CARs with CTLA4 or PD-1 Transmembrane Domains
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Solution Overview
Problem
Current methods for modifying T lymphocytes to enhance their antigen-specific activation and proliferation are limited by the need for two signals, which can be complex to achieve, and existing chimeric antigen receptors (CARs) do not effectively incorporate inhibitory signals to regulate immune responses.
Innovation Solution
Development of polypeptides with a transmembrane domain from CTLA4 or PD-1, combined with an extracellular antigen-binding domain and an intracellular signaling domain, to create chimeric antigen receptors (CARs) that provide both activation and inhibitory signals upon antigen binding, enabling T lymphocytes to target and kill antigen-expressing cells while regulating immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing chimeric antigen receptors (CARs) are used to activate T lymphocytes, then antigen-specific activation and proliferation are enhanced, but the complexity of achieving two signals increases and inhibitory signals are not effectively incorporated
Solution Approach 1:
The patent combines the antigen-binding domain (extracellular), transmembrane domain, and intracellular signaling domain into a single chimeric antigen receptor polypeptide. This merging of functions into one integrated structure simplifies the delivery mechanism while maintaining the necessary activation signals, directly resolving the contradiction between activation reliability and signal delivery complexity
Solution Approach 2:
The CAR structure employs a composite design combining domains from different proteins: the extracellular antigen-binding domain (from antibodies or TCRs), the transmembrane domain (from CD3ζ or other signaling proteins), and intracellular signaling domains (from CD3ζ, CD28, CTLA4, or PD-1). This composite architecture enables multiple functions within a single receptor, achieving reliable T cell activation without complex signal delivery mechanisms
2Productivity
If CARs with only activation signals are used, then T lymphocyte proliferation is enhanced, but immune response regulation is insufficient
Solution Approach 1:
The patent introduces dynamic regulation to the CAR system by incorporating inhibitory domains (CTLA4 or PD-1 intracellular domains) that can modulate the activation signal based on cellular context. This dynamic control allows the T lymphocyte to adjust its proliferation and activation levels, achieving both high productivity when needed and appropriate regulation to prevent excessive immune responses
Solution Approach 2:
The inclusion of inhibitory signaling domains creates a feedback mechanism within the CAR system. When the T lymphocyte becomes overly activated or encounters persistent antigen stimulation, the inhibitory domains can dampen the signal, providing negative feedback that regulates the immune response. This feedback loop enables the system to maintain productivity while adapting to different physiological conditions
Data Source
AI summary
Provided herein are therapeutic polypeptides, e.g., chimeric antigen receptors, able to direct an immune cell, e.g., a T lymphocyte to a target antigen, and able to cause the T cell to proliferate or to kill cells displaying the antigen when the antigen binds to the polypeptide, wherein the polypeptides comprise a transmembrane domain from a T cell co-inhibitory protein such as CTLA4 or PD-1. Also provided herein are T lymphocytes expressing the polypeptides, and use of such T lymphocytes to treat diseases such as cancer.