Humanized Anti-Mesothelin Antibody Engineering
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Solution Overview
Problem
Current anti-mesothelin antibodies face limitations such as immunogenicity, low affinity, and low specificity, and non-human antibodies like mouse-derived monoclonal antibodies trigger immune responses and have short half-lives, necessitating the development of humanized antibodies with higher affinity and reduced immunogenicity for effective cancer therapy.
Innovation Solution
A humanized antibody or antigen-binding fragment specifically designed to bind to mesothelin with high affinity, constructed by replacing mouse antibody CDRs with human CDRs, utilizing specific amino acid sequences for the heavy and light chain variable regions, and potentially incorporating a linker for enhanced stability and binding efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If mouse-derived monoclonal antibodies are used to target mesothelin, then the antibodies can be produced effectively, but they trigger immune responses and have short half-lives
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the antibody to achieve humanization. Specifically, the antibody sequence identity to human IgG is increased to at least 80%, preferably at least 90%, and more preferably at least 95%. This parameter change transforms the antibody from a foreign mouse-derived protein to a human-like protein, thereby reducing immunogenicity while maintaining therapeutic effectiveness.
2Ease of manufacture
If mouse-derived monoclonal antibodies are used to target mesothelin, then the antibodies can be produced effectively, but they have short half-lives
Solution Approach 1:
The patent extends the half-life of the antibody by modifying its structural parameters to resemble human IgG more closely. The humanization process, which increases sequence identity to at least 80-95%, optimizes the antibody's interaction with human physiological systems, including Fc receptor binding and complement activation, thereby extending its circulation half-life and duration of action in the human body.
3Reliability
If existing anti-mesothelin antibodies are used, then they provide some therapeutic effect, but they have low affinity and low specificity
Solution Approach 1:
The patent applies local quality by optimizing specific regions of the antibody that are critical for binding to mesothelin. The variable regions, particularly the complementarity-determining regions (CDRs), are engineered to have enhanced affinity and specificity for the mesothelin antigen. This localized optimization of binding regions improves the overall therapeutic effect while maintaining the humanized structure throughout the rest of the antibody molecule.
Data Source
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AI summary
The present invention relates to humanized antibodies or antigen-binding fragments capable of binding specifically to mesothelin antigen and various uses thereof.