CD6-Modified CAR-T Cells for Hematopoietic Engraftment
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Solution Overview
Problem
Current immunotherapies, such as CAR-T therapies, can cause 'on-target, off-disease' effects where healthy cells expressing the targeted antigen are depleted, leading to severe side effects or rendering the therapy ineffective, due to shared antigen expression on both malignant and healthy cells.
Innovation Solution
Genetically engineered cells with reduced or modified CD6 expression are produced using guide RNAs and RNA-guided nucleases like CRISPR/Cas to avoid recognition by immunotherapies, allowing these cells to engraft and differentiate without being targeted by immunotherapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapy targeting a specific antigen is administered, then therapeutic efficacy against malignant cells is improved, but healthy cells expressing the same antigen are depleted causing severe side effects
Solution Approach 1:
The patent applies local quality by creating immunotherapy cells with heterogeneous antigen expression patterns. Some cells express the target antigen at high levels while others express it at low or undetectable levels. This localized differentiation allows the therapy to maintain efficacy through high-expressing cells while protecting healthy tissue through low-expressing cells, directly resolving the contradiction between therapeutic efficacy and on-target off-disease cytotoxicity
Solution Approach 2:
The patent changes the parameter of antigen expression levels across the cell population. By generating a heterogeneous population where antigen expression varies from high to undetectable, the therapy transforms the uniform high expression that causes cytotoxicity into a distributed range of expression levels. This parameter change allows the system to maintain therapeutic function while avoiding harmful effects on healthy cells
2Ease of manufacture
If immunotherapy targets an antigen expressed on immune effector cells, then the therapy can be produced, but fratricide occurs rendering the therapy ineffective
Solution Approach 1:
The patent applies inversion by reversing the uniform high antigen expression pattern that causes fratricide. Instead of all cells expressing the target antigen at high levels, the invention creates a population where antigen expression is distributed across different levels, with many cells expressing it at low or undetectable levels. This inverted expression pattern prevents fratricide while maintaining production capability
Solution Approach 2:
The patent applies local quality by creating spatial and functional heterogeneity in antigen expression within the therapy cell population. Different cells within the same therapeutic product have different antigen expression levels, allowing some cells to serve as protective reservoirs that prevent fratricide while others maintain targetability for therapeutic effect
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
The genetically modified cells effectively engraft and reconstitute hematopoietic lineages, reducing on-target, off-disease cytotoxicity and enhancing the safety and efficacy of immunotherapies by avoiding healthy cell depletion.
Implementation Method 1
a gRNA comprising a targeting domain comprising a sequence... an RNA-guided nuclease that binds the gRNA, thus forming a ribonucleoprotein (RNP) complex... for the RNP complex to bind a target domain in the genome of the cell
Implementation Method 2
The RNA-guided nuclease is a CRISPR/Cas nuclease... the RNP complex to bind a target domain in the genome of the cell... results in a loss-of function of CD6
Implementation Method 3
the gRNA comprises one or more nucleotide residues that are chemically modified... one or more nucleotide residues that comprise a 2′O-methyl moiety... one or more nucleotide residues that comprise a phosphorothioate
Data Source
AI summary
Provided herein are gRNA comprising a targeting domain that targets CD6, which may be used, for example, to make modifications in cells. Also provided herein are methods of genetically engineered cell having a modification (e.g., insertion or deletion) in the CD6 gene and methods involving administering such genetically engineered cells to a subject, such as a subject having a hematopoietic malignancy.