Chimeric Suicide Modules for Safe Allogeneic Cell Therapy
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Solution Overview
Problem
Current autologous and allogeneic cell therapies face challenges such as Graft versus Host Disease (GvHD), Host versus Graft rejection, cytokine release syndrome, and neurotoxicity due to immune cell mismatch and side effects from suicide switch modules, which require more effective and safer solutions for cell therapy applications.
Innovation Solution
Development of chimeric transmembrane proteins with suicide modules, specifically comprising a ligand binding domain linked to a heterologous transmembrane domain, including a B cell maturation antigen (BCMA) extracellular domain, and a CD8 transmembrane domain, designed to allow selective killing of cells by binding specific ligands or antibodies, thereby preventing adverse reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If allogeneic cell therapies are used to treat diseases, then higher numbers of healthier cells can be administered, but Graft versus Host Disease (GvHD) can occur when donor and recipient are not matched for HLA class I genes
Solution Approach 1:
The patent extracts and removes the problematic HLA class I genes from the donor cells through gene editing methods, specifically disrupting the TRAC locus. This allows the therapeutic cells to be administered in high numbers without causing GvHD, as the cells can no longer recognize foreign HLA class I genes on recipient cells.
Solution Approach 2:
The patent changes the genetic parameters of the donor cells by disrupting specific loci (TRAC for preventing GvHD, B2M for preventing Host versus Graft rejection). These parameter changes transform the cells into a state where they can be administered in high quantities without causing immune-mediated side effects.
2Reliability
If B2M locus is disrupted to prevent Host versus Graft rejection, then grafted cells are protected from host immune attack, but cells become vulnerable to killing by host natural killer (NK) cells
Solution Approach 1:
The patent creates composite cells with multiple genetic modifications: B2M disruption to prevent Host versus Graft rejection, combined with HLA-E expression to protect against NK cell killing. This composite approach combines multiple protective mechanisms in a single cell therapy product.
Solution Approach 2:
The patent anticipates the vulnerability to NK cell killing beforehand and pre-equips the donor cells with HLA-E expression before administration. This prior cushioning ensures that when the B2M-disrupted cells are administered, they are already protected from NK cell-mediated killing.
3Ease of operation
If suicide switch modules are engineered into cells to enable selective killing, then cell depletion can be controlled, but side effects such as cytokine release syndrome and neurotoxicity can occur
Solution Approach 1:
The patent introduces an intermediary control mechanism where suicide switch modules are engineered into the cells, allowing selective depletion through antibody or small molecule activation. This intermediary system provides precise control over cell persistence and depletion, enabling management of cytokine release syndrome and neurotoxicity by selectively removing problematic cells.
Data Source
AI summary
Chimeric transmembrane proteins comprising one or more suicide modules and methods of making and using these constructs are disclosed. The chimeric transmembrane proteins comprise one or more suicide module and a transmembrane domain. Engineered cells comprising such chimeric transmembrane proteins and methods of using such engineered cells are also disclosed.