Humanized Anti-CLDN18.2 Antibodies for Specific Tumor Targeting
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Solution Overview
Problem
There is a need for antibodies that specifically target Claudin 18.2 (CLDN18.2) with high specificity and lower toxic side effects for the treatment of cancers such as gastric and pancreatic cancer, as existing antibodies like Zolbetuximab (IMAB362) face challenges due to high similarity with Claudin 18.1, leading to potential off-target effects.
Innovation Solution
Development of mouse antibodies that are further modified to create chimeric and humanized antibodies with high specificity for CLDN18.2, retaining biological functions while minimizing immunogenic responses in humans, and incorporating specific CDR sequences as described in SEQ ID NOs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a human-mouse chimeric antibody (Zolbetuximab) is used to target CLDN18.2, then antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity are induced, but high similarity with Claudin 18.1 leads to potential off-target effects and toxic side effects
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure from human-mouse chimeric to fully humanized format. This structural parameter change eliminates the immunogenic mouse components while preserving the anti-CLDN18.2 binding capability, thereby reducing off-target effects and toxic side effects associated with the chimeric antibody format
Solution Approach 2:
The patent creates a humanized antibody that copies the antigen-binding specificity of the original mouse antibody against CLDN18.2 while using human framework regions. This copying approach maintains the desired therapeutic function (ADCC and CDC) while eliminating the harmful immunogenic responses to mouse protein sequences
2Reliability
If mouse antibodies are developed to target CLDN18.2, then high binding affinity is achieved, but immunogenic responses are triggered in human subjects
Solution Approach 1:
The patent changes the compositional parameter of the antibody from mouse-derived to humanized format. By replacing mouse framework regions with human sequences while retaining the CDRs that provide CLDN18.2 specificity, the antibody maintains high binding affinity while becoming immunologically compatible with human subjects
Solution Approach 2:
The patent segments the antibody structure into functional regions (CDRs for antigen binding) and framework regions (for structural support and immunogenicity). By selectively retaining mouse CDRs and replacing mouse framework regions with human sequences, the patent separates the binding function from the immunogenic components, achieving both high affinity and low immunogenicity
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 humanized antibodies exhibit high affinity and specificity for CLDN18.2, providing effective therapeutic options for tumors with reduced toxicity and improved clinical efficacy.
Implementation Method 1
The antibodies specifically bind to CLDN 18.2 without binding to CLDN 18.1
Implementation Method 2
It binds to Claudin 18.2 expressed on tumor cells inducing antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC)
Data Source
AI summary
The present application relates to the field of treatment of diseases, and in particular, to an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, nucleic acid molecules for encoding said antibody and fragment, and method for preparing said antibody and fragment. The anti-CLDN18.2 antibody or the antigen-binding fragment thereof has high specificity and affinity to CLDN18.2, and can effectively bind to CLDN18.2 and mediate the killing of CLDN18.2 expressing cells. Therefore, the present application further relates to a pharmaceutical composition comprising the antibody or the antigen-binding fragment thereof, and use thereof in the preparation of drugs, wherein the drugs are used for the prevention and/or treatment of tumors.