Humanized Anti-IL-23p19 Antibodies Reducing Immunogenicity
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Solution Overview
Problem
Current therapeutic antibodies targeting IL-23p19 face challenges due to immunogenicity issues, as they often trigger an immune response in humans, leading to reduced efficacy and potential anaphylactic reactions, and existing humanization methods struggle to predict binding and biological properties effectively.
Innovation Solution
Development of humanized or chimeric recombinant antibodies with specific CDR loops and framework regions that bind to human IL-23p19, using sequences from SEQ ID NOs: 32-46 for light chain and 15-31 for heavy chain, with conservative amino acid substitutions to minimize immunogenicity and maintain high affinity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rodent-derived monoclonal antibodies are used to target IL-23p19, then therapeutic efficacy is achieved, but immunogenicity increases leading to reduced efficacy and potential anaphylactic reactions
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence composition of the antibody to shift from rodent-derived sequences to humanized sequences. Specifically, the antibody heavy chain variable domain comprises amino acid residues 1-116 of SEQ ID NO: 6 and the light chain variable domain comprises amino acid residues 1-108 of SEQ ID NO: 14, representing a fundamental change in the molecular parameters of the antibody structure to reduce immunogenicity while maintaining therapeutic efficacy.
2Object-affected harmful factors
If humanization methods are applied to reduce immunogenicity, then immunogenicity decreases, but binding and biological properties become unpredictable
Solution Approach 1:
The patent applies preliminary action by pre-optimizing the humanized antibody sequence through rational design before clinical use. The specific sequences for heavy chain (SEQ ID NO: 6) and light chain (SEQ ID NO: 14) variable domains were predetermined through computational modeling and structural analysis to ensure both low immunogenicity and high binding affinity, eliminating the unpredictability associated with conventional humanization methods.
Solution Approach 2:
The patent incorporates feedback mechanisms by using detailed structural and functional characterization data to guide sequence optimization. The amino acid sequences were refined based on feedback from binding affinity measurements, structural stability assessments, and immunogenicity predictions, creating a closed-loop design process that ensures both reduced immunogenicity and predictable binding properties.
3Object-affected harmful factors
If conservative amino acid substitutions are made to minimize immunogenicity, then immunogenicity reduces, but maintaining high affinity and specificity becomes more difficult
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions specifically in the framework regions of the antibody variable domains while preserving the complementarity determining regions (CDRs) that are critical for antigen binding. This localized modification strategy allows reduction of immunogenicity in non-critical regions while maintaining high affinity and specificity in the antigen-binding CDR regions, resolving the contradiction between reducing immunogenicity and maintaining binding affinity.
Data Source
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AI summary
Engineered antibodies to human IL-23p 19 are provided, as well as uses thereof, e.g., in treatment of inflammatory, autoimmune, and proliferative disorders.