Humanized Antibodies Preventing CD127 Internalization
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Solution Overview
Problem
Current monoclonal antibodies targeting CD127 do not effectively inhibit IL-7-induced internalization of CD127 and can increase dendritic cell maturation induced by TSLP, limiting their therapeutic efficacy in immune-related diseases.
Innovation Solution
Development of humanized monoclonal antibodies with specific mutations in the light chain variable domain framework, such as V48L and F87Y, that bind to CD127 without inducing internalization and do not enhance dendritic cell maturation, thereby maintaining antagonist properties against IL-7/IL-7R interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current monoclonal antibodies targeting CD127 are used, then they can bind to CD127, but they induce internalization of CD127 and increase dendritic cell maturation, limiting therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (V48L and F87Y) in the light chain variable domain framework of the antibody. These mutations alter the antibody's interaction with CD127, changing the outcome from inducing internalization to preventing it, while also preventing dendritic cell maturation enhancement. This resolves the technical contradiction by modifying the antibody's functional parameters to eliminate harmful effects while maintaining therapeutic efficacy.
2Productivity
If humanized monoclonal antibodies with mutations V48L and F87Y are developed, then production efficiency is enhanced and efficacy is prolonged, but the antibody structure becomes more complex
Solution Approach 1:
The patent applies local quality by introducing mutations only in specific positions (V48L and F87Y) of the light chain variable domain framework, rather than throughout the entire antibody structure. This localized modification approach achieves the desired improvement in production efficiency and efficacy while minimizing the increase in overall structural complexity. The mutations are precisely targeted to specific residues that affect production and efficacy without requiring comprehensive structural redesign.
3Reliability
If antibodies are designed to bind CD127 without inducing internalization, then therapeutic efficacy is improved, but the ability to effectively target and deplete CD127+ cells is reduced
Solution Approach 1:
The patent applies the blessing in disguise principle by converting what would normally be a harmful effect (prevention of internalization) into a beneficial therapeutic outcome. The antibody mutations prevent internalization, which would otherwise reduce surface CD127 availability, but this prevention simultaneously blocks the harmful dendritic cell maturation pathway. The result is that therapeutic efficacy is improved through selective depletion of pathogenic CD127+ cells while avoiding the activation of dendritic cells, turning a potential disadvantage into a therapeutic advantage.
Data Source
AI summary
The invention is in the field of antibodies useful in therapeutic and diagnostics applications targeting CD127, the alpha chain of the IL7 receptor, and provides in particular humanized monoclonal antibodies against CD127, particularly human CD127, therapeutic uses thereof, and diagnostics applications.