DARIC Immunoreceptor Complexes for Spatiotemporal T Cell Signaling
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Solution Overview
Problem
Existing adoptive cell therapies lack spatial and temporal control over cellular signal initiation and downstream responses, limiting their therapeutic efficacy in cancer treatment.
Innovation Solution
Development of dimerizing agent regulated immunoreceptor complexes (DARIC) compositions that utilize polypeptides with specific multimerization, transmembrane, and costimulatory domains, along with bridging factors, to form polypeptide complexes on cell surfaces, enabling precise modulation of cellular signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell therapies are used to treat cancer, then therapeutic value is achieved through delivering biological signals, but spatial and temporal control over cellular signal initiation is lacking
Solution Approach 1:
The immunoreceptor complex is divided into separate components: a first polypeptide with a first multimerization domain and a second polypeptide with a second multimerization domain. These domains can independently associate with different bridging factors, allowing separate control of signaling pathways in space and time.
Solution Approach 2:
Bridging factors serve as intermediary molecules that connect the multimerization domains to downstream signaling components. Different bridging factors can be used to regulate different aspects of cellular signaling, providing temporal and spatial control over signal initiation and downstream responses.
2Adaptability or versatility
If cells are outfitted with signaling machinery to enhance therapeutic value, then ability to sense and integrate chemical and biological information is improved, but device complexity increases
Solution Approach 1:
The multimerization domains are designed to be universal interfaces that can bind multiple different bridging factors. This allows a single receptor complex structure to perform multiple sensing and signaling functions by simply changing which bridging factors are present, rather than requiring separate receptor structures for each function.
Solution Approach 2:
The signaling complex is designed to be dynamically configurable through the association and dissociation of bridging factors with multimerization domains. This allows the cell to adapt its signaling capabilities in response to changing chemical and biological environmental cues without permanent structural changes.
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
Enhances the spatial and temporal control of cellular signaling, improving the therapeutic potential of adoptive immunotherapy by outfitting cells with machinery for sensing and integrating chemical and biological information from local environments.
Implementation Method 1
a bridging factor promotes the formation of a polypeptide complex on the non-natural cell surface with the bridging factor associated with and disposed between the first and second multimerization domains
Data Source
AI summary
The present disclosure generally provides improved compositions and methods for regulating the spatial and temporal control of adoptive T cell therapies using costimulatory dimerizing agent regulated immunoreceptor complexes (DARICs) for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.