Pretargeted NK-Cell Therapy via Bioorthogonal Click Chemistry
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Solution Overview
Problem
Current CAR-T cell and NK-cell therapies are limited by requiring genetic modification of NK cells, being specific to only one cancer type, and being susceptible to treatment resistance due to antigen shedding and heterogeneity.
Innovation Solution
The use of antibodies or fragments with a targeting ligand and engineered cytotoxic cells with a targeting agent, allowing for 'off-the-shelf' pretargeted NK-cell mediated cancer therapy through bioorthogonal 'click' chemistry, which enables targeted binding and cytotoxicity without genetic modification, enabling dual or triple antigen targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetic modification of NK cells is used to create CAR-NK therapy, then targeted cytotoxicity against cancer cells is improved, but treatment resistance due to antigen shedding and heterogeneity increases
Solution Approach 1:
The targeting function is segmented from the cytotoxic cell into a separate antibody component. The antibody binds to the cancer cell antigen and presents a targeting ligand, while the NK cell expresses a targeting agent that recognizes this ligand. This segmentation allows the targeting mechanism to be independent of the cytotoxic cell's genetic makeup, reducing susceptibility to antigen variation and shedding.
Solution Approach 2:
A targeting ligand acts as an intermediary between the antibody and the cytotoxic cell. The ligand is presented on the antibody complexed with the cancer cell antigen, and the targeting agent on the NK cell binds to this ligand. This intermediary mechanism provides an additional binding interface that is not directly dependent on the cancer cell antigen alone, thereby reducing the impact of antigen shedding and heterogeneity on treatment efficacy.
2Measurement precision
If CAR-T or CAR-NK cell therapy is used, then cancer cell specificity is improved, but applicability to multiple cancer types deteriorates
Solution Approach 1:
The system achieves universality through modular design. The antibody component can be selected or engineered to target different cancer-specific antigens for different cancer types, while the NK cell component remains universal, expressing the same targeting agent that recognizes the targeting ligand. This allows a single NK cell product to potentially treat multiple cancer types by simply changing the antibody component, thereby achieving multi-functionality.
Solution Approach 2:
The system allows dynamic reconfiguration of the antibody component to match different cancer targets. The NK cell product is not fixed to a single antigen target; instead, the antibody component can be adapted or selected based on the specific cancer type being treated, providing flexibility and dynamic adaptability across different therapeutic indications while maintaining the same core NK cell mechanism.
3Productivity
If antibody-dependent cellular cytotoxicity is enhanced by pretargeting, then cancer cell killing efficacy is improved, but complexity of the treatment protocol increases
Solution Approach 1:
The antibody is administered first to bind to cancer cells and present the targeting ligand before the NK cells are administered. This preliminary action prepares the target sites with the ligand, ensuring that when NK cells arrive, they can immediately recognize and bind to the ligand-presenting cancer cells through their targeting agents, thereby enhancing cytotoxicity efficiency without requiring complex real-time coordination.
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 enhances antibody-dependent cellular cytotoxicity (ADCC) and allows for effective cancer cell killing, overcoming antigen paucity and escape, and increasing treatment efficacy by anchoring cytotoxic cells to cancer cells, thereby reducing tumor volume.
Implementation Method 1
the first antigen binding portion of the first antibody or fragment thereof binds the first antigen on the surface of the cancer cell
Implementation Method 2
engineered cytotoxic cells comprising a targeting agent specific for the targeting ligand, for use in inducing cytotoxicity in a cancer cell... through bioorthogonal 'click' chemistry, which enables targeted binding
Data Source
AI summary
This invention relates to methods and compositions comprising antibodies or fragments thereof comprising a targeting ligand and engineered cytotoxic cells comprising a targeting agent specific for the targeting ligand, for use in inducing cytotoxicity in a cancer cell, in delivering a cytotoxic cell to a cancer cell in a subject, and in treating cancer.