Antibody CDR Mutations for EGFR Binding Affinity
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Solution Overview
Problem
Current anti-EGFR monoclonal antibodies, such as nimotuzumab, have limitations in efficacy for tumors with medium or low expression of EGFR, as they do not effectively inhibit ligand-mediated EGFR phosphorylation and have reduced antitumor effects due to their affinity profile.
Innovation Solution
Development of recombinant monoclonal antibodies and antigen-binding fragments with specific mutations in the CDR1 and CDR2 regions of the heavy chain variable region, which exhibit 3 to 4 times higher affinity for the extracellular region of human EGFR, allowing for enhanced recognition and inhibition of EGFR phosphorylation, particularly in cells with medium or low EGFR expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-EGFR monoclonal antibodies (such as nimotuzumab) are used, then they can recognize and bind to EGFR, but they have limited efficacy for tumors with medium or low expression of EGFR due to insufficient binding affinity
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences in the CDR1 and CDR2 regions of the heavy chain variable region. Specific mutations (such as H31Y, H31F, H31L, H31P, H31W, H31Q, H31R, H31K, H31E, H31D, H31N, H31S, H31T, H31V, H31G, H31A, H31C, H31M, H31I, H31H, H31X, H31Z, H31_) were introduced to enhance the binding affinity of the antibody variants for EGFR, achieving 3 to 4 times higher affinity compared to the parent nimotuzumab antibody.
2Strength
If the affinity of anti-EGFR antibodies is increased to improve tumor targeting, then binding strength increases, but toxicity may increase due to capture by normal cells with low EGFR expression
Solution Approach 1:
The patent applies local quality by making specific localized mutations only in the CDR1 and CDR2 regions of the heavy chain, while maintaining the overall antibody structure and other regions unchanged. This localized modification approach enhances binding affinity at the antigen-binding site without globally increasing non-specific binding, thereby improving tumor targeting while potentially reducing toxicity to normal cells.
3Reliability
If mutations are introduced in CDR1 and CDR2 regions to enhance binding affinity, then recognition capability improves, but antibody structure and stability may be affected
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations in the CDR1 and CDR2 regions while carefully selecting mutations that enhance binding affinity without disrupting the overall antibody fold and stability. The mutations were designed and screened to optimize the balance between improved recognition capability and maintenance of structural integrity.
Data Source
AI summary
This invention provides new antibodies (Ab) and fragments that recognize the extracellular region of the human epidermal growth factor receptor (hEGFR) with a higher affinity than the Ab nimotuzumab, thus been able to recognize more efficiently lines with medium expression of EGFR. The present invention also relates to pharmaceutical compositions comprising as active principle the disclosed Abs and fragments and their use in the therapy of tumors with EGFR expression. In addition, it relates to the use of the Abs and fragments disclosed linked to a radioisotope or fluorophore for the localization of EGFR positive tumors. Additionally, the Abs and fragments disclosed can be used in the directionalization of the immune response to EGFR positive tumor cells when they are fused to protein or protein domains of immunological interest.