CLDN18.2 Antibody CDR Optimization for Specificity and Efficacy
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Solution Overview
Problem
There is a lack of effective antibodies, particularly humanized antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptors (CARs) targeting CLDN18.2 with improved specificity, affinity, and efficacy for treating cancers such as gastric, pancreatic, esophageal, and lung cancers.
Innovation Solution
Development of a humanized antibody, bispecific antibody, and antibody-drug conjugate targeting CLDN18.2 with optimized CDR sequences for enhanced binding activity and pharmacokinetics, along with a CAR molecule designed for improved specificity and safety, utilizing specific CDR sequences and structural modifications to achieve better tumor targeting and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic antibodies against CLDN18.2 are developed, then tumor treatment efficacy is improved, but development difficulty increases due to target specificity and structural similarity between CLDN18.1 and CLDN18.2
Solution Approach 1:
The patent applies local quality by designing antibodies that specifically target the ECL1 domain of CLDN18.2, which has distinct amino acid sequences compared to CLDN18.1's ECL1. This localized targeting approach enables specific recognition of CLDN18.2 while avoiding cross-reactivity with CLDN18.1, thereby improving treatment efficacy despite the overall structural similarity between the two proteins.
Solution Approach 2:
The patent segments the CLDN18.2 protein structure by focusing antibody binding on the extracellular loop 1 (ECL1) domain, separating it from ECL2 which is identical between CLDN18.1 and CLDN18.2. This segmentation strategy allows for specific antibody-antigen interaction at the ECL1 region, overcoming the challenge of developing specific therapeutics against CLDN18.2.
2Reliability
If antibodies with high affinity and endocytic activity are developed, then therapeutic effect is improved, but finding such antibodies becomes more difficult
Solution Approach 1:
The patent employs preliminary action by using phage display technology to pre-screen and select antibody variants with high affinity and endocytic activity against the CLDN18.2 ECL1 domain. This preliminary selection process identifies candidate antibodies that meet the required functional criteria before further therapeutic development, making the overall process more efficient.
Solution Approach 2:
The patent applies parameter changes by optimizing antibody properties such as affinity constants and endocytic rates through iterative selection and engineering. The patent reports achieving antibodies with affinity constants in the picomolar range and enhanced endocytic activity, demonstrating how parameter optimization leads to improved therapeutic effects.
3Reliability
If existing antibody IMAB362 is used, then CLDN18.2 binding is achieved, but immunogenicity risk increases and therapeutic effect is limited due to chimeric structure and low affinity
Solution Approach 1:
The patent applies parameter changes by transitioning from a chimeric antibody structure to a fully humanized antibody structure. This structural parameter change reduces immunogenicity while maintaining or improving affinity through optimized CDR sequences. The patent reports achieving fully humanized antibodies with picomolar affinity and reduced immunogenic risk compared to the chimeric IMAB362.
Solution Approach 2:
The patent uses composite materials by combining human antibody variable regions with optimized CDR sequences derived from murine antibodies. This composite approach creates humanized antibodies that maintain high affinity for CLDN18.2 while reducing immunogenicity, effectively combining the advantages of both murine and human antibody structures.
Data Source
AI summary
Provided is an antibody targeting CLDN18.2. The antibody targeting CLDN118.2 comprises VL and/or VH; the VL comprises the following CDR sequences: a VL CDR1 amino acid sequence as shown in SEQ ID NO: 11 or SEQ ID NO: 12; a VL CDR2 amino acid sequence as shown in SEQ ID NO: 13; and a VL CDR3 amino acid sequence as shown in SEQ ID NO: 14; and the VH comprises the following CDR sequences; a VH CDR1 amino acid sequence as shown in SEQ ID NO: 15; a VH CDR2 amino acid sequence as shown in SEQ ID NO: 16; and a VH CDR3 amino acid sequence as shown in SEQ ID NO: 17. Further disclosed are a bispecific antibody targeting CLDN18.2, a conjugates of the antibody, a CAR molecule targeting CLDN18.2 and a cell comprising same, and applications thereof.