Guided Peptide Scanning With Reduced Mutational Testing
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Solution Overview
Problem
Existing methods for identifying alternative target peptides of binding moieties, such as TCRs and antibodies, are inefficient and lack specificity, leading to increased testing and potential off-target interactions.
Innovation Solution
A reduced mutational scan using a replacement matrix to select alternative amino acids for target peptides, combined with scoring and ranking methods, identifies alternative target peptides without additional experimentation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a full mutational scan using all 19 alternative naturally-occurring amino acids is performed at each position of the target peptide, then the ability to observe the effect of substitution with other amino acids is improved, but the amount of alternative peptides to be synthesized and tested vastly increases
Solution Approach 1:
The patent segments the comprehensive mutational scan into two phases: an initial reduced scan with selected amino acid substitutions to identify critical positions, followed by a focused analysis on those specific positions. This segmentation reduces the total number of peptides that need to be synthesized and tested while maintaining the ability to observe substitution effects at critical positions.
Solution Approach 2:
The patent applies local quality by concentrating testing resources on critical amino acid positions identified through the replacement matrix, rather than uniformly testing all positions. This allows for detailed observation of substitution effects at positions that matter most for binding, while reducing or eliminating testing at non-critical positions.
2Productivity
If amino acid positions such as anchor positions are excluded from the mutational scan to reduce testing requirements, then the amount of testing required is reduced, but the specificity and sensitivity of identifying alternative targets is affected
Solution Approach 1:
The patent performs preliminary action by conducting an initial reduced mutational scan with strategically selected amino acid substitutions before the main identification process. This preliminary scan identifies critical positions including anchor positions, allowing these positions to be included in subsequent focused testing rather than excluded, thereby maintaining specificity and sensitivity while controlling the overall testing burden.
Solution Approach 2:
The patent uses feedback from the initial reduced scan results to guide the subsequent focused mutational scan. The replacement matrix is updated based on observed binding effects, and this feedback loop ensures that critical positions are identified and tested appropriately, maintaining reliability while managing the number of tests required.
3Productivity
If a reduced mutational scan with fewer alternative amino acids is used, then the number of tests required is reduced, but the ability to comprehensively identify alternative target peptides may be compromised
Solution Approach 1:
The patent applies dynamics by making the mutational scan adaptive and iterative. The replacement matrix is dynamically updated based on results from each scanning phase, allowing the methodology to progress from a reduced initial scan to a more comprehensive focused scan on identified critical positions. This dynamic approach ensures comprehensive identification capability while maintaining control over the number of tests required at each stage.
Data Source
AI summary
The present invention relates to methods for identifying alternative target peptides of a binding moiety.