Humanized APRIL Antibodies Framework Mutations
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Solution Overview
Problem
Current antibodies targeting APRIL, such as hAPRIL.01A, have limitations for use in human medicine due to their murine origin, necessitating the development of human APRIL-binding antibodies with improved binding properties and stability for therapeutic and diagnostic applications.
Innovation Solution
The development of hAPRIL.01A analogues with specific substitutions in the VH and VL domain framework regions, including amino acid substitutions like R72S and R67K-V68A, to enhance binding affinity and stability, while maintaining or improving the ability to block APRIL's interaction with BCMA and TACI.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine antibodies (e.g., hAPRIL.01A) are used to target APRIL, then binding activity against APRIL is achieved, but the antibodies exhibit poor stability and limited suitability for human medicine
Solution Approach 1:
The patent applies parameter changes by systematically mutating amino acid residues in the framework regions of the antibody's variable domains. Specific substitutions (e.g., R72S, R67K-V68A) are introduced to alter the structural and functional parameters of the antibody, thereby improving stability while preserving binding activity against human APRIL.
Solution Approach 2:
The invention creates composite antibody molecules by combining human framework regions with murine complementarity-determining regions (CDRs). This chimeric approach integrates the stability advantages of human antibodies with the binding specificity of murine CDRs, resulting in a composite antibody structure that overcomes the limitations of purely murine antibodies.
2Adaptability or versatility
If murine antibody frameworks are used, then initial binding capability is obtained, but the antibodies lack the stability and human compatibility required for clinical applications
Solution Approach 1:
The patent applies local quality by making targeted modifications only in specific framework region residues while preserving the overall antibody structure and CDR sequences. This localized approach allows the antibody to adapt to human APRIL while maintaining human compatibility and reducing immunogenicity.
Solution Approach 2:
The invention uses copying by transferring the CDR sequences from the murine hAPRIL.01A antibody to human framework regions. This creates a humanized antibody that copies the binding specificity of the original murine antibody while using human structural components, thereby achieving both binding capability and human compatibility.
3Stability of the object's composition
If framework region substitutions are made to improve stability, then antibody stability is enhanced, but binding affinity may be compromised
Solution Approach 1:
The patent applies partial action by introducing only specific, targeted substitutions in the framework regions rather than comprehensive redesign. The substitutions are made at critical positions (e.g., R72S, R67K-V68A) where they provide maximum stability benefit with minimal impact on binding affinity, avoiding excessive modifications that could compromise functionality.
Data Source
AI summary
The invention relates to APRIL-binding antibodies, which bind the same epitope of human APRIL as an antibody having an antigen binding site of hAPRIL.01A. The antibodies of the present invention comprise specific selections of framework sequences of the VH and VL domains and have unexpected features in comparison to hAPRIL.01A. The invention further relates to compositions comprising an antibody of the invention and to the medical and diagnostic uses of the antibodies and compositions.