CDR-Targeted Anti-HIV Antibody Mutations Preserve Broad Neutralization
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Solution Overview
Problem
Existing broadly neutralizing antibodies (bNAbs) against HIV, such as NIH45-46 G54W, suffer from biophysical issues like polyreactivity, short in vivo half-life, and a propensity to aggregate, hindering their development as human therapeutics while maintaining neutralization activity.
Innovation Solution
Development of novel anti-HIV antibodies with improved biophysical properties, including reduced polyreactivity and prolonged half-life, through specific amino acid substitutions in the heavy and light chains, such as G54W and combinations like Q27E, S28H, S30D, and S74T, while retaining broad and potent neutralization activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broadly neutralizing antibodies are engineered to improve neutralization breadth and potency, then neutralization activity is improved, but biophysical properties such as polyreactivity, aggregation propensity, and half-life deteriorate
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues at specific positions (e.g., K12, L13, S27, T28, Q32, N35 in CDR regions) to alter the antibody's biophysical properties. These point mutations change the chemical parameters of the antibody molecule, reducing polyreactivity and aggregation while preserving neutralization function.
Solution Approach 2:
The invention applies local quality by making targeted modifications only in specific regions of the antibody molecule, particularly in the CDR (complementarity-determining region) sequences. Rather than modifying the entire antibody, only specific local residues are changed to achieve the desired balance between neutralization activity and reduced polyreactivity.
2Object-generated harmful factors
If antibody sequences are modified to reduce polyreactivity, then biophysical properties are improved, but neutralization potency may be reduced
Solution Approach 1:
The patent applies partial action by implementing a tiered approach to mutation introduction. Rather than applying all possible mutations simultaneously, the invention uses progressive schemes where mutations are introduced in stages (e.g., first round with certain mutations, second round with additional mutations). This allows optimization of polyreactivity reduction while monitoring and preserving neutralization potency at each stage.
Data Source
AI summary
This disclosure provides novel broadly neutralizing anti-HIV antibodies and antigen-binding fragments thereof. The disclosed anti-HIV antibodies exhibited improved biophysical properties, e.g., reduced polyreactivity, prolonged half-life, while retaining broad and potent neutralization activity. The anti-HIV bNAb variants as disclosed constitute a novel therapeutic strategy for treating and/or preventing HIV infection.