Mesothelin Antibodies with Optimized CDRs for High Affinity Binding
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Solution Overview
Problem
Current antibodies targeting mesothelin for cancer treatment face challenges such as low affinity, rapid removal from the bloodstream, immunogenicity, and limited cross-reactivity with rodent homologues, which affects their efficacy in clinical trials and stability in vivo.
Innovation Solution
Development of novel mesothelin-specific antibodies with optimized heavy and light chain variable regions, including specific CDR sequences, to enhance binding affinity and persistence, while minimizing immunogenicity and improving cross-reactivity, using a combination of immunization and phage display techniques to produce antibodies like MI323, MI329, and MS502 with improved properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies (e.g., mAb K1, SS1-(dsFv)-PE38) are used to target mesothelin, then tumor cell binding is achieved, but binding affinity is low and antibodies are rapidly removed from the bloodstream
Solution Approach 1:
The patent applies parameter changes by optimizing the amino acid sequences of the antibody variable regions (VH and VL) and specifically the complementarity-determining regions (CDRs). Through systematic mutation and selection processes, antibodies with enhanced binding affinity (lower KD values) and improved persistence were developed, directly addressing the low affinity and rapid removal issues of conventional antibodies.
2Adaptability or versatility
If rodent-derived antibodies are used for treatment, then mesothelin targeting is achieved, but cross-reactivity with rodent homologues is limited and immunogenicity occurs
Solution Approach 1:
The patent employs parameter changes by humanizing the antibody sequence - replacing rodent-derived amino acid sequences with human framework regions while preserving the CDR sequences that provide mesothelin binding specificity. This reduces immunogenicity by making the antibody more similar to human proteins, while maintaining cross-reactivity through careful selection and optimization of the CDR regions that recognize conserved epitopes across species.
3Reliability
If antibody affinity is increased through optimization, then binding strength improves, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody into functional modules - the variable regions (VH and VL) are further divided into framework regions and CDRs. This modular approach allows independent optimization of each CDR for affinity while using standardized framework regions, thereby managing development complexity through systematic segmentation of the antibody structure into optimizable units.
Solution Approach 2:
The patent employs universality by developing a platform approach where optimized CDR sequences can be combined with different constant regions and used against various mesothelin-expressing tumors. The standardized variable region frameworks and modular CDR design create a universal platform that can be adapted to different therapeutic needs while maintaining high affinity binding, reducing overall development complexity through reuse of optimized components.
Data Source
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AI summary
The present invention relates to an antibody specifically bound to mesothelin (MSLN), a nucleic acid encoding the antibody, a vector and a host cell including the nucleic acid, a method for producing the antibody, and a pharmaceutical composition for treating cancer or tumor including the antibody as an active ingredient. The antibody specifically bound to the mesothelin according to the present invention has high affinity and specificity to an antigen, such that it is possible to develop an antibody effectively usable for treatment or diagnosis of cancer or tumor diseases.