CT83-Derived Peptide MHC Complexes for Targeted Cancer Immunotherapy
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Solution Overview
Problem
Current immunotherapeutic approaches for cancer treatment face challenges in identifying T cells and T cell receptors (TCRs) that recognize tumor-associated antigen (TAA)-derived peptides with high affinity, leading to inefficient targeting of tumor cells.
Innovation Solution
Development of novel peptides derived from the Kita-kyushu lung cancer antigen 1 (CT83) that form complexes with Major Histocompatibility Complex (MHC) molecules, along with binding moieties that can be used to create immunotherapeutic reagents for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current immunotherapeutic approaches are used to identify T cells and TCRs that recognize TAA-derived peptides, then the therapeutic window can be established, but the identification efficiency is low and affinity is insufficient
Solution Approach 1:
The patent changes the parameter of peptide selection by identifying specific peptides from CT83 antigen that exhibit high affinity for HLA-A*02:01 MHC molecules. The selected peptides (SEQ ID NOS: 1-9) have been experimentally validated to form stable complexes with HLA-A*02:01, with some peptides showing particularly strong binding. This parameter change from general TAA-derived peptides to specifically selected high-affinity peptides resolves the contradiction between identification efficiency and affinity.
2Object-affected harmful factors
If TAAs are targeted for immunotherapeutic intervention, then tumor cells can be targeted, but off-tumour on-target toxicity may occur
Solution Approach 1:
The patent applies local quality by selecting peptides from CT83 antigen that are specifically presented on tumor cells with HLA-A*02:01 expression. The invention focuses on localized targeting of tumor cells that express both CT83 and HLA-A*02:01, rather than attempting to target all cells expressing the antigen. This localized approach allows the therapeutic to affect only the specific tumor cell population, minimizing off-target toxicity to healthy tissues that may also express CT83 but lack the specific peptide-MHC complex.
Solution Approach 2:
The patent uses peptide-MHC complex structures as copies or models to identify and isolate TCRs with high specificity. By creating peptide-HLA-A*02:01 complexes and using them to screen TCR libraries, the invention generates TCRs that are precisely tuned to recognize the specific tumor antigen presentation, thereby improving the therapeutic window by ensuring specificity for tumor cells while sparing healthy tissues.
3Reliability
If T cells with high affinity for TAA-derived peptides are sought, then targeted killing of tumor cells is improved, but such T cells are scarce in the circulating repertoire
Solution Approach 1:
The patent performs preliminary action by pre-identifying and characterizing high-affinity TCRs against selected CT83-derived peptides before clinical application. The invention involves screening TCR libraries against peptide-HLA-A*02:01 complexes in advance, isolating and characterizing TCRs with high affinity and specificity, and validating their ability to recognize tumor cells. This preliminary identification and characterization allows for the selection of optimal TCRs for therapeutic use, ensuring high targeted killing efficiency while overcoming the scarcity of naturally occurring high-affinity T cells.
Data Source
AI summary
The present invention relates to novel peptides derived from Kita-kyushu lung cancer antigen 1 (CT83), complexes comprising such peptides bound to recombinant MHC molecules, and cells presenting said peptide in complex with MHC molecules. Also provided by the present invention are binding moieties that bind to the peptides and/or complexes of the invention. Such moieties are useful for the development of immunotherapeutic reagents for the treatment of diseases such as cancer.