Modified Antibody with Environment-Responsive Bond for Targeted Delivery
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Solution Overview
Problem
Current antibody therapies, such as immune checkpoint blockade therapy, face challenges in delivering antibodies effectively across the blood-brain barrier and often result in immune-related adverse events due to non-specific binding to normal tissues.
Innovation Solution
A modified antibody is developed by attaching a non-charged hydrophilic polymer block, such as polyethylene glycol (PEG), and an environment-responsive bond. This modification reduces the antibody's binding affinity in non-target tissues but allows the antibody to regain its affinity in target tissues, such as the brain or tumor, upon cleavage of the environment-responsive bond.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an antibody is systemically administered to target cancer antigens, then therapeutic effect is achieved, but off-target binding to normal tissues occurs causing immune-related adverse events
Solution Approach 1:
The antibody is pre-modified with a non-charged hydrophilic polymer block (such as PEG) before administration to reduce its binding affinity and inactivate it systemically. This preliminary inactivation prevents off-target binding and immune-related adverse events during circulation. The antibody is then reactivated at the target site through cleavage of the environment-responsive bond by the target antigen, allowing it to exert its therapeutic effect only where needed.
Solution Approach 2:
The antibody exhibits different binding properties in different locations: inactivated (low binding affinity) in systemic circulation and activated (high binding affinity) at the target tissue. This spatial differentiation of function is achieved through the environment-responsive bond that responds to local conditions (such as pH or enzyme presence) at the target site, enabling the antibody to be selectively activated only where the target antigen is present.
2Reliability
If an anti-PD-L1 antibody is administered to treat glioblastoma, then immune checkpoint blockade is achieved, but delivery beyond the blood-brain barrier is limited
Solution Approach 1:
The antibody is pre-modified with a non-charged hydrophilic polymer block that facilitates its transport across the blood-brain barrier. This preliminary modification enables the antibody to be delivered to the brain before it needs to exert its therapeutic effect. Once at the target site in the brain, the environment-responsive bond is cleaved to reactivate the antibody, allowing it to bind to PD-L1 and achieve immune checkpoint blockade therapy in the central nervous system.
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
The modified antibody achieves enhanced specificity and reduced side effects by maintaining a low binding affinity in non-target tissues while recovering full activity in target tissues, thereby improving therapeutic efficacy and minimizing adverse events.
Implementation Method 1
a non-charged hydrophilic polymer block, an environment-responsive bond and the antibody are linked in this order
Implementation Method 2
the affinity of the antibody for an antigen can be reduced to bring the antibody into an inactivated state
Implementation Method 3
the environment-responsive bond is cleaved under a reducing environment
Data Source
AI summary
The present invention relates to a technique for delivering an antibody to the brain or a tumor tissue. The present invention provides a modified antibody that is targeted. The present invention provides an inactivated antibody that is targeted, wherein the antibody is a modified antibody that is reactivated in the brain or a tumor tissue.