MHC Chimeric Receptors for T Cell Redirection
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for T cells do not fully utilize the modularity of the existing signaling apparatus, leading to incomplete signals and potential side effects due to cross-pairing with endogenous TCRs, resulting in autoimmune specificities and unintended consequences.
Innovation Solution
Development of novel chimeric receptors (MHCRs) comprising a major histocompatibility complex (MHC) molecule portion and a T cell receptor (TCR) portion, optionally with a surrogate co-receptor (SCR), to mimic antigen presenting cells and initiate targeted signaling cascades or instruct specific effector functions in T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If chimeric antigen receptors (CARs) are introduced into T cells to reprogram T cell specificity, then T cell redirection capability is improved, but cross-pairing events with endogenous TCRs occur leading to autoimmune specificities and incomplete signaling
Solution Approach 1:
The patent segments the T cell activation signaling into two distinct functional modules: (1) the MHCR-TCR binding module that provides antigen recognition and initial signaling, and (2) the surrogate coreceptor module that provides additional co-stimulatory signaling. This segmentation allows each module to perform its specific function without interference, eliminating cross-pairing issues while maintaining complete signaling through the use of separate, dedicated components for each signaling function.
2Adaptability or versatility
If ectopic TCRs are introduced into T cells to alter T cell specificity, then T cell redirectability is improved, but cross-pairing with endogenous TCRs results in novel TCRs with autoimmune specificities
Solution Approach 1:
The patent introduces the MHCR as an intermediary structure that mediates T cell redirection without relying on ectopic TCRs. The MHCR consists of an MHC portion that presents antigen and a TCR portion that provides signaling capability, allowing the T cell to be redirected to specific targets through MHC-TCR interactions rather than through direct TCR-antigen binding. This intermediary approach eliminates the risk of cross-pairing between introduced and endogenous TCRs, as the MHCR functions as a distinct, self-contained signaling unit.
3Ease of operation
If CARs are designed with scFv and signaling domains, then T cell targeting is achieved, but the existing signaling apparatus modularity is not充分利用 leading to incomplete signals
Solution Approach 1:
The patent creates a universal signaling platform that can be applied to multiple different T cell targeting scenarios. The MHCR system works with the endogenous T cell signaling apparatus through universal MHC-TCR interaction mechanisms, while the surrogate coreceptor provides universal co-stimulatory signaling. This universal approach allows the same basic structure to be used for targeting different antigens and different T cell types, while always providing complete signaling through the standardized two-module architecture.
Data Source
AI summary
Chimeric receptors featuring major histocompatibility molecules grafted onto T cell receptor molecules and surrogate co-receptors featuring cell surface receptor ligands fused with signaling molecule domains. The chimeric receptors can be used to redirect cells, altering their specificity. T cells expressing chimeric receptors may bind to ICRs of target T cells for which their chimeric receptors are specific. Surrogate co-receptors may be used to help enhance TCR-CD3 signaling as part of this modular receptor system. The chimeric receptors and surrogate coreceptors may be used to help eliminate autoreactive T cells or program T cells to desired effector functions.