Hinge Antibody With Cleavable Linkers for Selective Activation
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Solution Overview
Problem
Current antibody-based therapeutic agents face challenges in selectivity of action, leading to off-target effects due to non-specific binding to target molecules present in non-disease cells, necessitating the development of more targeted and cost-effective solutions that avoid unnecessary immune responses.
Innovation Solution
The development of hinge antibodies with inhibitory domains and cleavable linkers that are specifically activated in target cells or tissues by enzymes, such as MMP-2 or MMP-9, allowing for enhanced selectivity and reduced off-target effects by masking the antibody's binding site until activation at the disease site.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used as therapeutic agents, then they can bind to and neutralize target molecules, but they may also bind to non-disease normal cells or tissues causing off-target action and unwanted side effects
Solution Approach 1:
The patent applies preliminary action by introducing a masking moiety that pre-blocks the antibody's binding site before administration. This masking moiety is designed to be cleaved by specific enzymes (such as MMP-2 or MMP-9) that are present at the disease site, allowing the antibody to be activated only where needed. The masking moiety is attached to the antibody via a cleavable linker, creating a pro-drug format that remains inactive until reached by the specific enzyme at the target location.
Solution Approach 2:
The patent uses an intermediary approach by introducing a masking moiety as a temporary blocker between the antibody and its target. This masking moiety acts as a mediator that prevents off-target binding while allowing the antibody to reach the disease site where enzymatic cleavage removes the mask. The cleavable linker serves as another intermediary element that controls the release of the masking moiety in response to specific enzymatic conditions.
2Reliability
If a masking moiety is introduced to improve selectivity, then off-target action is reduced, but the development process becomes time-consuming and expensive requiring specific design for each antibody
Solution Approach 1:
The patent applies universality by developing a general platform approach where the same masking moiety design and cleavable linker system can be applied across different antibody therapies. Instead of creating custom masking moieties for each antibody, the invention provides a standardized framework that can be adapted to various antibodies targeting different diseases. The cleavable linker sequence and masking moiety structure are designed to be universally applicable with antibody-specific modifications only in the binding region.
3Reliability
If a masking moiety is attached to the antibody, then binding site is blocked, but there is risk of inducing unnecessary immune response to the subject
Solution Approach 1:
The patent applies the disposable principle by using a masking moiety that is temporarily attached to the antibody and then deliberately removed through enzymatic cleavage at the disease site. The masking moiety is designed to be short-lived in the sense that it serves its blocking function only during circulation and is then discarded through cleavage of the linkage. This temporary nature reduces the risk of prolonged immune response compared to permanent modifications.
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 significantly improves the selectivity and efficacy of antibody-based therapeutics by ensuring activation only at the intended site, reducing off-target effects and immune response risks, while maintaining or enhancing the therapeutic action of the antibodies.
Implementation Method 1
The cleavable linker is degraded by matrix metalloproteinases (MMP-2 or MMP-9) to release the inhibitory domain from the antibody, activating the antibody at the disease site
Data Source
AI summary
Disclosed herein is a hinge antibody capable of being selectively activated in a target cell or tissue to treat a condition therein. The hinge antibody includes a functional antibody, two inhibitory domains and four cleavable linkers. The functional antibody is capable of treating the condition in an activated state, and has two light chains and two heavy chains. Each inhibitory domain includes a hinge domain of an immunoglobulin and consists of two peptide arms. Each cleavable linker includes a peptide substrate cleavable by an enzyme specifically or highly expressed in the target cell or tissue, and connects one of the peptide arms of the inhibitory domains to the N-terminal of one of the light chains and heavy chains of the functional antibody. Also disclosed herein are methods for preparing and using this hinge antibody.