Anti-MSLN Single-Domain Antibody for Tumor Penetration
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Solution Overview
Problem
Traditional monoclonal antibodies have limitations such as high molecular weight, poor tissue permeability, and high immunogenicity, making them less effective for cancer therapy, while the development of fully human monoclonal antibodies is hindered by high costs and long development cycles.
Innovation Solution
Development of an anti-human MSLN antibody using a single-domain antibody approach, specifically a VHH domain that binds to MSLN with a dissociation constant not greater than 20 nM, which is smaller, more permeable, and less immunogenic, and can be used in various forms including chimeric, humanized, or full human antibodies, and multispecific antibodies, as well as conjugated with therapeutic agents or linked to functional molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional monoclonal antibodies are used for cancer therapy, then they can target MSLN-expressing cancer cells, but they have high molecular weight which results in poor tissue permeability
Solution Approach 1:
The patent extracts only the essential antigen-binding fragment (VHH domain) from the complete monoclonal antibody structure, removing the heavy constant regions and other non-essential portions. This extraction reduces the molecular weight from the full antibody size to just the variable heavy chain domain, improving tissue permeability while retaining the ability to bind MSLN on cancer cells
Solution Approach 2:
The patent segments the monoclonal antibody into separate functional domains, specifically isolating the VHH variable domain that contains the antigen-binding capability. This segmentation allows the small molecule VHH to penetrate tissues effectively while maintaining its therapeutic function of targeting MSLN-expressing cancer cells
2Reliability
If traditional monoclonal antibodies are used, then they can provide therapeutic function, but they have high immunogenicity
Solution Approach 1:
The patent changes the structural parameters of the antibody by selecting VHH domains with high sequence homology to human antibodies and optimizing framework regions. This parameter optimization reduces the immunogenic differences between the therapeutic antibody and human immune system proteins, thereby reducing immunogenicity while preserving the ability to neutralize MSLN and treat cancer
3Object-affected harmful factors
If fully human monoclonal antibodies are developed, then immunogenicity is reduced, but development cost and time increase significantly
Solution Approach 1:
The patent uses phage display technology to create a library of VHH domain variants that can be screened in vitro for optimal binding to MSLN. This copying and screening approach allows rapid identification of high-affinity, low-immunogenicity VHH sequences without requiring lengthy in vivo immunization protocols, thereby reducing both development time and cost while achieving reduced immunogenicity
Data Source
AI summary
The present invention relates to a single-domain antibody against MSLN (mesothelin) and a preparation method therefor and an application thereof. The MSLN antibody has high affinity for MSLN, and therefore can be applied to the preparation of a medicament for treating tumors, etc.