Humanized Anti-IL-17 Antibodies High Affinity Binding
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Solution Overview
Problem
There is a need for a neutralizing anti-IL-17 antibody that binds human IL-17 with high affinity and specificity, allowing for minimal effective therapeutic doses and reduced immune response, capable of targeting IL-17 in both human and non-human mammals for preclinical and clinical studies, and effective in treating autoimmune and inflammatory disorders.
Innovation Solution
Development of humanized anti-IL-17 monoclonal antibodies that specifically bind to the non-linear epitope comprising amino acids DGNVDYH, characterized by high affinity (K_D < 4 pM) and slow off-rate, allowing for subcutaneous administration and reduced dosing frequency, while minimizing immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a neutralizing anti-IL-17 antibody is developed to treat autoimmune and inflammatory disorders, then therapeutic effectiveness is improved, but the risk of immune response against the antibody increases
Solution Approach 1:
The antibody structure was modified by humanizing the variable regions and optimizing constant region isotype selection to reduce immunogenicity while preserving therapeutic effectiveness. This involved changing the amino acid sequence parameters of the antibody to match human immunoglobulin structures more closely.
Solution Approach 2:
Chimeric antibody structures were used as intermediaries between fully murine and fully human antibodies, combining murine variable regions for IL-17 binding with human constant regions to reduce immune response while maintaining therapeutic function.
2Ease of operation
If the antibody binding affinity to IL-17 is increased to reduce dosing frequency, then treatment convenience is improved, but the complexity of antibody engineering increases
Solution Approach 1:
The binding affinity parameters of the antibody were optimized through directed evolution and affinity maturation techniques, systematically improving Kd values to achieve sub-picomolar binding to IL-17 while managing engineering complexity through iterative optimization.
Solution Approach 2:
In vitro affinity maturation and humanization were performed in advance during antibody development to pre-optimize binding characteristics before clinical use, thereby achieving high affinity without requiring complex real-time adjustments during treatment.
3Quantity of substance
If the antibody is designed to bind with high affinity and slow off-rate to minimize effective therapeutic dose, then treatment efficacy is improved, but the manufacturing precision requirements increase
Solution Approach 1:
The kinetic parameters (ka and kd rates) of the antibody were independently optimized through molecular engineering to achieve both high affinity and slow off-rate, requiring precise control of binding interface interactions during manufacturing.
Solution Approach 2:
Traditional empirical antibody optimization was replaced with structure-based rational design and computational modeling to predict and optimize binding kinetics, reducing reliance on iterative trial-and-error manufacturing approaches.
Data Source
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AI summary
Anti-IL-17 antibodies are identified that are characterized as having a high affinity and slow off rate for human IL-17. The antibodies of the invention may be chimeric, humanized or fully human antibodies, immunoconjugates of the antibodies or antigen-binding fragments thereof. The antibodies of the invention are useful in particular for treating autoimmune, inflammatory, cell proliferative and developmental disorders.