De-immunized Anti-TNF-α Antibody Framework Region Replacement
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Solution Overview
Problem
Adalimumab, a fully human anti-TNF-α antibody, exhibits high immunogenicity in patients, leading to anti-drug antibodies and reduced efficacy due to its interaction with the immune system, causing treatment failures and accelerated drug clearance.
Innovation Solution
Development of de-immunized human anti-TNF-α antibodies by replacing the framework regions (FRs) of Adalimumab with lower immunogenic FR sequences from other human antibodies, maintaining similar affinities and specificities while reducing immunogenicity, thereby extending the drug's half-life and improving efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Adalimumab is used as a fully human anti-TNF-α antibody, then it maintains human compatibility, but it exhibits high immunogenicity leading to anti-drug antibody formation and reduced efficacy
Solution Approach 1:
The antibody structure is segmented into CDRs (complementarity determining regions) and FRs (framework regions). The invention retains the CDRs from Adalimumab which provide the specific binding affinity to TNF-α, while replacing the immunogenic FRs with sequences from other fully human antibodies. This segmentation allows preservation of therapeutic function while reducing immunogenicity.
Solution Approach 2:
Different regions of the antibody are treated differently: the CDR regions maintain their original sequence to preserve binding specificity and affinity, while the FR regions are modified by replacing them with sequences from other human antibodies to reduce immunogenicity. This local differentiation resolves the contradiction between maintaining efficacy and reducing immunogenicity.
2Reliability
If Adalimumab is administered to patients, then it provides TNF-α neutralization, but anti-drug antibodies are formed causing accelerated drug clearance and treatment failure
Solution Approach 1:
By segmenting the antibody into CDR and FR regions and selectively modifying only the FR regions, the invention preserves the pharmacodynamic properties (binding affinity to TNF-α) while altering the immunogenic properties. This results in prolonged drug half-life due to reduced anti-drug antibody formation and accelerated clearance.
Solution Approach 2:
The invention changes the amino acid sequence parameters of the framework regions while maintaining the critical binding parameters of the CDRs. This parameter modification approach reduces immunogenicity and extends drug half-life without compromising the neutralization efficacy against TNF-α.
Data Source
AI summary
Disclosed herein are low immunogenic human anti-TNF-αantibodies which can inhibit the apopotosis of cells induced by TNF-α. The invented low immunogenic human anti-TNF-α antibodies are capable of binding to TNF-α specifically. The invention presents the human anti-TNF-αantibodies which bind to TNF-α with similar affinities as Adalimumab. Most importantly, the invented human anti-TNF-α antibodies showed reduced immunogenicities in vivo, which made them safer candidate for antibody drug and other biotherapy. The invention also features method of de-immunogenicity of antibody drugs by identification, replacement of high immunogenic FR sequence(s) of the human antibody with low immunogenic FR sequences from other human IgGs, and significantly reduce the risk of human anti-human immunogenicity and improve the efficacy of antibody drugs.