Anti-CLDN6 Antibody Specificity Against CLDN3 Cross-Reactivity
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Solution Overview
Problem
The expression of recombinant CLDN6 protein is challenging, and it is difficult to develop antibodies that specifically target CLDN6 without cross-reacting with other family members, particularly CLDN3, which is widely expressed in normal tissues, posing a risk of toxicity.
Innovation Solution
Development of an anti-CLDN6 chimeric or humanized monoclonal antibody with specific CDR sequences that bind to human CLDN6, minimizing cross-reactivity with CLDN3 and CLDN4, and demonstrating high affinity and specificity, enabling therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody development methods are used, then antibodies can be generated, but they cross-react with CLDN3 and other family members causing toxicity
Solution Approach 1:
The patent applies local quality by engineering specific CDR regions (particularly CDRH3) of the antibody to have unique structural characteristics that recognize CLDN6-specific epitopes while avoiding cross-reactivity with CLDN3. The CDRH3 length of 10-14 amino acids and specific consensus sequences create a localized binding interface that is highly selective for CLDN6.
Solution Approach 2:
The patent employs parameter changes by optimizing specific physical and structural parameters of the antibody, including CDRH3 length (10-14 amino acids), Kabat numbering positions, and framework region sequences. These parameter optimizations enable the antibody to achieve high affinity for CLDN6 while maintaining selectivity against other claudin family members.
2Ease of manufacture
If recombinant CLDN6 protein expression is attempted, then antigen for immunization could be obtained, but expression is extremely challenging
Solution Approach 1:
The patent applies copying by using synthetic peptide antigens that replicate key epitopic regions of CLDN6, particularly targeting the extracellular loops. Instead of requiring full-length recombinant CLDN6 protein expression, the invention uses synthesized peptide sequences that capture the essential antigenic determinants, greatly simplifying the immunization process.
Solution Approach 2:
The patent extracts the critical antigenic information from the complex CLDN6 protein structure by identifying and using specific peptide sequences from the extracellular loops as immunogens. This extraction approach isolates the essential epitopic regions needed for antibody generation without requiring expression of the entire transmembrane protein.
3Reliability
If antibodies are screened for CLDN6 specificity, then cross-reactivity can be reduced, but screening complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody structure into functionally distinct regions (CDR and framework regions) and optimizing them independently. The CDR regions are engineered for specific CLDN6 recognition while framework regions are humanized to reduce immunogenicity. This segmentation allows systematic optimization of specificity without requiring complex whole-antibody screening.
Solution Approach 2:
The patent employs preliminary action by pre-engineering the CDR sequences with consensus motifs known to recognize CLDN6-specific epitopes before screening. The CDRH3 region is designed with specific length and sequence characteristics that predispose the antibody toward CLDN6 specificity, reducing the need for extensive screening and increasing the probability of obtaining specific antibodies.
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 antibody effectively targets CLDN6-expressing cells, including tumor cells, through ADCC and CDC mechanisms, providing a targeted therapeutic approach with reduced off-target effects.
Implementation Method 1
The antibody effectively targets CLDN6-expressing cells, including tumor cells, through ADCC and CDC mechanisms
Implementation Method 2
The antibody effectively targets CLDN6-expressing cells, including tumor cells, through ADCC and CDC mechanisms
Data Source
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AI summary
Provided is an anti-claudin-6 (CLDN6) antibody or an antigen-binding fragment thereof, including a chimeric monoclonal antibody and a humanized monoclonal antibody. This application further provides a nucleic acid encoding the anti-CLDN6 antibody, an expression vector and a host cell for expressing the anti-CLDN6 antibody, a conjugate, a multispecific antibody, a chimeric antigen receptor (CAR), and a pharmaceutical composition including the anti-CLDN6 antibody, and a method for verifying a function and efficacy of the anti-CLDN6 antibody. The anti-CLDN6 antibody of this application can be used for diagnosing a cancer and/or determining whether a cancer cell expresses CLDN6, and can also be used for treating and/or preventing various cancers or diseases associated with CLDN6-expressing cells in a subject.