Hypoimmunogenic Cells Evading Immune Rejection via HLA-E and PD-L1
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Solution Overview
Problem
The vigorous host-versus-graft immune response against histoincompatible cells limits the expansion and persistence of allogeneic cells in cell-based therapies, such as CAR-T cells, leading to reduced efficacy in treating various disorders.
Innovation Solution
Engineered cells with reduced expression of MHC class I and II antigens and the expression of exogenous receptors like HLA-E, HLA-G variant proteins, and PD-L1 proteins are developed to evade immune detection, making them hypoimmunogenic and capable of evading NK cell-mediated cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic cells are used in cell-based therapies, then ease of manufacture and quality control are improved, but host-versus-graft immune response increases causing reduced cell persistence and efficacy
Solution Approach 1:
The patent modifies the immunogenicity parameters of allogeneic cells by reducing MHC class I and II expression and introducing exogenous HLA-E, HLA-G, and PD-L1 proteins. This parameter change enables the cells to evade host immune detection while maintaining their therapeutic function, thereby resolving the contradiction between ease of manufacture and cell persistence.
Solution Approach 2:
The patent uses exogenous HLA-E, HLA-G, and PD-L1 proteins as intermediary molecules that mediate immune evasion. These proteins act as protective intermediaries between the allogeneic cells and the host immune system, allowing the cells to persist without triggering vigorous host-versus-graft responses.
2Duration of action of stationary object
If MHC class I and II antigens are reduced, then immune recognition is decreased improving cell persistence, but cell identity and immunogenicity control become more difficult
Solution Approach 1:
The patent applies local quality by selectively reducing MHC class I and II expression on specific cell surfaces while simultaneously introducing exogenous HLA-E, HLA-G, and PD-L1 proteins at controlled locations. This localized modification allows precise control over immune recognition, maintaining cell persistence while enabling measurable immunogenicity control through the exogenous protein expression.
Data Source
AI summary
Disclosed herein are engineered cells and/or hypoimmunogenic cells including hypoimmunogenic stem cells, hypoimmunogenic cells differentiated therefrom, and hypoimmunogenic CAR-T cells and related methods of their use and generation comprising one or more exogenous receptors selected from the group consisting of a human leukocyte antigen E (HLA-E) variant protein, a human leukocyte antigen G (HLA-G) variant protein, and an exogenous PD-L1 protein. Provided herein are cells further exhibiting reduced expression of MHC I and MHC II human leukocyte antigens and T-cell receptors.