Allosteric Antibody Modulation for Site-Specific Antigen Binding
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Solution Overview
Problem
Therapeutic antibodies often cause undesirable side effects due to systemic inhibition of target molecules with additional functions unrelated to the disease, leading to increased susceptibility to infections and severe adverse reactions.
Innovation Solution
Development of allosteric antibodies with amino acid substitutions forming a contiguous cavity, allowing for spatial and temporal control of antigen binding through the use of an effector molecule to restore or increase antigen binding activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If therapeutic antibodies are administered in large doses to achieve effective treatment, then treatment efficacy is improved, but systemic side effects increase
Solution Approach 1:
The antibody is engineered to dynamically change its binding affinity state based on the presence or absence of an effector molecule. In the absence of the effector, the antibody has low binding affinity to minimize systemic side effects. Upon addition of the effector molecule, the antibody transitions to a high binding affinity state to effectively treat the disease at the target site.
Solution Approach 2:
The antibody exhibits different binding properties at different locations: systemic circulation (low affinity to avoid off-target effects) versus tumor microenvironment (high affinity when activated by effector). This spatial differentiation of functional properties allows effective treatment at the tumor site while minimizing systemic toxicity.
2Productivity
If therapeutic antibodies bind to target molecules with additional functions, then disease treatment is improved, but susceptibility to infections increases
Solution Approach 1:
The antibody's binding activity is dynamically controlled by the effector molecule. Without the effector, the antibody remains inactive and does not bind to target molecules, preventing interference with additional functions like infection defense. When the effector is present at the tumor site, the antibody activates and binds to the target to provide therapeutic effect.
Solution Approach 2:
The antibody activity is activated periodically or conditionally based on the presence of the effector molecule, rather than being continuously active. This periodic activation allows the antibody to perform its therapeutic function when needed while remaining inactive during other times, thus not interfering with normal immune functions.
3Productivity
If checkpoint inhibitor antibodies are used to activate T-cells, then cancer treatment promise is improved, but severe adverse side effects occur
Solution Approach 1:
The checkpoint inhibitor antibody is engineered with dynamic binding affinity controlled by an effector molecule. In the absence of the effector, the antibody has low affinity and does not activate T-cells, avoiding severe adverse reactions. When the effector is administered at the tumor site, the antibody transitions to high affinity and activates T-cells locally to attack cancer cells.
Solution Approach 2:
The effector molecule serves as an intermediary that controls the activity of the antibody. It binds to the allosteric site on the antibody, inducing a conformational change that increases binding affinity and activates the therapeutic function. This intermediary control mechanism allows precise regulation of T-cell activation to minimize systemic toxicity.
Data Source
AI summary
Compositions and methods for modulating antibody activity are disclosed.