Immunoconjugate T Cell Cytotoxicity MHC Class I
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current approaches to inducing MHC class I restricted CTL responses against exogenous antigens are inefficient due to the antigens not being routed to the cytoplasm for processing, leading to high IC50 values and limited cell-mediated immunity against target cells such as tumor cells.
Innovation Solution
Development of immunoconjugates with naturally occurring T cell response eliciting peptides coupled to a target cell binding moiety via a cleavable bond, allowing direct presentation on MHC class I molecules without further processing within the target cell, specifically within the endosomal compartment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous antigens are used to induce MHC class I restricted CTL responses, then the antigen can be delivered to target cells, but the antigens are not routed to the cytoplasm for processing leading to inefficient presentation
Solution Approach 1:
The immunoconjugate is segmented into distinct functional domains: a target cell binding moiety (antibody) that anchors the construct to the target cell, a translocation domain (from Shiga toxin) that enables cytoplasmic delivery, and a T cell response eliciting peptide that serves as the antigen. This segmentation allows each component to perform its specific function optimally, with the translocation domain specifically responsible for routing the antigen to the cytoplasm where MHC class I processing occurs.
Solution Approach 2:
The translocation domain acts as an intermediary that bridges the extracellular antigen and the intracellular MHC class I processing pathway. This domain enables the antigen to traverse the cell membrane and reach the cytoplasm, where it can be processed and presented by MHC class I molecules to CTLs, thus mediating the connection between external antigen delivery and internal immune recognition.
2Reliability
If high concentrations of peptide are used to achieve CTL response, then T cell cytotoxicity can be induced, but the IC50 values remain high and treatment efficiency is limited
Solution Approach 1:
The invention extracts and utilizes the translocation capability from Shiga toxin, separating this function from the antigen itself. By attaching this translocation domain to the antigen, the system gains the ability to actively deliver the antigen into the cytoplasm where it can be efficiently processed by the proteasome and presented by MHC class I molecules, thereby reducing the amount of antigen needed to achieve effective CTL responses.
Solution Approach 2:
The immunoconjugate represents a composite material combining three distinct functional elements: the target cell binding antibody, the translocation domain from Shiga toxin, and the T cell response eliciting peptide. This composite structure integrates targeting, delivery, and immune stimulation functions into a single molecular construct, enhancing overall efficacy while reducing the quantity of peptide required.
3Ease of operation
If conventional antigen delivery methods are used, then antigen can be introduced to target cells, but cell-mediated immunity is limited and IC50 values are high
Solution Approach 1:
The translocation domain is pre-attached to the antigen in the immunoconjugate, preparing the antigen for cytoplasmic delivery before it reaches the target cell. This preliminary configuration ensures that once the immunoconjugate binds to the target cell and is internalized, the antigen is already equipped with the necessary machinery to reach the cytoplasm and undergo efficient MHC class I processing, eliminating the need for additional delivery steps.
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
This approach significantly reduces IC50 values and enhances the efficiency of T cell cytotoxicity against target cells, enabling faster and more effective cell-mediated immunity with lower peptide concentrations.
Implementation Method 1
the unmodified T cell response eliciting peptide is covalently coupled to the target cell binding antibody via a disulfide bond
Implementation Method 2
the cleavable bond is arranged such that upon cleavage said T cell response eliciting peptide, which is directly presentable via a MHC class I molecule, is released from the immunoconjugate
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 1E
AI summary
The present invention relates to immunoconjugates for specific induction of T cell cytotoxicity against a target cell, comprising at least one T cell response eliciting peptide that is presentable via MHC class I coupled to a target cell binding moiety via a cleavable bond and methods of their production and uses thereof.