Polypeptide Isoelectric Point Modification for Reduced Liver Uptake
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Solution Overview
Problem
Fast-clearing polypeptides used for in vivo applications often exhibit rapid liver uptake, kidney retention, or rapid blood clearance, which can interfere with imaging applications, necessitating methods to modify their biokinetics for improved tissue penetration and clearance profiles.
Innovation Solution
Modifying polypeptides by substituting basic or neutral amino acid residues with acidic residues to alter their isoelectric point, reducing liver uptake while maintaining binding affinity, and appending signal generators or targeting moieties for imaging purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If fast-clearing polypeptides are used for in vivo imaging, then rapid migration to target site and tissue penetration are improved, but liver uptake increases causing interference with imaging applications
Solution Approach 1:
The patent applies parameter changes by modifying the isoelectric point of the polypeptide through amino acid substitution. Specifically, basic or neutral residues are replaced with acidic residues to lower the isoelectric point, which alters the polypeptide's charge characteristics and reduces liver uptake while preserving rapid clearance and tissue penetration properties
2Loss of time
If fast-clearing polypeptides are used for in vivo imaging, then rapid clearance from body is improved, but kidney retention increases resulting in unacceptable radiation dose
Solution Approach 1:
The patent modifies the polypeptide's biokinetic parameters by changing its isoelectric point through amino acid substitution. This parameter change redirects clearance pathways away from the kidneys, reducing radiation dose exposure while maintaining rapid overall clearance from the body
3Productivity
If fast-clearing polypeptides are used for in vivo imaging, then rapid clearance is improved, but background noise in liver during imaging increases
Solution Approach 1:
The patent employs parameter changes by adjusting the polypeptide's isoelectric point to optimize its biodistribution. This modification reduces hepatic accumulation and associated background noise, thereby improving image quality while preserving the rapid clearance kinetics necessary for effective imaging
Data Source
AI summary
Provided herein are methods of reducing liver uptake in vivo of a polypeptide that specifically binds to a target comprising: (a) providing a polypeptide that specifically binds to a target; and (b) substituting at least one basic or at least one neutral amino acid residue of the native polypeptide from step (a) with an acidic amino acid residue to produce a modified polypeptide, wherein the modified polypeptide demonstrates an isoelectric point at least 0.05-0.1 pH points less than the isoelectric point of the native polypeptide. Also provided are polypeptides made using the inventive methods as well as imaging techniques that employ the methods and agents.