Humanized Anti-Human Alpha9 Integrin Antibody Design
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current humanized antibodies face challenges in achieving improved affinity to antigens, stability, and reduced antigenicity, which affects their efficacy and dosing requirements, particularly for targeting α9 integrin in diseases like rheumatoid arthritis.
Innovation Solution
Development of humanized anti-human α9 integrin antibodies with specific amino acid sequences for the heavy and light chain variable regions, combined with human Igγ1 and Igκ constant regions, to enhance binding affinity and stability, while minimizing antigenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a mouse-derived antibody (Y9A2) is used to target human α9 integrin, then high binding affinity and inhibitory activity are achieved, but antigenicity increases and half-life is shortened when administered to humans
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the antibody. Specifically, it humanizes the mouse-derived Y9A2 antibody by replacing mouse-specific amino acid sequences with human antibody sequences while maintaining the complementarity determining regions (CDRs) that bind to α9 integrin. This sequence modification reduces antigenicity and extends half-life in human patients while preserving binding affinity.
Solution Approach 2:
The patent creates a humanized version of the mouse antibody Y9A2 by copying the essential binding regions (CDRs) and framework regions that are responsible for α9 integrin recognition. The humanized antibody RY9A2v501 replicates the binding function of the original mouse antibody while using human antibody sequences, thereby reducing immunogenicity.
2Object-affected harmful factors
If the amino acid sequence of the antibody is modified to reduce antigenicity, then safety and half-life are improved, but binding affinity and inhibitory activity may be reduced
Solution Approach 1:
The patent applies local quality by making targeted modifications only to specific regions of the antibody sequence. The CDRs and critical framework regions that are essential for α9 integrin binding are preserved with high sequence identity to the original Y9A2 antibody, while non-critical regions are humanized. This localized approach maintains binding affinity while reducing antigenicity.
Solution Approach 2:
The patent carefully controls the degree of sequence identity parameters in different regions. By maintaining ≥80% sequence identity in CDRs and ≥70% in framework regions compared to the original Y9A2 antibody, the patent ensures that binding affinity is preserved while achieving sufficient humanization to reduce antigenicity.
3Reliability
If higher dosing is used to compensate for shortened half-life of mouse antibodies, then therapeutic effect is maintained, but treatment cost and patient burden increase
Solution Approach 1:
The patent addresses dosing frequency by changing the half-life parameter through humanization. The humanized antibody RY9A2v501 has an extended half-life in human patients compared to the mouse-derived Y9A2 antibody, allowing for less frequent administration (e.g., every 2-4 weeks instead of more frequent dosing) while maintaining therapeutic efficacy.
Data Source
Figure 1~2
Figure 3
Figure 4
AI summary
The present invention provides a humanized anti-human α9 integrin antibody having improved activity and/or property as compared to a donor mouse anti-human α9 integrin antibody, namely, a humanized anti-human α9 integrin antibody containing a heavy-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:11 and a light-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:17, a humanized anti-human α9 integrin antibody containing a heavy-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:13 and a light-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:17, a humanized anti-human α9 integrin antibody containing a heavy-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:15 and a light-chain variable region consisting of the amino acid sequence shown by SEQ ID NO:9, and a means for the prophylaxis or treatment of various diseases involving human α9 integrin in the pathogenesis, which uses the antibody.