Chimeric Engulfment Receptors for Targeted Tumor Cell Clearance
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Solution Overview
Problem
Current compositions and methods are inadequate for effectively enhancing the removal of infected, transformed, malignant, apoptotic, or damaged cells from the body, particularly in treating cancers, infections, and inflammatory diseases, without inducing unnecessary inflammation.
Innovation Solution
Development of chimeric engulfment receptors (CERs) that include an extracellular domain for binding to phosphatidylserine, a transmembrane domain, and an engulfment signaling domain, which stimulate engulfment signaling activity to enhance the phagocytic activity of host cells, including those that do not naturally exhibit such activity, thereby promoting targeted cell clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric engulfment receptors are designed to induce inflammatory response to apoptotic tumor cells, then immune response and clearance are enhanced, but unnecessary inflammation may be induced in non-tumor contexts
Solution Approach 1:
The CER is designed with a specific extracellular binding domain that recognizes phosphatidylserine exposed on apoptotic tumor cells, creating localized inflammatory response only at the target site. The signaling domain is configured to activate inflammatory pathways specifically when bound to the target antigen, ensuring spatially restricted inflammation rather than systemic activation.
Solution Approach 2:
The patent modifies the signaling domain configuration of the engulfment receptor to tune the inflammatory response parameters. By adjusting the signaling domain structure and composition, the CER achieves optimal balance between inducing sufficient inflammatory response for effective tumor cell clearance while preventing excessive or inappropriate inflammation in healthy tissues.
2Productivity
If chimeric engulfment receptors are designed to enhance phagocytic activity of host cells, then cell clearance is improved, but device complexity increases
Solution Approach 1:
The CER combines multiple functional domains into a single chimeric protein structure: an extracellular binding domain for phosphatidylserine recognition, a transmembrane domain for cell membrane integration, and an intracellular signaling domain for engulfment activation. This merging of functions into one receptor molecule simplifies the overall system compared to using multiple separate components.
Solution Approach 2:
The chimeric engulfment receptor is designed as a multi-functional molecule that performs antigen binding, signal transduction, and engulfment activation all through a single receptor structure. This universal design allows one receptor to execute multiple steps of the phagocytic process, reducing the need for additional separate molecular components.
3Ease of manufacture
If conventional compositions are used for cell clearance, then manufacturing is simpler, but effectiveness in removing infected, transformed, malignant, apoptotic, or damaged cells is inadequate
Solution Approach 1:
The CER represents a composite protein structure combining different functional domains from various sources: the extracellular binding domain may be derived from natural phosphatidylserine-binding proteins, while the signaling domain is engineered from known engulfment signaling components. This composite architecture enables the receptor to achieve superior cell clearance effectiveness compared to natural receptors, while still being manufacturable using recombinant protein expression techniques.
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
The CERs induce an inflammatory response to apoptotic tumor cells, enhancing their clearance and inducing an immune response, while also conferring additional phenotypes like enhanced proliferative and cytolytic activities to host cells, thus effectively treating diseases by targeted cell removal.
Implementation Method 1
The extracellular domain comprises a binding domain that binds to phosphatidylserine (PtdSer)
Implementation Method 2
an engulfment signaling domain that stimulates engulfment signaling activity to enhance the phagocytic activity of host cells
Implementation Method 3
cytoskeletal rearrangement to engulf the apoptotic cell
Implementation Method 4
Anti-microbe phagocytosis clears and degrades disease-causing microbes
Implementation Method 5
the ingested apoptotic cell is digested and specific phagocytic responses are elicited
Data Source
Figure 1A~1B
Figure 2A~2B
Figure 3
AI summary
The present disclosure relates to chimeric engulfment receptor molecules, host cells modified to include the phagocytic engulfment molecules, and methods of making and using such receptor molecules and modified cells.