MHC Class I Editing: Selective HLA-B Reduction to Limit NK Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for reducing MHC class I protein expression in allogeneic cells are challenging due to the need for multiple gene edits and the risk of immune rejection, including NK cell activation and low editing efficiencies, which hinder practical application in cell therapy.
Innovation Solution
Genetically modifying human cells to reduce or eliminate surface expression of HLA-B protein, making them homozygous for HLA-A and HLA-C, or reducing/eliminating HLA-A and HLA-B protein, while optionally modifying CIITA for MHC class II expression, using targeted genetic modifications and guide RNAs to achieve partial MHC class I compatibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple gene edits are used to reduce all MHC protein expression, then immune rejection is reduced, but cell safety is compromised due to NK cell activation
Solution Approach 1:
The patent segments the MHC class I reduction strategy by selectively targeting only HLA-B protein expression while preserving HLA-A and HLA-C. This partial reduction approach (reducing only one MHC component rather than all MHC proteins) achieves sufficient immune rejection reduction without triggering NK cell activation, which occurs when all MHC class I is eliminated.
Solution Approach 2:
The invention applies local quality by making cells homozygous for specific HLA alleles (HLA-A and HLA-C) while reducing HLA-B expression. This creates a non-uniform MHC profile where certain MHC molecules are preserved for NK cell inhibition while others are reduced for immune rejection minimization, achieving both safety and efficacy simultaneously.
2Reliability
If multiple gene edits are performed to reduce MHC class I, then allogeneic cell compatibility is improved, but editing efficiency decreases
Solution Approach 1:
The patent divides the MHC class I reduction into a focused single-gene edit targeting HLA-B rather than performing multiple simultaneous edits across HLA-A, HLA-B, and HLA-C. This segmented approach reduces the cumulative editing complexity and improves overall editing efficiency while still achieving sufficient compatibility for allogeneic cell therapy.
Solution Approach 2:
The invention applies partial action by reducing only HLA-B expression rather than eliminating all MHC class I molecules. This partial reduction is sufficient to achieve the desired allogeneic cell compatibility without requiring the more complex and less efficient multiple gene edit strategy that would be needed for complete MHC class I elimination.
3Reliability
If full HLA matching is performed between donor and recipient, then transplant rejection is minimized, but donor matching difficulty increases
Solution Approach 1:
The patent segments the HLA matching requirement by focusing only on HLA-B reduction rather than requiring matching across all HLA molecules (HLA-A, HLA-B, HLA-C, and others). This reduces the matching complexity from 10 HLA loci to essentially 1-2 loci, dramatically increasing the pool of compatible donors while still minimizing transplant rejection through the engineered cell's reduced HLA-B expression.
Solution Approach 2:
The invention changes the parameter of HLA expression levels rather than requiring HLA type matching. By reducing HLA-B protein expression to low or undetectable levels, the patent transforms the matching problem from a discrete allele-matching problem to a continuous expression-level control problem, enabling compatibility with a broader donor population.
Data Source
AI summary
Compositions and methods for reducing MHC class I protein expression in a cell comprising genetically modifying MHC class I for use e.g., in adoptive cell transfer therapies.