WT-1 Specific TCR Binding Proteins for High-Affinity Tumor Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current T cell receptor (TCR) gene therapies face challenges in targeting tumor antigens like WT-1, as high-affinity T cells specific for these antigens are rare due to thymic selection, and existing immunotherapies elicit low-affinity responses due to WT-1 being a self-protein, leading to limited efficacy in cancer treatment.
Innovation Solution
Development of binding proteins comprising specific TCR α and β chain variable domains with high affinity for the RMFPNAPYL:HLA complex, capable of inducing IFNγ production, which can be used to create modified immune cells for targeted immunotherapy against WT-1 expressing cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional T cell adoptive immunotherapy is used to target tumor antigens, then tumor-specific T cell responses can be generated, but the process requires extensive time and labor for isolation, characterization, and expansion of tumor antigen-specific T cells
Solution Approach 1:
The patent applies preliminary action by pre-characterizing and pre-expanding tumor antigen-specific T cells in a controlled laboratory setting before administration to the patient. The T cells are isolated, characterized, and expanded ex vivo prior to therapy, eliminating the need for time-consuming in-vivo selection and expansion processes during treatment.
Solution Approach 2:
The patent uses copying by creating engineered T cell receptors (TCRs) that replicate the specificity of naturally occurring tumor antigen-specific T cells. The TCRs are designed to recognize tumor-associated antigens with high affinity, allowing rapid generation of functional T cell clones without requiring extensive isolation and characterization time.
2Reliability
If T cells with high affinity for self-protein tumor antigens are used, then effective tumor targeting is achieved, but such T cells are generally eliminated during thymic selection and are rare or non-existent in the peripheral repertoire
Solution Approach 1:
The patent applies the extraction principle by isolating and purifying T cell receptors with high affinity for tumor-associated antigens from the peripheral blood mononuclear cells (PBMCs) of patients. The TCRs are extracted, characterized, and then used to engineer T cell products, effectively removing the limitation of rare natural high-affinity T cells.
Solution Approach 2:
The patent changes the affinity parameter by engineering T cell receptors with optimized binding characteristics. The TCRs are designed to have high affinity for tumor-associated antigens while maintaining compatibility with the host immune system, achieving effective tumor targeting without relying on rare natural high-affinity T cells.
3Reliability
If WT-1 is targeted as a self-protein antigen, then tumor-specific immunity can be induced, but immunization elicits responses only by T cells with low affinity TCRs due to thymic selection
Solution Approach 1:
The patent uses copying by creating engineered T cell receptors that replicate and enhance the binding capability for WT-1 antigen. The TCRs are designed to recognize WT-1 peptide-MHC complexes with high affinity, effectively copying the specificity needed for tumor targeting while overcoming the affinity limitation imposed by thymic selection of self-protein responses.
Solution Approach 2:
The patent changes the TCR affinity parameter by engineering receptors with optimized binding characteristics for WT-1. The TCRs are designed to have high affinity for the antigen while maintaining physiological functionality, transforming the low-affinity response into a high-affinity response that effectively targets tumor cells.
4Reliability
If high affinity TCRs specific for self-proteins are generated, then effective tumor targeting is achieved, but such T cells are eliminated during thymic selection
Solution Approach 1:
The patent applies extraction by isolating TCRs from the peripheral repertoire that can recognize tumor-associated self-proteins, bypassing the thymic selection process. The TCRs are extracted from PBMCs, characterized, and used to engineer T cell products, effectively removing the harmful effect of thymic selection that eliminates high-affinity self-protein specific T cells.
Solution Approach 2:
The patent uses an intermediary approach by introducing engineered T cell receptors that mediate the recognition of tumor-associated self-proteins. The TCRs serve as intermediaries that bridge the gap between self-protein recognition and effective tumor targeting, overcoming the thymic selection barrier that would normally eliminate such T cells.
Data Source
AI summary
The present disclosure provides binding proteins specific for human Wilms tumor protein 1 (WT-1) epitopes, as well as host cells that express the binding proteins. Also provided are polynucleotides that encode a binding protein and vectors that comprise a polynucleotide. Related methods and uses of the presently disclosed compositions are provided for treating diseases or disorders associated with WT-1 expression, such as various cancers.