Chimeric Receptor Spacer Tuning for In Vivo T-Cell Efficacy
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Solution Overview
Problem
Existing chimeric antigen receptor designs for T cells do not reliably translate superior in vitro function into improved in vivo therapeutic activity, necessitating the identification of elements for enhanced survival and efficacy in clinical applications.
Innovation Solution
Customization of chimeric receptor nucleic acids by varying the length of the polypeptide spacer and combining it with specific intracellular signaling domains to optimize T cell activation and target molecule recognition, using expression vectors and host cells to enhance immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric receptor designs are optimized for superior in vitro function, then T cell activation and cytotoxicity are improved in laboratory settings, but the in vivo therapeutic activity does not reliably translate or improve
Solution Approach 1:
The patent applies parameter changes by systematically varying the spacer length (10-229 amino acids) and intracellular signaling domain composition to optimize chimeric receptor function. Different spacer lengths and signaling domains are tested to determine which parameters yield the best in vivo therapeutic activity, moving beyond fixed designs to parameter-optimized variants that translate effectively from in vitro to in vivo settings.
Solution Approach 2:
The patent applies local quality by customizing specific regions of the chimeric receptor (spacer length, signaling domain composition) to match the requirements of different target molecules and clinical applications. Rather than using a uniform design, the spacer and signaling domains are locally optimized based on the specific target antigen and desired therapeutic outcome, enabling better in vivo performance.
2Reliability
If the polypeptide spacer length is increased to improve T cell activation, then in vitro cytotoxicity may be enhanced, but in vivo efficacy and survival are not reliably improved
Solution Approach 1:
The patent systematically changes the spacer length parameter within a defined range (10-229 amino acids) to identify the optimal length for in vivo efficacy. By treating spacer length as a variable parameter rather than a fixed element, the patent identifies specific length ranges that improve both in vitro activation and in vivo survival, resolving the contradiction between activation enhancement and reliable therapeutic effect.
3Reliability
If multiple intracellular signaling domain combinations are tested to optimize T cell function, then in vitro activation may be improved, but the complexity of determining optimal in vivo configurations increases
Solution Approach 1:
The patent segments the intracellular signaling domain into modular components that can be independently combined and tested. By dividing the signaling function into discrete, interchangeable elements, the patent enables systematic optimization of in vivo therapeutic activity through combinatorial approaches, while maintaining a standardized framework that facilitates manufacturing and clinical translation.
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.