Chimeric Adaptor Polypeptides for Stable Tumor Cell Killing
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Solution Overview
Problem
Existing adoptive cellular therapies face challenges such as antigen escape and downregulation of receptors like NKG2D, leading to reduced efficacy in treating diseases like cancer, due to mechanisms like TGF-β downregulating NKG2D, which sensitizes tumor cells to immune cell-mediated destruction.
Innovation Solution
Mammalian cells engineered with a chimeric adaptor (CAD) polypeptide comprising a DAP10 domain and a chimeric receptor, which enhances receptor stability, promotes favorable signaling pathways, and improves cytolytic, proliferative, and costimulatory properties by engaging target antigens on cell surfaces.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cellular therapy is used to treat cancer, then immune cell-mediated destruction of tumor cells is enhanced, but antigen escape and receptor downregulation occur leading to reduced efficacy
Solution Approach 1:
The invention divides the receptor complex into separate functional components: an extracellular domain for antigen recognition and an intracellular signaling domain for signal transduction, connected through an adaptor molecule. This segmentation allows the signaling function to be decoupled from the antigen-binding function, preventing downregulation of the signaling component while maintaining antigen recognition capability.
Solution Approach 2:
The patent introduces DAP10 adaptor molecules as intermediaries between the chimeric receptor and the intracellular signaling pathways. These adaptor molecules serve as stable mediators that transmit signals from the antigen-binding portion to the cytoplasmic signaling domains, ensuring continuous signaling even when receptor expression fluctuates.
2Reliability
If TGF-β signaling is active in the tumor microenvironment, then tumor cell survival is promoted, but NKG2D receptor expression is downregulated reducing immune cell killing activity
Solution Approach 1:
The invention converts the harmful effect of TGF-β signaling into a beneficial outcome by designing chimeric receptors that use TGF-β pathway components (such as FKBP12 and rapamycin-binding domains) to trigger immune cell activation and cytotoxicity upon antigen recognition, thereby turning the suppressive pathway into an activating one.
3Reliability
If chimeric antigen receptors are engineered to recognize target antigens, then tumor cell targeting is improved, but receptor stability and signaling efficiency are reduced
Solution Approach 1:
The patent creates composite receptor structures combining multiple functional domains: extracellular antigen-binding domains (such as scFv or NKG2D ectodomains), transmembrane domains, and intracellular signaling domains (such as CD3ζ, DAP12, or DAP10). This composite architecture integrates the stability of natural receptors with the targeting specificity of engineered domains, achieving both recognition accuracy and structural stability.
Data Source
AI summary
Aspects of the disclosure include compositions and methods for treatment of a wide variety of diseases/conditions with engineered host cells, where the engineered host cells comprise a chimeric adaptor (CAD) polypeptide comprising DAP10 and at least one chimeric receptor. The CAD polypeptide may comprise substitution mutations and/or additional protein domains that function in conjunction with associated receptors to enhance cell survival and proliferation of the host cells, and to enhance cell killing activities of non-host cells.