Humanized CLDN18.2 Antibodies With High Affinity and Low Immunogenicity
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Solution Overview
Problem
Existing anti-CLDN18.2 antibodies, such as IMAB362, suffer from immunogenicity and reduced affinity, necessitating further modification to enhance therapeutic efficacy and reduce patient immune response.
Innovation Solution
Development of humanized antibodies with specific HCDR and LCDR sequences that exhibit higher affinity and selective binding to CLDN18.2 without cross-reactivity to CLDN18.1, as exemplified by novel consensus sequences and amino acid combinations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chimeric antibody structure is used, then therapeutic activity is improved, but immunogenicity increases leading to enhanced clearance and safety concerns
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure from chimeric to humanized format, specifically changing the constant region composition to reduce immunogenicity while preserving therapeutic activity. The humanized antibodies maintain the variable regions for target binding but replace mouse constant regions with human constant regions, fundamentally altering the molecular parameters of the antibody structure.
2Object-affected harmful factors
If humanized antibodies are developed, then immunogenicity is reduced, but binding affinity may be compromised
Solution Approach 1:
The patent applies segmentation by separating the antibody into distinct functional domains: variable regions (VH and VL) that provide target binding specificity and constant regions (CH and CL) that determine effector functions and immunogenicity. By independently optimizing each segment - particularly by grafting CDRs onto human framework regions - the patent achieves both reduced immunogenicity and maintained or improved binding affinity.
Solution Approach 2:
The patent applies local quality by making specific localized changes to the antibody sequence, particularly in the complementarity-determining regions (CDRs) and framework regions. The humanized antibodies retain the critical local binding determinants from the parent antibody while changing the surrounding framework to human sequences, thereby maintaining local binding quality while improving overall compatibility with the human immune system.
3Reliability
If chimeric antibodies are used, then therapeutic activity is achieved, but clearance rate increases reducing therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the constant region parameters of the antibody from mouse-derived to human-derived sequences. This fundamental parameter change in the molecular structure reduces recognition by the human immune system, thereby decreasing clearance rate and extending the duration of action of the therapeutic antibody in circulation.
Data Source
AI summary
The invention provides humanized antibodies binding to CLDN18.2 with a high affinity. Further, the antibodies do not exhibit cross-reactivity to CLDN18.1. The invention also provides nucleic acids, vectors, host cells and medical uses.