Humanized Anti-TRBV9 Antibodies Balancing Affinity and Solubility
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Solution Overview
Problem
Current monoclonal antibodies targeting the TRBV9 family of T cell receptors have a low degree of humanization, leading to potential decreases in affinity and solubility, limiting their effectiveness in treating autoimmune and oncological diseases such as ankylosing spondylitis, celiac disease, and T cell leukemias.
Innovation Solution
Development of humanized monoclonal antibodies with specific binding affinity to the TRBV9 family beta-chain region, incorporating amino acid substitutions in the framework regions to enhance humanization while maintaining antibody specificity and functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to target TRBV9 family T cell receptors, then therapeutic effectiveness against autoimmune and oncological diseases is improved, but the degree of humanization is low leading to decreased affinity and solubility
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid sequences in the framework regions of the antibody variable domains. Specifically, rat framework region sequences are replaced with human framework region sequences through site-directed mutagenesis, while preserving the complementarity determining regions that bind to TRBV9. This gradual humanization process (creating intermediates with 50%, 70%, and 90% humanization) optimizes both affinity and solubility parameters while maintaining therapeutic effectiveness against TRBV9-expressing T cells
2Manufacturing precision
If humanization of monoclonal antibodies is increased, then affinity and solubility are improved, but the ability to specifically bind TRBV9 may be compromised
Solution Approach 1:
The patent applies local quality by differentiating the treatment of different antibody regions: the complementarity determining regions (CDRs) are preserved with their original rat sequences to maintain specific binding affinity to TRBV9, while only the framework regions are humanized to improve solubility and reduce immunogenicity. This localized approach ensures that the binding interface remains unchanged while the structural framework gains human compatibility
Solution Approach 2:
The antibody variable domain is segmented into functionally distinct regions: CDRs (residues 31-35, 50-56, 89-97 in Kabat numbering) that contact the antigen and framework regions (residues 1-30, 40-49, 70-88, 98-104) that provide structural support. This segmentation allows independent optimization of each region's properties, enabling humanization of framework regions without affecting CDR-mediated specific binding to TRBV9
Data Source
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AI summary
The invention relates to a monoclonal humanized antibody or antigen-binding fragment thereof that specifically bind to the TRBV9 family of the human T cell receptor. The invention also relates to a nucleic acid encoding said antibody or antigen-binding fragment thereof, an expression vector, a method for preparing said antibody, and use of said antibody in treatment of diseases or disorders associated with the human T cell receptor family. The invention is directed to generation of antibodies that can be used for treating, in particular AS, celiac disease and malignant blood diseases, the pathogenesis of which involves the TRBV9 family TCRs.