Adalimumab Variants with Reduced Immunogenicity
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Solution Overview
Problem
Adalimumab, a therapeutic anti-TNF alpha antibody, is immunogenic in a significant number of patients, leading to the formation of antibodies that reduce its efficacy, and existing methods to address this, such as increasing doses or co-administering with immunosuppressants, are unsatisfactory, as they do not completely prevent immunogenicity.
Innovation Solution
Development of adalimumab variants with specific mutations in the CDRH2 and CDRH3 regions that reduce immunogenic potential while maintaining or enhancing TNF alpha binding affinity, achieved through combinatorial libraries and deep mutational scanning to identify substitutions that stabilize the antibody's function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adalimumab is used as a therapeutic anti-TNF alpha antibody, then treatment efficacy for autoimmune inflammatory diseases is improved, but immunogenicity increases leading to formation of anti-drug antibodies
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at positions 49, 50, 52, 54, and 57 in the CDRH2 and CDRH3 regions of adalimumab. These mutations modify the protein sequence parameters to reduce immunogenicity while preserving therapeutic activity, directly addressing the contradiction between treatment efficacy and immunogenicity
Solution Approach 2:
The patent applies local quality by making targeted modifications specifically in the CDRH2 and CDRH3 regions of the heavy chain variable domain, where T cell epitopes are located. This localized approach reduces immunogenicity in specific areas while maintaining the overall functional integrity of the antibody
2Reliability
If doses of adalimumab are increased to reduce ADA effect, then treatment response is improved, but patient safety and cost increase
Solution Approach 1:
The patent modifies the molecular parameters of adalimumab through amino acid substitutions that reduce immunogenicity, allowing patients to maintain effective treatment response at standard doses without requiring dose increases that would compromise safety
3Object-generated harmful factors
If methotrexate is co-administered to inhibit ADA production, then immunogenicity is reduced, but treatment complexity and side effects increase
Solution Approach 1:
The patent extracts and eliminates the root cause of immunogenicity by modifying the adalimumab protein sequence itself, removing T cell epitopes through amino acid substitutions. This intrinsic modification eliminates the need for concurrent immunosuppressant therapy like methotrexate, simplifying the treatment regimen
4Object-generated harmful factors
If T cell epitopes are eliminated through de-immunization, then immunogenicity is reduced, but binding affinity for TNF alpha may be compromised
Solution Approach 1:
The patent applies local quality by making targeted modifications specifically in the CDRH2 and CDRH3 regions where T cell epitopes are located, while preserving the overall structure and function of the antibody. The substitutions are designed to maintain TNF alpha binding affinity while reducing immunogenicity
Solution Approach 2:
The patent uses parameter changes through specific amino acid substitutions that have been shown to reduce immunogenicity while maintaining or improving binding affinity. The mutations at positions 49, 50, 52, 54, and 57 are selected to preserve the antibody's functional parameters
Data Source
AI summary
The invention relates to adalimumab variants with reduced immunogenic potential and retained or increased affinity and therapeutic applications thereof.