Engineered Cell Co-localizing Beta-2 Microglobulin to Reduce Immune Rejection

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Solution Overview

Problem

Current approaches to reducing cellular mediated immune rejection of engineered cells, such as those expressing chimeric antigen receptors (CAR) or T-cell receptors (TCR), often lead to unintended immunosuppression or activation of natural killer cells, highlighting the need for alternative methods to specifically target and eliminate reactive T-cells.

Innovation Solution

The development of a cell comprising a chimeric antigen receptor or T-cell receptor, coupled with a polypeptide that co-localizes the beta-2 microglobulin component of MHC class I with an intracellular signaling domain, allowing for the presentation of peptides and interaction with reactive T-cells, thereby activating cytotoxic-mediated cell killing and reducing immune rejection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If conventional methods are used to reduce cellular mediated immune rejection, then immune rejection is reduced, but unintended immunosuppression or natural killer cell activation occurs

Engineering Contradiction:

Improveimmune rejectionVSAvoidunintended immunosuppression or natural killer cell activation

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The invention converts the harmful immunogenic peptides presented by MHC class I molecules into a beneficial mechanism by enabling reactive T-cells to recognize and kill themselves through cytotoxic-mediated cell killing, thereby reducing immune rejection without causing unintended immunosuppression or natural killer cell activation

Inventive Principle:

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

Solution Approach 2:

The invention uses MHC class I molecules as intermediaries to present immunogenic peptides to reactive T-cells, facilitating specific recognition and elimination of these reactive T-cells through a controlled immune response rather than broad immunosuppression

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If reactive T-cells are eliminated to prevent immune rejection, then immune rejection is reduced, but normal T-cell function may be affected

Engineering Contradiction:

Improveimmune rejectionVSAvoidnormal T-cell function

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The invention applies local quality by enabling MHC class I molecules to specifically present only immunogenic peptides derived from non-self or junctional sequences, allowing reactive T-cells to be targeted selectively without affecting normal T-cells that recognize self-peptides

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention converts the potentially harmful presence of reactive T-cells into a beneficial mechanism where they recognize and eliminate themselves through specific recognition of immunogenic peptides presented by MHC class I, thereby reducing immune rejection while preserving normal T-cell function

Inventive Principle:

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

Data Source

PatentUS11643453B2Cell

Publication Date: 2023.05.09 AUTOLUS LIMIED

AI summary

The present invention provides a cell which comprises; (i) a chimeric antigen receptor (CAR) or a transgenic T-cell receptor (TCR); and (ii) a polypeptide capable of co-localizing a beta-2 microglobulin component of a MHC class I molecule with an intracellular signalling domain within the cell.