NKG2D-DAP10-CD3zeta Chimeric Receptor for NK Cell Therapy

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Solution Overview

Problem

Despite the promise of NK cells for anti-cancer therapy, some cancer subtypes remain insensitive to activated NK cells, and genetic modification of T cells is often used to express chimeric receptors for redirecting T cells against tumor cells, which can lead to graft-versus-host disease if non-autologous.

Innovation Solution

An artificial chimeric receptor complex composed of NK receptor NKG2D, DAP10, and CD3 zeta (NKG2D-DAP10-CD3zeta) is designed and expressed in activated NK cells to enhance their cytotoxicity and antitumor capacity, allowing for targeted cancer therapy without increasing cytotoxicity against normal cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If genetic modification of T cells is used to express chimeric receptors for redirecting T cells against tumor cells, then anti-tumor capacity is improved, but graft-versus-host disease occurs if non-autologous cells are used

Engineering Contradiction:

Improveanti-tumor capacityVSAvoidgraft-versus-host disease

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention inverts the conventional approach by using NK cells instead of T cells as the host for chimeric receptor expression. NK cells are naturally cytotoxic and do not cause graft-versus-host disease, thereby inverting the cell type selection to resolve the contradiction between anti-tumor efficacy and safety

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention introduces an artificial chimeric receptor complex (NKG2D-DAP10-CD3zeta) as an intermediary that bridges the ligand-binding function of NKG2D and the signaling function of CD3zeta. This intermediary complex enables NK cells to recognize tumor cells with high specificity while maintaining their natural safety profile

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If NK cells are used for anti-cancer therapy, then safety is improved by avoiding graft-versus-host disease, but some cancer subtypes remain insensitive to activated NK cells

Engineering Contradiction:

Improvegraft-versus-host diseaseVSAvoidanti-tumor capacity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The invention merges three distinct functional domains into a single chimeric receptor complex: the NKG2D extracellular domain for ligand recognition, the DAP10 transmembrane domain for signal transduction, and the CD3zeta cytoplasmic domain for enhanced signaling. This merging creates a potent receptor that overcomes NK cell insensitivity to certain cancer subtypes while preserving safety

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric receptor complex functions as a composite molecular structure combining elements from different receptor systems (NKG2D, DAP10, CD3zeta). This composite design integrates the ligand-binding specificity of NKG2D with the robust signaling capabilities of CD3zeta, enhancing anti-tumor capacity across diverse cancer types

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20240191196A1Chimeric receptor with NKG2d specificity for use in cell therapy against cancer and infectious disease

Publication Date: 2024.06.13 ST JUDE CHILDRENS RES HOSPITAL INC

AI summary

The invention provides a chimeric receptor comprising NKG2D, DAP10 and CD3 zeta. Also disclosed is a composition comprising this chimeric receptor and methods for making and using it to enhance the cytotoxicity and antitumor capacity of NK cells. The invention also encompasses methods for use of NKG2D-DAP10-CD3 zeta polypeptides, vectors and cells in methods for treating cancer and other proliferative disorders, as well as infectious diseases.