Chimeric Engulfment Receptors for Targeted Phagocytic Inflammation
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Solution Overview
Problem
Current methods are inadequate for enhancing the removal of infected, transformed, malignant, apoptotic, damaged, or necrotic cells from the body in treating various cancers, acute and chronic infections, and inflammatory and immune diseases, as they often fail to induce a targeted inflammatory response during apoptotic cell clearance.
Innovation Solution
Development of chimeric engulfment receptors (CERs) that include an extracellular domain targeting specific markers, a transmembrane domain, and an engulfment signaling domain, which upon binding, stimulate phagocytic activity and induce an inflammatory response to enhance the clearance of target cells or particles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If conventional phagocytosis methods are used for apoptotic cell clearance, then non-inflammatory removal is achieved, but inflammatory response induction is insufficient for treating certain diseases
Solution Approach 1:
The patent combines multiple functional domains into a single chimeric receptor molecule: an extracellular binding domain (from receptors like Tim-4, CD36, or antibody variable regions) that recognizes apoptotic cells, a transmembrane domain for membrane anchoring, and an intracellular signaling domain (from FcγR or other phagocytic receptors) that triggers engulfment and inflammatory responses. This merging creates a unified receptor that simultaneously performs target recognition and activates pro-inflammatory signaling pathways, resolving the contradiction between achieving inflammatory response induction and maintaining structural simplicity.
Solution Approach 2:
The chimeric engulfment receptor employs a composite molecular structure integrating different receptor components with distinct functions. The extracellular domain provides specific binding to apoptotic cell markers (such as phosphatidylserine or surface proteins), while the intracellular domain contains signaling motifs that activate NF-κB and other inflammatory pathways. This composite design enables the receptor to orchestrate both apoptotic cell recognition and inflammatory response activation within a single molecular entity, addressing the technical contradiction effectively.
2Productivity
If chimeric engulfment receptors with multiple signaling domains are used, then engulfment efficiency is enhanced, but molecular complexity increases
Solution Approach 1:
The patent merges multiple signaling functionalities into a single intracellular domain of the chimeric receptor. By incorporating well-characterized signaling motifs from FcγR or other professional phagocyte receptors, the design ensures efficient signal transduction for engulfment activation without requiring multiple separate receptor components. This merging strategy enhances engulfment efficiency while controlling molecular complexity through rational domain selection and streamlined architecture.
3Manufacturing precision
If specific binding domains are used to target disease markers, then treatment specificity is improved, but receptor design complexity increases
Solution Approach 1:
The patent applies local quality by confining the specificity-determining elements to the extracellular binding domain while keeping the intracellular signaling domain generic and constitutively active. The extracellular domain is engineered with disease-specific targeting capability through selection of appropriate binding modules (Tim-4 for phosphatidylserine, CD36 for oxidized lipids, or antibody variable regions for tumor-associated antigens), whereas the intracellular domain uses standardized signaling sequences. This localization of specificity functions to the appropriate domain reduces overall design complexity while maintaining high treatment specificity.
Solution Approach 2:
The chimeric receptor design employs universal, well-characterized signaling domains from professional phagocytes that can be paired with various disease-specific binding domains. This universal signaling module approach allows the same intracellular domain to work with multiple different extracellular binding specificities, thereby reducing the complexity of designing new receptors for different diseases while maintaining high treatment specificity through the interchangeable binding domain modules.
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 effectively promote the degradation and clearance of target cells or particles by stimulating phagocytic signal transduction in host cells, conferring enhanced engulfment and inflammatory responses, thereby treating diseases and disorders by promoting targeted cell removal.
Implementation Method 1
The extracellular domain comprises a binding domain and an optional extracellular spacer domain positioned between and connecting the binding domain and transmembrane domain
Implementation Method 2
an engulfment signaling domain that comprises a toll-like receptor (TLR) signaling domain, a Traf6 signaling domain, a Traf2 signaling domain, or a Traf3 signaling domain
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.