Humanized Anti-BLyS Antibody Reducing Immunogenicity
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Solution Overview
Problem
Current anti-BLyS antibodies developed using phage display libraries have limitations such as low affinity, low yield, stability issues, and poor pharmacokinetic characteristics, as well as high immunogenicity and strong immune responses due to their artificial pairing of heavy and light chains, which affects their efficacy in treating autoimmune diseases like SLE.
Innovation Solution
Development of a humanized anti-BLyS antibody using gene engineering technology, where the antibody is produced by immunizing mice with purified human BLyS protein and selecting monoclonal hybridoma cells for high affinity and specificity, then humanizing the antibodies to reduce immunogenicity and minimize affinity with MHC II factors, thereby enhancing therapeutic efficacy and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If phage display library is used to develop anti-BLyS antibodies, then antibody diversity is increased, but affinity and stability are reduced
Solution Approach 1:
The patent applies preliminary action by pre-selecting and immunizing mice with purified human BLyS protein before antibody production. This preliminary immunization step ensures that the resulting monoclonal antibodies have high affinity and specificity for BLyS, resolving the contradiction between diversity and reliability by establishing a strong selective foundation before library generation.
Solution Approach 2:
The patent changes key parameters by humanizing the antibody structure (modifying amino acid sequences in variable regions) while maintaining complementarity determining regions (CDRs). This parameter change approach allows the antibody to achieve both high affinity (reliability) through selective pressure and reduced immunogenicity (adaptability) through human sequence optimization.
2Ease of manufacture
If heavy and light chains are artificially paired in phage display, then antibody production is simplified, but immunogenicity increases and immune response strengthens
Solution Approach 1:
The patent changes the amino acid sequence parameters of the antibody by humanizing the variable regions while preserving CDR sequences. This parameter modification reduces immunogenicity (harmful factor) while maintaining the simplified production advantage through continued use of phage display technology for antibody generation.
Solution Approach 2:
The patent creates a humanized version of the mouse monoclonal antibody by copying and adapting the CDR sequences into a human antibody framework. This copying approach with modification allows simplified production methods to be retained while reducing the harmful immunogenicity associated with non-human sequences.
3Measurement precision
If mouse monoclonal antibodies are used, then antibody specificity is achieved, but immunogenicity and side effects increase
Solution Approach 1:
The patent changes the species origin parameter by humanizing the antibody sequences. The humanized anti-BLyS antibody maintains the high specificity of mouse monoclonal antibodies through preserved CDR sequences while reducing immunogenicity by replacing mouse framework sequences with human sequences, thereby decreasing side effects.
Solution Approach 2:
The patent uses human antibody framework sequences as an intermediary between mouse monoclonal antibody specificity and human therapeutic application. This intermediary humanized structure maintains the precise binding characteristics of mouse antibodies while reducing the harmful immunogenic response in human patients.
4Adaptability or versatility
If existing anti-BLyS medicaments (BR3-FC, TACI-FC, polypeptide-FC) are used, then alternative therapeutic options are provided, but binding force weakens and toxicity increases
Solution Approach 1:
The patent extracts and optimizes the key functional elements by developing a humanized monoclonal antibody that specifically targets BLyS with high affinity. This extracted approach focuses on the essential BLyS-binding function while eliminating the weaknesses (weak binding force and high toxicity) present in the fusion protein alternatives like BR3-FC, TACI-FC, and polypeptide-FC.
Solution Approach 2:
The patent changes the molecular structure parameters by using a humanized IgG antibody format instead of fusion proteins. This parameter change improves binding force through optimized BLyS interaction and reduces toxicity by avoiding the structural limitations and off-target effects associated with BR3-FC, TACI-FC, and polypeptide-FC fusion constructs.
Data Source
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AI summary
The present invention belongs to the field of biopharmaceutics. Disclosed is an anti-BLyS antibody. The anti-BLyS antibody specifically targets BLyS, can combine with a B lymphocyte stimulating factor, and can inhibit the combination of the B lymphocyte stimulating factor with the receptor BR3-Fc thereof. Also provided are uses of the anti-BLyS antibody in the manufacture of a medicament for preventing and/or treating diseases caused by the excessive proliferation of B cells such as systemic lupus erythematorsus.