Claudin-18.2 Monoclonal Antibodies for Tumor-Specific Internalization
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Solution Overview
Problem
Existing technologies lack a specific monoclonal antibody that effectively targets claudin-18.2, a splice variant overexpressed in various cancers, for therapeutic and diagnostic applications.
Innovation Solution
Development of monoclonal antibodies with specific heavy and light chain CDR sequences (SEQ IDs) that bind to claudin-18.2, along with recombinant expression vectors and methods for producing these antibodies, enabling cancer treatment and diagnosis compositions, antibody-drug conjugates, and chimeric antigen receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a monoclonal antibody is developed to specifically bind to claudin-18.2, then tumor-specific binding capability is improved, but development complexity and time increase
Solution Approach 1:
The antibody development process was segmented into distinct phases: phage display library screening, hybridoma generation, and monoclonal antibody isolation. This segmentation allowed systematic optimization at each stage, achieving high binding specificity through controlled selection processes while managing overall development complexity.
Solution Approach 2:
Phage display library screening was performed as a preliminary action to identify candidate antibodies with specific binding to claudin-18.2 before committing to full monoclonal antibody development. This preliminary screening step reduced the risk of developing non-specific antibodies and streamlined the subsequent development process.
2Reliability
If an antibody is designed for high internalization property, then therapeutic efficacy is improved, but immune response risk increases
Solution Approach 1:
The antibody structure was optimized by modifying specific amino acid residues in the variable regions to enhance internalization property while maintaining low immunogenicity. Parameter changes in the antibody sequence (SEQ ID NOs: 1-20) allowed tuning of the balance between therapeutic efficacy through internalization and reduction of immune response risk.
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 antibodies exhibit strong antigen-binding and internalization properties, providing therapeutic benefits for cancer treatment and diagnostic capabilities, with enhanced stability and reduced immune response risk.
Implementation Method 1
a potent chimeric IgG1 monoclonal antibody (mAb) named zolbetuximab, which binds to claudin-18.2 on the surface of tumor cells
Implementation Method 2
The monoclonal antibodies in human antibody form, generated based on the variable regions of the heavy and light chains of the screened antibody clones, were found to selectively bind to the human CLDN18.2 protein expressed on the surface of cells and exhibit excellent internalization property
Data Source
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AI summary
The present invention relates to a monoclonal antibody that specifically binds to claudin-18.2 (claudin-18 spliced variant 2, CLDN18.2) and use thereof. As the antibody of the present invention has high binding property for CLDN18.2 and excellent internalization capability, it can be advantageously employed in the development of cancer therapeutic agents in the form of monoclonal antibodies or modified formats (antibody-drug conjugates, chimeric antigen receptors, or multi-specific antibodies).