Chimeric Receptor Spacer Length for In Vivo T Cell Efficacy
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Solution Overview
Problem
Existing chimeric receptor designs for T cells in cancer therapy are uncertain in translating in vitro function to reproducible in vivo therapeutic activity, necessitating the identification of elements for enhanced survival and efficacy.
Innovation Solution
Customization of chimeric receptor nucleic acids and polypeptides with modular components, including a ligand binding domain, polypeptide spacer of specific length, transmembrane domain, and intracellular signaling domains, tailored for efficient T cell activation and target recognition, and the use of genetically modified CD8+ and CD4+ T cells to augment immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric receptor designs are customized with specific spacer lengths for different target molecules, then in vivo therapeutic efficacy is improved, but device complexity increases
Solution Approach 1:
The chimeric receptor is divided into modular components including ligand binding domain, spacer region, transmembrane domain, and intracellular signaling domain. Each component can be independently designed and optimized, with the spacer length specifically customized based on the target molecule's epitope location, enabling systematic optimization of in vivo efficacy without redesigning the entire receptor structure
Solution Approach 2:
The spacer region length is varied as a key parameter to optimize receptor function. Different spacer lengths (e.g., 12 amino acids for membrane-proximal epitopes, 119 amino acids for membrane-distal epitopes) are employed to accommodate different epitope locations, thereby improving in vivo therapeutic activity while maintaining a manageable design framework
2Productivity
If spacer length is optimized for specific epitope locations, then T cell activation efficiency is improved, but manufacturing precision requirements increase
Solution Approach 1:
Discrete spacer length options are provided based on epitope location categories (membrane-proximal vs. membrane-distal). This parameterization approach allows for optimized T cell activation efficiency while simplifying manufacturing requirements by establishing clear design guidelines rather than requiring continuous precision optimization
3Reliability
If multiple chimeric receptor variants are tested to determine optimal design elements, then therapeutic activity is improved, but loss of time increases
Solution Approach 1:
By segmenting the chimeric receptor into independent modular components, the optimization process is divided into focused tasks rather than requiring comprehensive testing of all possible combinations. The spacer region can be independently optimized based on target molecule characteristics, reducing the overall time required to identify effective design elements
Solution Approach 2:
Design guidelines and spacer length recommendations are established based on preliminary analysis of epitope locations and receptor function requirements. This allows for more rapid selection of appropriate receptor variants for testing, reducing the time needed to identify optimal therapeutic designs
Data Source
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AI summary
The present invention provides nucleic acids, vectors, host cells, methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring CD8+ central memory T cells or combinations of central memory T cells with CD4+ T cells that are genetically modified to express a chimeric receptor. In embodiments the genetically modified host cell comprises a nucleic acid comprising a polynucleotide coding for a ligand binding domain, a polynucleotide comprising a customized spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain. It has been surprisingly found that the length of the spacer region can affects the ability of chimeric receptor modified T cells to recognize target cells in vitro and affects in vivo efficacy of the chimeric receptor modified T cells. Pharmaceutical formulations produced by the method, and methods of using the same, are also described.