Chimeric Endocytic Receptor Enhances Antigen Presentation in T Cells
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Solution Overview
Problem
Current methods lack efficient mechanisms for regulating antigen uptake and presentation in T- and B-cells, particularly for treating cancers and immune system-related diseases, as they do not effectively initiate antigen-specific endocytosis or remove viruses and auto-antibodies.
Innovation Solution
A chimeric endocytic receptor (CER) based on the structure of FcγRI/γ chain is designed, incorporating an affinity domain to facilitate the uptake of specific antigens or antibodies, genetically engineering T cells (CER-T) or monocytes (CER-M) to enhance immune response and antigen presentation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If natural receptor-mediated endocytosis is used, then cells can take up extracellular materials, but the efficiency of antigen presentation and immune response initiation is insufficient
Solution Approach 1:
The patent creates a chimeric endocytic receptor that combines the extracellular domain of FcγRI (for high-affinity antibody binding) with the transmembrane and cytoplasmic domains of the FcR γ-chain (for signal transduction). This composite receptor structure enables both efficient antigen uptake and robust immune signaling, resolving the contradiction between uptake efficiency and immune response effectiveness.
Solution Approach 2:
The invention merges the antigen-binding function of FcγRI with the signaling capability of the γ-chain into a single chimeric receptor entity. This fusion allows the receptor to simultaneously perform antibody binding, antigen internalization, and immune signal activation, thereby improving both productivity and reliability of the immune response.
2Strength
If FcγRI is used to bind antibodies, then high-affinity binding is achieved, but the receptor cannot initiate effective signal transduction for immune activation
Solution Approach 1:
The chimeric receptor combines the extracellular domain of FcγRI (providing high-affinity antibody binding) with the transmembrane and cytoplasmic domains of the FcR γ-chain (providing signal transduction). This merging allows the receptor to simultaneously achieve strong binding and effective immune activation signaling.
Solution Approach 2:
The receptor is constructed as a composite of two functional domains: the FcγRI extracellular domain for binding and the γ-chain intracellular domain for signaling. This composite structure resolves the limitation of using FcγRI alone, which binds strongly but signals weakly.
3Productivity
If chimeric endocytic receptor is engineered into T cells or monocytes, then antigen uptake and presentation efficiency is enhanced, but the complexity of cellular therapy increases
Solution Approach 1:
The chimeric receptor is designed as a modular construct with distinct functional domains (FcγRI extracellular domain, transmembrane domain, γ-chain cytoplasmic domain), allowing for standardized genetic engineering protocols. This segmentation facilitates systematic production and clinical application, managing the complexity of cellular therapy.
Data Source
AI summary
The invention discloses chimeric endocytic receptor CER-based constructs for activating and regulating immune response, and method for using the same. The CER-based constructs are based on the structure of FcγRI/γ chain and incorporate high-affinity binding domain from receptors or antibodies shown to uptake specific antigen and present the antigen to T cells or B cells to initiate the antigen-specific immune response, Such design has the ability to transform native monocytes or T cells to CER-expressing monocytes (CER-M) or CER-expressing T cells (CER-T) in recognizing and uptake the target antigen and activate subsequent immune responses. Such engineered CER-M or CER-T can be used to treat tumor, viral diseases and autoimmune diseases directly. The endocytosis process with involvement of FcR-γ may enhance and coordinate T cell activation in combination with T cell activation by other types of constructs such as CAR.