FOLR1-Binding Antibody Affinity Maturation via CDR Mutation
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Solution Overview
Problem
Current antibodies targeting folate receptor alpha (FOLR1) have limitations in binding affinity, which affects their therapeutic efficacy in cancers such as ovarian cancer, breast cancer, and others where FOLR1 is overexpressed.
Innovation Solution
Development of a modified antibody with increased binding affinity for FOLR1 by introducing mutations in the complementarity-determining regions (CDRs) of the antibody, using phage display technology to select and purify antibodies with enhanced antigen-binding capabilities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a humanized monoclonal antibody is developed to reduce immunogenicity, then immunogenicity is reduced, but binding affinity for the antigen decreases
Solution Approach 1:
The patent applies affinity maturation techniques that introduce random mutations into the antibody gene, specifically targeting the complementarity-determining regions (CDRs). This changes the amino acid parameters in the CDR sequences to improve binding affinity. The process involves error-prone PCR, randomization of targeted residues using degenerate oligonucleotides, and chain shuffling to generate antibody variants with enhanced antigen binding while maintaining the humanized framework for low immunogenicity.
Solution Approach 2:
The patent replaces traditional mechanical antibody engineering methods with in vitro affinity maturation techniques. Instead of relying solely on phage display or traditional hybridoma methods, the invention uses molecular biology techniques like error-prone PCR and degenerate oligonucleotide randomization to directly modify the antibody gene sequence, enabling precise control over CDR region variations to optimize binding affinity.
2Measurement precision
If affinity maturation is applied to increase binding affinity, then binding affinity increases, but the complexity of the development process increases
Solution Approach 1:
The patent segments the antibody structure into distinct functional regions, focusing mutations specifically on the complementarity-determining regions (CDRs) while keeping the framework regions relatively intact. This segmentation allows targeted affinity maturation in the CDR-H3 and CDR-L3 regions which dominate antibody-antigen interaction, without unnecessarily complicating the entire antibody structure or development process.
3Measurement precision
If random mutations are introduced into CDR regions to improve binding affinity, then binding affinity increases, but the risk of losing specificity increases
Solution Approach 1:
The patent applies local quality changes by introducing random mutations only in specific CDR regions (particularly CDR-H3 and CDR-L3) that dominate antibody-antigen interaction, while maintaining the rest of the antibody structure unchanged. This localized approach to affinity maturation improves binding affinity without compromising the overall specificity determined by the conserved framework regions and other CDRs.
Data Source
AI summary
A modified antibody that binds specifically to folate receptor alpha (FOLR1) and blocks the activity of FOLR1 with an increased binding affinity, an antigen-binding fragment thereof, a composition containing the antibody or fragment, and their uses are disclosed. The modified antibody or antigen-binding fragment thereof may be used for the prevention or treatment of cancer proliferative disorder associated with an increased FOR1 expression, and may also be used for diagnosis of the disease. The proliferative disorder may be cancer.