HLA-A Reduction in Engineered Cells for Allogeneic Therapy

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for reducing immune rejection in allogeneic cell transplantation, such as modifying MHC class I and II proteins, face challenges like low editing efficiencies and susceptibility to natural killer cell lysis, making it difficult to achieve safe and effective cell therapy.

Innovation Solution

Engineered human cells with reduced or eliminated surface expression of HLA-A, being homozygous for HLA-B and HLA-C, and optionally with reduced MHC class II expression or modified T cell receptors, are developed using precise genetic modifications to minimize immune recognition and rejection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If MHC class I protein expression is reduced to avoid CTL activation, then immune rejection is reduced, but cells become susceptible to NK cell lysis

Engineering Contradiction:

Improveimmune rejection resistanceVSAvoidNK cell lysis susceptibility

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of reduced MHC class I expression (NK cell susceptibility) into a benefit by selectively eliminating HLA-A while preserving HLA-B and HLA-C. This partial reduction strategy maintains enough MHC class I expression to protect against NK cells while sufficiently reducing overall MHC class I to avoid CTL activation, thus resolving the contradiction between immune rejection resistance and NK cell lysis susceptibility

Inventive Principle:

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

Solution Approach 2:

The patent applies local quality by differentiating between specific HLA alleles rather than uniformly reducing all MHC class I expression. By selectively targeting HLA-A for reduction while maintaining HLA-B and HLA-C at normal levels, the patent creates a non-uniform distribution of MHC class I molecules that simultaneously achieves CTL evasion and NK cell protection

Inventive Principle:

Principle #3Local quality

2Reliability

If multiple gene edits are performed to reduce all MHC protein expression, then immune rejection is reduced, but editing complexity and difficulty increase

Engineering Contradiction:

Improveimmune rejection resistanceVSAvoidgene editing complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts and eliminates only the specific HLA-A component from the MHC class I system rather than attempting to edit all MHC proteins. This selective extraction approach reduces the complexity of gene editing by focusing on a single target (HLA-A) while accepting that HLA-B and HLA-C will remain, thereby achieving immune rejection resistance with simpler editing requirements

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If HLA matching between donor and recipient is improved, then transplant rejection is reduced, but donor selection becomes more difficult and time-consuming

Engineering Contradiction:

Improvetransplant rejection resistanceVSAvoiddonor selection time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent changes the HLA matching parameter from requiring match at HLA-A, HLA-B, and HLA-C to requiring match only at HLA-B and HLA-C. This parameter change in the matching criteria allows for broader donor selection while still achieving transplant rejection resistance, as the engineered cells will not activate CTLs regardless of HLA-A mismatch due to the HLA-A reduction

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20240024478A1Compositions and Methods for Reducing HLA-A in a Cell

Publication Date: 2024.01.25 INTELLIA THERAPEUTICS INC

AI summary

Compositions and methods for reducing HLA-A protein expression in a cell comprising genetically modifying HLA-A for use e.g., in adoptive cell transfer therapies.