Antibody Library CDR Composition for Tumor Penetration
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Solution Overview
Problem
Current antibody libraries face challenges in producing high-affinity, stable antibodies with reduced non-specific binding, which hampers the selection of clinically relevant molecules, especially in acidic tumor microenvironments.
Innovation Solution
Designing antibody libraries with restricted amino acid composition and length in CDR regions, such as Library AL2 and AL3, which favor high-affinity and stable antibody production by controlling the frequency of specific amino acids like tyrosine, serine, and histidine, and optimizing CDR3 lengths to enhance antigen binding and tumor penetration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If antibody libraries use natural CDR diversity with all 20 amino acids, then antigen recognition capability is improved, but non-specific binding increases and production yield decreases
Solution Approach 1:
The patent applies parameter changes by restricting the amino acid composition in CDR regions from all 20 natural amino acids to specific subsets (e.g., excluding cysteine, limiting tryptophan frequency to ≤5%, controlling charged amino acid ratios). This parameter restriction reduces non-specific binding while preserving sufficient diversity for antigen recognition, directly resolving the contradiction between adaptability and harmful non-specific binding.
2Adaptability or versatility
If antibody libraries use fully random CDR sequences, then diversity of antibody repertoire is improved, but manufacturing complexity and selection difficulty increase
Solution Approach 1:
The patent applies local quality by implementing different amino acid composition rules for different CDR regions. For example, CDR1 and CDR2 use restricted subsets (tyrosine, serine, glycine), while CDR3 allows greater diversity with specific constraints (≤5% tryptophan, excluded cysteine). This localized differentiation maintains overall repertoire diversity while simplifying manufacturing compared to fully random sequences.
3Strength
If antibody libraries include all amino acid types in CDR regions, then antigen binding capability is improved, but stability in acidic environments deteriorates
Solution Approach 1:
The patent applies parameter changes by controlling the frequency and distribution of pH-sensitive amino acids (histidine, aspartate, glutamate) in CDR regions. By limiting charged amino acid content and specific pH-sensitive residues, the antibody maintains stability in acidic tumor microenvironments while preserving antigen binding capability through controlled diversity in other residues.
4Adaptability or versatility
If antibody libraries use unrestricted CDR lengths, then antigen recognition diversity is improved, but production yield and affinity decrease
Solution Approach 1:
The patent applies parameter changes by restricting CDR length parameters to optimal ranges (e.g., CDR3 length of 10-15 residues). This length restriction improves production yield and affinity by preventing overly long or short CDRs that compromise folding and stability, while still providing sufficient diversity for antigen recognition through controlled amino acid variations within the restricted length framework.
Data Source
AI summary
The invention provides libraries of antibody molecules, libraries of nucleic acids encoding antibody molecules, methods of producing said libraries, and methods of using said libraries to select an antibody which specifically binds to an antigen. The libraries of antibody molecules include a plurality of different antibody variable domains generated by creating diversity in the CDR regions.