B2M RNA Knockdown for Allogeneic CAR Treg Immunogenicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cell-based therapies, such as CAR-T cell treatments, face challenges with immunogenicity, particularly in immunosuppressive therapies like engineered T regulatory lymphocytes (Tregs), leading to immune reactions and limitations in large-scale production due to the need for autologous cell sources.
Innovation Solution
The use of beta 2 microglobulin (B2M) modifying RNA, encoded in vectors like siRNA or shRNA, to reduce HLA class I MHC expression in cells, thereby minimizing immunogenicity and allowing for the use of non-autologous cell sources, combined with chimeric antigen receptors (CAR) and additional genes for targeted therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If autologous cells are used to reduce immunogenicity, then immune reaction risk is reduced, but treatment time is delayed and large-scale production is prevented
Solution Approach 1:
The patent modifies the immunogenicity parameters of cells by knocking down HLA class I MHC expression through B2M gene interference. This allows cells to be recognized as 'self' by the immune system even when derived from non-autologous sources, thereby enabling the use of allogeneic or third-party cells for therapy without triggering strong immune rejection, thus resolving the contradiction between reducing immune reactions and maintaining treatment speed/production scale
Solution Approach 2:
The patent creates universally applicable cell therapy products that can be used across multiple patients rather than being limited to autologous applications. By engineering cells with reduced HLA class I expression, the same cell product can be manufactured at scale and administered to multiple recipients, achieving both large-scale production and reduced immunogenicity
2Object-affected harmful factors
If HLA class I MHC expression is reduced to minimize immunogenicity, then immune response is minimized, but cell recognition as foreign is reduced
Solution Approach 1:
The patent applies local quality modification by specifically targeting the reduction of HLA class I MHC expression while preserving other cell surface molecules and cellular functions. The B2M gene knockdown selectively affects HLA class I presentation without compromising the cell's immunosuppressive capabilities or viability, allowing cells to maintain their therapeutic function while becoming less immunogenic
Solution Approach 2:
The patent converts the potential harm of reduced HLA class I expression (which could impair immune recognition) into a benefit by exploiting the fact that Tregs naturally suppress immune responses. The reduced HLA class I expression further enhances their ability to evade detection by cytotoxic T cells, turning a potential vulnerability into an advantage for therapeutic persistence
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces immunogenicity, enabling the use of non-autologous cell sources for therapies, facilitating larger-scale production and effective treatment of autoimmune and inflammatory diseases by minimizing immune responses.
Implementation Method 1
B2M modifying RNA can include small interfering RNA (siRNA), or small hairpin RNA (shRNA) can be engineered to target B2M-encoding mRNA and disrupt translation thereof resulting in B2M knockdown cells with reduced class I MHC expression
Data Source
AI summary
The invention provides compositions and methods for reducing the immunogenicity of cells for transplant including cell-based immunotherapies. Vectors encoding beta 2 microglobulin (B2M) modifying RNAs along with targeting moieties and other signaling and/or suicide genes allow for efficient production of engineered CAR T-regulatory or other therapeutic cells from any source.