Bispecific CD3-PDL1 T-Cell Engager Against PD1 Immune Suppression
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Solution Overview
Problem
Existing bi-specific T-cell engagers fail to effectively reduce immune suppression in cancer patients, limiting their therapeutic efficacy as they do not simultaneously activate T-cells, induce cytotoxicity, and kill tumor cells despite the presence of immune suppression mediated by PD1.
Innovation Solution
A bispecific T-cell engager recombinant protein that binds to CD3 on T-cells and PDL1 on tumor cells, activating T-cells and redirecting them to tumor cells while neutralizing PD1-mediated suppression, comprising specific amino acid sequences and linkers for effective binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing bi-specific T-cell engagers are used to activate T-cells and kill tumor cells, then tumor cell cytotoxicity is improved, but immune suppression mediated by PD1 is not reduced
Solution Approach 1:
The patent merges two distinct functions into a single bi-specific T-cell engager molecule: (1) T-cell activation through CD3 binding, and (2) PD1-mediated immune suppression neutralization through PDL1 binding. This unified approach allows the single molecule to simultaneously enhance T-cell cytotoxicity while counteracting immune suppression, resolving the contradiction between tumor cell killing efficiency and therapeutic reliability under immune suppression conditions.
Solution Approach 2:
The bi-specific T-cell engager exhibits multi-functionality by performing three critical roles simultaneously: (a) activating T-cells via CD3 engagement, (b) redirecting T-cells to tumor cells through PDL1 binding, and (c) neutralizing PD1-mediated immune suppression. This universal design enables the single agent to address multiple barriers to effective cancer immunotherapy, thereby improving both productivity and reliability under immune suppression.
2Productivity
If a bi-specific T-cell engager binds to CD3 and PDL1 simultaneously, then T-cell activation and tumor targeting are improved, but the complexity of the protein structure increases
Solution Approach 1:
The bi-specific T-cell engager is constructed by segmenting two separate antibody variable regions (anti-CD3 and anti-PDL1) and linking them through a flexible peptide linker. This segmentation allows each functional domain to maintain its independent binding capability while being integrated into a single polypeptide chain, thereby achieving dual functionality without excessive structural complexity.
Solution Approach 2:
The protein structure employs a composite design combining antibody variable regions from different specificities (CD3-binding and PDL1-binding domains) into a single fusion protein. This composite structure leverages the proven binding capabilities of separate antibody fragments while integrating them through standardized linker sequences, balancing functional complexity with structural manageability.
3Reliability
If existing immunotherapy strategies are used, then some clinical efficacy is achieved, but robust levels of antibody and T-cell responses are not established due to tumor immune evasion
Solution Approach 1:
The bi-specific T-cell engager applies preliminary anti-action by proactively neutralizing PD1-mediated immune suppression before it can inhibit T-cell responses. By incorporating PDL1-binding capability directly into the T-cell engager structure, the molecule preemptively blocks the immunosuppressive pathway, preventing tumor cells from evading immune attack and thereby establishing robust and sustained immune responses.
Solution Approach 2:
The invention converts the harmful immunosuppressive interaction between PD1 and PDL1 into a beneficial therapeutic mechanism. By designing the bi-specific engager to bind PDL1, the molecule harnesses the tumor cell's own PDL1 expression (which normally mediates immune evasion) as a targeting handle to recruit and activate T-cells directly at the tumor site, transforming the immune suppression mechanism into a tool for enhanced tumor targeting and killing.
Data Source
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AI summary
The present invention relates generally to the field of generating fusion proteins to be used in cancer therapy, and more specifically, a bispecific T-Cell engager recombinant polypeptide comprising an antibody, fragment thereof, or single chain variable fragment that binds to CD3 of a T-cell antigen receptor and an antibody, fragment thereof, or single chain variable fragment that binds to Programmed Death Ligand 1 (PDL1) on a cancerous tumor cell to counteract the immune tolerance of cancer cells.