CD5-Modified Cells Mitigating On-Target Off-Disease Cytotoxicity
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Solution Overview
Problem
Immunotherapies targeting specific antigens, such as CAR-T therapies, often result in 'on-target, off-disease' effects where healthy cells expressing the antigen are depleted, leading to severe side effects or reduced efficacy due to fratricide among therapeutic cells.
Innovation Solution
Genetically engineered cells with reduced or modified CD5 expression are created using guide RNAs and RNA-guided nucleases like CRISPR/Cas to avoid recognition by immunotherapeutic agents, allowing these cells to engraft and differentiate without being targeted, thereby mitigating on-target, off-disease cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapeutic agents targeting specific antigens are administered, then therapeutic efficacy against pathological cells is improved, but on-target off-disease cytotoxicity to healthy cells occurs
Solution Approach 1:
The patent applies preliminary action by genetically modifying hematopoietic stem cells or progenitor cells ex vivo to reduce or eliminate antigen expression before administering them to the patient. This pre-modification ensures that when immunotherapeutic agents are administered, the engineered cells are already protected from on-target off-disease cytotoxicity, allowing the therapy to selectively target pathological cells while preserving healthy tissue.
Solution Approach 2:
The patent uses an intermediary approach by introducing genetically engineered cells as a mediator between the immunotherapeutic agent and the patient's hematopoietic system. These engineered cells serve as a protective intermediary that can be selectively modified to resist antigen-targeted therapy, thereby shielding healthy cells from damage while allowing the therapy to maintain its efficacy against pathological cells.
2Reliability
If immunotherapeutic agents targeting antigens on immune effector cells are administered, then therapeutic effect is achieved, but fratricide among therapeutic cells occurs rendering the therapy ineffective
Solution Approach 1:
The patent applies preliminary action by pre-modifying the immune effector cells ex vivo to reduce or eliminate the expression of the target antigen on their surface before they are administered as part of the immunotherapy. This ensures that when the immunotherapeutic agent is administered, the therapeutic cells themselves are protected from being targeted and destroyed by the same agent, preventing fratricide and maintaining therapeutic effectiveness.
3Reliability
If antigen expression on healthy cells is depleted, then pathological cells are effectively targeted, but severe side effects occur due to loss of cells required for subject survival
Solution Approach 1:
The patent applies preliminary action by genetically modifying hematopoietic stem cells or progenitor cells ex vivo to reduce or eliminate antigen expression before they are transplanted into the patient. This creates a reservoir of antigen-negative healthy cells that can repopulate the patient's hematopoietic system, providing protection against on-target off-disease cytotoxicity and preventing severe side effects while maintaining the ability to target pathological cells.
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 engineered cells effectively engraft and reconstitute hematopoietic lineages with reduced susceptibility to immunotherapeutic agents, enhancing the safety and efficacy of treatments by minimizing side effects and maintaining therapeutic potency.
Implementation Method 1
contacting the cell with (i) any of the gRNAs described herein, or a gRNA targeting a targeting domain targeted by any of the gRNAs described herein; and (ii) an RNA-guided nuclease that binds the gRNA, thus forming a ribonucleoprotein (RNP) complex
Data Source
AI summary
Provided herein are gRNA comprising a targeting domain that targets CD5, 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 CD5 gene and methods involving administering such genetically engineered cells to a subject, such as a subject having a hematopoietic malignancy.