Adaptable CAR System with Tag-Binding Domain
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Solution Overview
Problem
Conventional chimeric antigen receptors (CARs) have a fixed design, limiting their ability to target multiple antigens and increasing manufacturing costs, making them less versatile for adoptive cell therapy applications.
Innovation Solution
A universal chimeric antigen receptor system with adaptable receptor specificity (arCAR) is developed, comprising an immune effector cell with a chimeric antigen receptor and a second polypeptide with an antigen-binding domain and a tag recognized by the receptor's tag-binding domain, allowing for modulation of receptor specificity using tag polypeptide affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional CARs with fixed design are used, then manufacturing process is simple, but adaptability to target multiple antigens is limited
Solution Approach 1:
The CAR system is divided into two independent polypeptides: (1) a stable CAR polypeptide containing tag-binding domain, transmembrane domain, and signaling domain; and (2) a separate antigen-specific polypeptide containing antigen-binding domain and tag. This segmentation allows the stable CAR to remain fixed while the antigen-specific polypeptide can be exchanged to target different antigens, thereby improving adaptability without increasing the complexity of the stable CAR component.
Solution Approach 2:
The stable CAR polypeptide with tag-binding domain is designed as a universal component that can bind to multiple different tags through affinity interactions. This universal tag-binding domain enables a single CAR construct to recognize multiple antigens by binding to different tag-polypeptide combinations, providing multi-functionality without requiring multiple distinct CAR designs.
2Adaptability or versatility
If conventional CARs with fixed design are used, then CAR structure is stable, but versatility for treating different diseases is limited
Solution Approach 1:
By segmenting the CAR into a stable reusable polypeptide and exchangeable antigen-specific polypeptides, the manufacturing process can produce the stable CAR once and then simply exchange the antigen-specific polypeptides for different disease indications. This reduces manufacturing cost compared to producing entirely new CARs for each disease target.
Solution Approach 2:
The antigen-specific polypeptides can be discarded and replaced with new ones targeting different antigens, while the stable CAR polypeptide is recovered and reused. This approach reduces manufacturing costs by avoiding the need to manufacture entirely new CAR constructs for each disease indication.
3Adaptability or versatility
If multiple custom-made antigen-specific CARs are generated, then each targets specific antigen precisely, but manufacturing cost increases significantly
Solution Approach 1:
The stable CAR polypeptide with tag-binding domain serves as a universal platform that can be paired with multiple different antigen-specific polypeptides containing different tags. This universal platform approach allows a single manufactured CAR product to target multiple antigens by simply exchanging the antigen-specific polypeptides, significantly reducing manufacturing costs compared to producing multiple custom-made CARs.
Solution Approach 2:
Instead of manufacturing multiple unique CAR constructs, the invention creates copies of the stable CAR polypeptide that can be paired with different antigen-specific polypeptides. This copying approach allows the same stable CAR structure to be reused across multiple disease indications, reducing the overall manufacturing burden and cost.
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
Enables flexible targeting of various antigens, reducing manufacturing costs and enhancing the versatility of CARs for treating diseases such as cancer and autoimmune disorders by allowing multiple receptors to be present on a cell therapy.
Implementation Method 1
the tag comprises an antibody, or antigen-binding fragment thereof, or an alternative scaffold and the tag-binding domain comprises an anti-idiotype molecule that binds to the tag
Data Source
AI summary
The present disclosure provides chimeric antigen receptors (CARs), particularly CARs that have adaptable receptor specificity (arCARs). Also provided are polypeptides of the CARs and other related molecules, polynucleotides, vectors, and cell compositions comprising the same. Pharmaceutical compositions comprising the polypeptides, polynucleotides, vectors, or cells of the present disclosure, and their uses in treating a disease in a subject are also provided.