Antibody Drug Conjugate with Stable Linker Architecture
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Solution Overview
Problem
Existing antibody drug conjugates targeting mesothelin have stability issues due to disruption of disulfide bonds and random coupling sites, leading to shortened half-life and increased toxic side effects when administered.
Innovation Solution
Development of an anti-mesothelin antibody drug conjugate with specific linker configurations, such as Py-MAA-Val-Cit-PAB and Mc-Val-Cit-PAB, which stabilize the antibody and therapeutic agent, enhancing affinity and reducing toxicity by controlling the release of the drug within the tumor environment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If coupling is performed by thiol groups of cysteines on the antibody, then the antibody drug conjugate can be formed, but the original disulfide bond between peptide chains is lost, resulting in reduced stability and increased toxic side effects
Solution Approach 1:
The patent introduces a maleimide group as an intermediary coupling reagent that reacts with thiol groups to form stable thioether bonds, while preserving the original disulfide bonds through controlled reduction and reoxidation steps. This intermediary approach allows conjugation without permanently disrupting the antibody's native disulfide architecture
Solution Approach 2:
The patent employs controlled changes in oxidation state parameters - reducing disulfide bonds to thiols for coupling, then reoxidizing to reform disulfide bonds - to achieve conjugation while maintaining structural stability. This dynamic parameter control resolves the contradiction between coupling requirements and stability preservation
2Ease of manufacture
If coupling is performed by amino groups of lysines on the antibody, then the antibody drug conjugate can be formed, but the coupling sites become random, affecting the targeting ability of the antibody
Solution Approach 1:
The patent introduces cysteine residues at specific local positions (e.g., position 22 of the heavy chain) to create localized coupling sites with unique chemical properties. This localized functionalization replaces random lysine coupling, providing precise control over conjugation sites while maintaining ease of manufacture through site-specific chemistry
Solution Approach 2:
The patent segments the antibody structure by introducing distinct cysteine sites in specific regions (heavy chain vs light chain, different domains), allowing controlled conjugation at predetermined locations. This segmentation approach transforms the homogeneous random coupling into targeted regional conjugation, improving precision without complicating the manufacturing process
3Object-affected harmful factors
If monoclonal antibodies are used alone, then they have high therapeutic target specificity and low side effects, but their efficacy is limited
Solution Approach 1:
The patent creates a composite structure by conjugating cytotoxic drugs (such as auristatins or calicheamicins) to the monoclonal antibody framework. This composite antibody-drug conjugate combines the high specificity and low immunogenicity of monoclonal antibodies with the potent cytotoxic activity of the attached drug, achieving both low side effects and high therapeutic efficacy
Solution Approach 2:
The patent uses a cleavable linker as an intermediary between the antibody and cytotoxic drug, designed to be stable in circulation but cleavable within the target cell. This intermediary mechanism allows the antibody to deliver the drug specifically to tumor cells while maintaining stability in the bloodstream, thereby achieving high efficacy with minimal systemic side effects
Data Source
AI summary
The present invention discloses an antibody drug conjugate that targets MSLN. The present invention also disclosed a method of making the antibody drug conjugate (ADC). The present invention further discloses a novel MSLN antibody or a functional fragment thereof comprising engineered heavy and light chains.