing, cell line characterization, and matching processes, while still achieving reliable immune rejection avoidance through direct NK cell modulation.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

Instead of creating personalized cell lines that replicate each patient's HLA profile, the invention uses a universal agonist binder approach that copies the protective function of self-recognition. The binders mimic the natural agonist ligands that activate inhibitory KIR receptors, providing a simplified copy of the immune tolerance mechanism that works across all patients without personalized customization.

Inventive Principle:

Principle #26Copying

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 developed agonist binders effectively inhibit NK cell cytocidal activity, reducing immune rejection in allogeneic transplantation and cell therapy by selectively targeting inhibitory KIR receptors, thereby enhancing the efficacy and safety of these treatments.

Implementation Method 1

a substance having activity of binding to inhibitory KIR and inhibiting the cytocidal activity of an NK cell

Methodology Applied

Scientific EffectReceptor-ligand binding:

Data Source

PatentEP4610277A1Method for avoiding immune rejection using agonist for inhibitory kir

Publication Date: 2025.09.03 DAIICHI SANKYO CO LTD

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AI summary

This invention provides a substance having activity of binding to inhibitory KIR and inhibiting the cytocidal activity of an NK cell that is useful for the allogeneic technology associated with organ transplantation or cell therapy and a method for producing such substance. This invention provides a substance having activity of binding to inhibitory KIR and inhibiting the cytocidal activity of an NK cell and a cell comprising such substance expressed on the surface.