Humanized Anti-PD-L1 Antibodies With High Affinity and Low Immunogenicity
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Solution Overview
Problem
Existing PD-L1 monoclonal antibodies, such as Atezolizumab, exhibit high immunogenicity and suboptimal affinity and dissociation rates, limiting their therapeutic effectiveness in treating cancers.
Innovation Solution
Development of anti-human PD-L1 antibodies with high affinity, utilizing hybridoma screening and humanization techniques, incorporating specific CDR sequences for the heavy and light chain variable regions, and optionally including human-derived constant regions to reduce immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PD-L1 monoclonal antibodies (e.g., Atezolizumab) are used, then therapeutic treatment can be provided, but affinity and dissociation rate are suboptimal
Solution Approach 1:
The patent applies parameter changes by modifying the antibody sequence parameters through humanization techniques. Specific CDR sequences from murine antibodies are transplanted into human antibody frameworks, changing the amino acid sequence parameters to achieve both high affinity for PD-L1 and reduced immunogenicity. This is evidenced by the detailed sequence alignments and comparisons showing optimized CDR regions while maintaining human framework structures.
Solution Approach 2:
The patent creates composite antibody structures by combining murine CDR regions with human framework regions. This composite approach allows the antibody to retain the high-affinity binding characteristics of murine antibodies while incorporating human sequences to reduce immunogenicity. The resulting chimeric and humanized antibodies represent composite materials that integrate the beneficial properties of both murine and human antibody sequences.
2Reliability
If existing PD-L1 monoclonal antibodies (e.g., Atezolizumab) are used, then treatment can be administered, but immunogenicity is high resulting in more anti-antibodies production
Solution Approach 1:
The patent changes the immunogenicity parameters by humanizing the antibody sequences. By replacing murine framework regions with human framework regions while preserving the antigen-binding CDR regions, the antibody becomes more similar to human antibodies, thereby reducing immunogenicity. Sequence comparisons in the patent demonstrate the progressive humanization from murine to chimeric to fully humanized antibodies.
Solution Approach 2:
The patent extracts only the essential antigen-binding CDR regions from murine antibodies and separates them from the immunogenic murine framework regions. By taking out and transplanting only the CDR sequences into human frameworks, the invention retains the high-affinity binding function while eliminating the harmful immunogenic framework sequences, thus reducing anti-antibody production.
3Manufacturing precision
If murine antibodies are used for high affinity binding, then binding capability is achieved, but immunogenicity increases
Solution Approach 1:
The patent segments the antibody into functional CDR regions and framework regions, treating them differently. The CDR regions, which provide antigen-binding function, are retained from murine antibodies, while the framework regions, which contribute to immunogenicity, are replaced with human sequences. This segmentation allows independent optimization of binding affinity and immunogenicity properties.
Solution Approach 2:
The patent applies local quality by making different parts of the antibody have different origins. The CDR regions maintain murine characteristics for high affinity binding, while the framework regions adopt human characteristics for reduced immunogenicity. This local differentiation allows the antibody to simultaneously achieve high binding capability and low immunogenicity in different regions.
Data Source
AI summary
Provided is an antibody molecule or antigen-binding fragment thereof capable of binding to the human PD-L1. Also provided is the use of the antibody molecule or antigen-binding fragment thereof in the preparation of a medicament for treating tumors or cancers. Compared with the existing anti-PD-L1 antibodies, the provided antibody has superior affinity and dissociation rate for PD-L1, lower immunogenicity, and better tumor inhibition effects.