Chimeric NKG2D Protein for Full T-Cell Activation

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Solution Overview

Problem

Current CAR-T cell therapies for solid tumors face challenges due to the lack of tumor-selective targets, as most tumor antigens are intracellular and difficult for CAR-T cells to recognize, and existing NKG2D-based CARs do not provide full T-cell activation.

Innovation Solution

A chimeric NKG2D protein comprising a human extracellular domain and a murine transmembrane domain is engineered to associate with DAP10 and/or DAP12, forming a compact adaptor-based CAR that drives full T-cell activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If human NKG2D is used with human DAP10 adaptor, then co-stimulatory signalling is achieved through YxxM motif, but full T-cell activation cannot be obtained due to lack of ITAM motif

Engineering Contradiction:

ImproveT-cell activationVSAvoidincomplete activation signal

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent creates a chimeric NKG2D protein by combining the human NKG2D extracellular domain with the murine NKG2D transmembrane and intracellular domains. This composite structure allows the receptor to associate with both DAP10 (providing co-stimulatory signaling via YxxM motif) and DAP12 (providing activating signal via ITAM motif), thereby achieving full T-cell activation that neither human component could provide alone.

Inventive Principle:

Principle #40Composite materials

2Reliability

If murine NKG2D transmembrane domain is used in human NKG2D chimera, then association with DAP12 is enabled for full activation, but potential immunogenicity concerns arise

Engineering Contradiction:

Improvefull T-cell activationVSAvoidimmunogenicity risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The chimeric NKG2D protein applies local quality by using human sequence for the extracellular domain (which interacts with ligands and is exposed to immune system) and murine sequence only for the transmembrane and intracellular domains (which are hidden from external immune surveillance). This localized use of heterologous sequence minimizes immunogenicity risk while achieving the desired functional benefit of DAP12 association.

Inventive Principle:

Principle #3Local quality

3Reliability

If conventional CAR design is used for solid tumors, then intracellular tumor antigens can be targeted, but tumor selectivity is lost as targets are upregulated in normal tissues too

Engineering Contradiction:

Improvetumor targetingVSAvoidtumor selectivity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent converts the previously harmful or unwanted recognition of NKG2D ligands on normal tissues into a beneficial feature. By engineering the chimeric NKG2D receptor to recognize stress-induced NKG2D ligands, the therapy exploits the fact that these ligands are aberrantly expressed on virtually all tumor cell types while being absent from healthy tissues, thereby achieving high tumor selectivity.

Inventive Principle:

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

Data Source

PatentUS20230257443A1Chimeric NKG2d protein

Publication Date: 2023.08.17 LEUCID BIO LTD

AI summary

This invention relates to an immunoresponsive cell comprising a chimeric NKG2D protein. The immunoresponsive cell is a T-cell, natural killer (NK) cell, macrophage or neutrophil and the chimeric NKG2D protein comprises a human NKG2D extracellular domain or a variant thereof, and a murine NKG2D transmembrane domain or a variant thereof. The disclosure also relates to isolated polynucleotide(s) encoding the chimeric NKG2D protein and the use of the immunoresponsive cells or isolated polynucleotides in therapy or the treatment of cancer.