TK1-Targeted CAR-T and BiTEs Using Antibody scFv
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Solution Overview
Problem
Current cancer therapies, including antibody-based treatments, are limited by their inability to target a cancer-specific yet universal antigen, and T-cell therapies face challenges with clonal tolerance and mispairing of introduced TCRs, hindering effective immunotherapy progress against various cancer types.
Innovation Solution
Development of chimeric antigen receptors (CARs) and bispecific T-cell engagers (BiTEs) using monoclonal antibodies specific to Thymidine Kinase 1 (TK1), which is expressed on the surface of cancer cells but not normal cells, to genetically modify T-cells and macrophages for targeted tumor attack.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional chemotherapy and antibody therapies are used, then some cancer types show progress, but overall cancer mortality rates and incidence rates remain high with very little headway against cancer as a disease
Solution Approach 1:
The patent applies universality by developing CAR-T cell therapy that targets TK1, a protein universally overexpressed in virtually all cancer types. The engineered T-cells are designed to recognize and attack any cancer cell expressing TK1, making the therapy broadly applicable across different cancer types rather than type-specific like traditional antibodies such as Herceptin
2Reliability
If T-cell therapies with introduced TCRs are used, then T-cell potency is enhanced, but clonal tolerance and mispairing of introduced TCRs occur
Solution Approach 1:
The patent extracts the antigen recognition function from the TCR complex and replaces it with a CAR that contains an antibody-derived single-chain variable fragment (scFv) for antigen binding. This removes the problematic TCR components that cause clonal tolerance and mispairing while retaining the essential T-cell cytotoxic function against TK1-expressing cancer cells
Solution Approach 2:
The patent introduces an intermediary structure - the CAR molecule - that mediates between the T-cell and the cancer cell. The CAR contains an scFv that binds TK1 on cancer cells and transmits the signal to the T-cell through intracellular domains, serving as an intermediary that avoids the problems of direct TCR engagement while maintaining therapeutic effectiveness
3Reliability
If antibodies against tumor associated epitopes are used, then passive immunization shows promise, but these are limited to antigens presented on the cell surface of tumors
Solution Approach 1:
The patent applies self-service by engineering the patient's own T-cells to express CARs that autonomously seek out and destroy TK1-expressing cancer cells. The modified T-cells function as living therapeutics that continuously patrol and eliminate tumor cells without requiring external antibody administration, overcoming the limitations of passive immunization
Data Source
AI summary
Modified T-cells have paratopes against human TK1 epitopes, are made by producing monoclonal antibodies that are specific to TK1, creating chimeric antigen receptors (CARs) by fusion of the single-chain variable fragments (scFv) of the monoclonal antibodies to T-cell signalling domains, and transducing the CARs to the T-cells.