CLDN18.2 Antibody HCDR Sequences for Binding and Half-Life
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Solution Overview
Problem
There is a lack of effective and safe monoclonal antibodies targeting human CLDN18.2, as well as bispecific antibodies that can bind to both human CLDN18.2 and CD3, with existing antibodies facing issues such as short half-lives, poor drug effects, and cytokine release syndrome.
Innovation Solution
Development of a CLDN18.2-targeting monoclonal antibody and a CLDN18.2 and CD3-targeting bispecific antibody with specific amino acid sequences in the heavy chain variable region, including combinations of HCDR1, HCDR2, and HCDR3, and potential heavy chain constant regions like IgG1, to enhance binding and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If existing CLDN18.2-targeting antibodies are used, then some binding activity is achieved, but the half-life is short and drug effects are poor
Solution Approach 1:
The patent modifies the heavy chain variable region parameters by specifying particular HCDR1, HCDR2, and HCDR3 amino acid sequences that optimize both binding affinity and pharmacokinetic properties, thereby extending half-life while maintaining or improving drug effect
Solution Approach 2:
The patent creates a composite antibody structure combining specifically selected HCDR1 (SEQ ID NO: 16-18), HCDR2 (SEQ ID NO: 42-54), and HCDR3 (SEQ ID NO: 77-82) regions with constant regions to achieve synergistic effects that simultaneously improve half-life and therapeutic efficacy
2Reliability
If existing CLDN18.2-targeting antibodies are used, then some binding activity is achieved, but safety issues arise due to cytokine release syndrome
Solution Approach 1:
The patent optimizes the amino acid sequences in the heavy chain variable region, particularly the HCDR regions, to modulate the antibody's interaction with immune cells and reduce excessive immune activation that leads to cytokine release syndrome, thereby improving safety
Solution Approach 2:
The patent converts the potentially harmful high-affinity binding that causes cytokine release into beneficial targeted binding by carefully selecting HCDR sequences that achieve optimal affinity without triggering excessive immune responses, transforming the harmful effect into therapeutic benefit
3Reliability
If antibodies targeting ECL1 region or spatial structure of CLDN18.2 are developed, then specific binding to CLDN18.2 is achieved, but the development work becomes more difficult
Solution Approach 1:
The patent segments the antibody structure into specifically defined HCDR1, HCDR2, and HCDR3 regions with predetermined amino acid sequences, allowing systematic optimization of each segment's contribution to binding specificity while simplifying the overall development process
Solution Approach 2:
The patent applies local quality by specifying particular amino acid sequences in the HCDR regions (HCDR1: SEQ ID NO: 16-18, HCDR2: SEQ ID NO: 42-54, HCDR3: SEQ ID NO: 77-82) that are critical for binding to the ECL1 region or spatial structure of CLDN18.2, ensuring high specificity while managing development complexity through focused sequence selection
Data Source
AI summary
The present invention discloses CLDN18.2-targeting antibodies, bispecific antibodies and use thereof. The CLDN18.2-targeting antibody is a single-domain heavy-chain antibody that has high affinity for tumor cells endogenously expressing CLDN18.2 and can induce high endocytic activity. The bispecific antibody can target CLDN18.2 and CD3 and retains the binding effect of an Fc to an FcRn; meanwhile, a mutant Fc is preferred so as to reduce the binding to an FcgR and thus the activation of non-specific T cells caused by the cross-linking of an FcgR. The CD3-terminus activity is optimized so that the release of common cytokines in CRS, such as IL6 and TNFα can be reduced.