DNA Origami Nanostructure for Conditional T-Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current bispecific antibody therapies for cancer treatment face challenges in balancing on-tumor T-cell-mediated target-cell killing with unwanted off-tumor activity due to non-exclusive tumor-specific antigens, leading to immune overstimulation and toxicity, especially in cases without a single identifiable tumor-specific antigen.
Innovation Solution
Development of a rigid nucleic acid nanostructure with multiple targeting agents, such as antibodies, positioned on a DNA-origami platform that requires specific binding to multiple antigens for cell interaction, ensuring targeted proximity and activation of cytotoxic T cells only when all targeting agents bind to their respective targets, thereby reducing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific antibody therapies target cancer cells using single tumor antigens, then on-tumor T-cell-mediated target-cell killing is achieved, but off-tumor activity increases leading to immune overstimulation and toxicity
Solution Approach 1:
The patent segments the targeting function by requiring multiple distinct targeting agents (e.g., anti-CD3 and anti-CD19 antibodies) to bind to different antigens on different cells simultaneously. This segmentation of the targeting requirement ensures that T cells are activated only when specific combinations of antigens are present, reducing off-target effects while maintaining on-tumor efficacy.
Solution Approach 2:
The bispecific antibody structure combines multiple functions in a single molecule: it simultaneously targets both the T cell (via CD3 binding) and the tumor cell (via CD19 binding), and can engage multiple tumor antigens. This multi-functionality allows the system to achieve specific T cell activation while requiring precise antigen matching to avoid off-tumor activity.
2Reliability
If multiple targeting agents are used to increase specificity, then off-target binding is reduced, but device complexity increases
Solution Approach 1:
The patent merges multiple targeting agents onto a single DNA-origami nanostructure platform, combining their functions into one integrated system. The nanostructure serves as a common scaffold that presents multiple antibodies or targeting molecules, reducing the complexity of managing separate therapeutic agents while maintaining high specificity through the combined targeting requirement.
Solution Approach 2:
The DNA-origami nanostructure acts as an intermediary platform that organizes and presents multiple targeting agents in a controlled manner. This intermediary structure simplifies the delivery and coordination of multiple targeting molecules, reducing the overall system complexity while enabling precise multi-antigen recognition and T cell activation.
Data Source
AI summary
The present invention relates to a nucleic acid nanostructure comprising a first surface and a second surface, wherein said first surface and said second surface are located at opposing sides of said nanostructure, wherein said first surface comprises at least a first targeting agent and said second surface comprises at least a second targeting agent and at least a third targeting agent. The present invention further relates to a composition comprising a nucleic acid nanostructure. The invention also relates to a nanostructure and a composition for use in medicine, and to a nanostructure and a composition for use in a method of preventing or treating a disease. Furthermore, the present invention relates to a method of preparing a nanostructure and to a use of a nanostructure for binding first target and the second target.