Antibody Tumor-Targeting Assembly Complexes for Selective Immune Activation
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Solution Overview
Problem
Current immunotherapeutic approaches for cancer, such as bispecific T-cell engaging antibodies, lack specificity for cancer cells, leading to over-activation of the immune response, cytokine release syndrome, and activation of unwanted T cells like regulatory T cells, which can inhibit the cytolytic function of CD8 T cells.
Innovation Solution
The development of antibody tumor-targeting assembly complexes (ATTACs) that consist of a targeted immune cell binding agent with a targeting moiety and a selective immune cell binding agent, where the immune cell engaging domains are only activated upon cleavage by enzymes or proteases expressed by cancer cells, allowing for selective targeting and activation of desirable immune cells like CD8+ T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific T-cell engaging antibodies are used to activate T cells via CD3, then immune cell engagement activity is improved, but specificity to cancer cells deteriorates leading to over-activation of the immune response
Solution Approach 1:
The antibody is divided into two separate components: Component 1 contains the cancer-targeting moiety and half of the immune cell engaging domain, while Component 2 contains the other half of the immune cell engaging domain. These components must come together at the tumor site to form the complete functional antibody, ensuring localized immune activation only where both components are present.
Solution Approach 2:
A cleavable linker serves as an intermediary element connecting the two antibody components. This linker is designed to be stable in circulation but cleavable by tumor-associated proteases, allowing controlled release and assembly of the complete antibody specifically at the tumor microenvironment, thereby mediating between systemic delivery and localized activation.
2Power
If all T cells are activated at the tumor site, then immune response strength is improved, but activation of unwanted T cells such as regulatory T cells deteriorates causing inhibition of cytolytic function
Solution Approach 1:
The immune cell engaging domain is designed with local quality differentiation through the use of specific T cell subset markers. Component 2 targets markers expressed by desirable T cell subsets (such as CD8+ cytotoxic T cells or CD4+ helper T cells) while avoiding markers on regulatory T cells, creating spatially selective immune activation that enhances anti-tumor immunity without recruiting suppressive cells.
3Object-affected harmful factors
If extreme low doses are used to avoid over-activation, then safety is improved, but treatment efficacy deteriorates
Solution Approach 1:
The two-component antibody system performs preliminary action by circulating separately in a stable, safe state. The complete functional antibody is assembled in situ at the tumor site, allowing the system to prepare for potent immune activation only when and where needed, thus enabling high local efficacy without systemic over-activation or cytokine release syndrome.
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
ATTACs provide enhanced specificity and safety by selectively activating CD8+ T cells at the tumor site, reducing the risk of cytokine release syndrome and unwanted T cell activation, thereby improving cancer treatment efficacy while minimizing side effects.
Implementation Method 1
The inert binding partner and the immune cell engaging domain to which it binds are separated by a cleavage site that is cleaved by an enzyme or protease expressed by cancer cells
Implementation Method 2
The inert binding partner and the immune cell engaging domain to which it binds are separated by a cleavage site that is cleaved by an enzyme or protease expressed by cancer cells
Data Source
AI summary
The present disclosure provides antibody tumor-targeting assembly complexes (ATTACs) for selectively activating desired immune cells in the tumor microenvironment.