Engineered Polypeptides with Albumin Binding Domain for Extended Half-Life
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Solution Overview
Problem
There is a need for polypeptides with extended half-lives to effectively treat metabolic diseases such as obesity, diabetes, and central nervous system disorders, as existing treatments do not provide sufficient duration of action or convenience in dosing regimens.
Innovation Solution
Engineered polypeptides are developed that incorporate an albumin binding domain (ABD) combined with a biologically active hormone domain (HD), such as exendin, which binds to albumin, leading to increased duration of action due to decreased renal clearance and degradation, and can be administered orally for convenient dosing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If existing polypeptide treatments are used, then therapeutic efficacy is achieved, but duration of action is insufficient and dosing frequency is high
Solution Approach 1:
The patent introduces albumin as an intermediary carrier molecule. The polypeptide is engineered to bind to albumin, which acts as a mediator to extend circulation time and reduce renal clearance. This intermediary approach allows the therapeutic polypeptide to be sequestered in circulation, thereby extending its duration of action without requiring frequent dosing.
Solution Approach 2:
The patent creates a composite structure by fusing the therapeutic polypeptide with an albumin-binding domain (ABD). This composite construct combines the therapeutic function of the original polypeptide with the prolonged circulation properties of albumin, achieving extended duration of action while maintaining therapeutic efficacy.
2Duration of action of stationary object
If polypeptide half-life is extended through modification, then duration of action increases, but molecular structure complexity increases
Solution Approach 1:
The patent segments the polypeptide structure into distinct functional modules: the original therapeutic domain and the albumin-binding domain (ABD). This segmentation allows the ABD to be added as a separate, standardized module that specifically confers prolonged half-life without complicating the core therapeutic mechanism, making the overall structure more manageable and designable.
Solution Approach 2:
The patent modifies specific parameters of the polypeptide by introducing the ABD with defined amino acid sequences (such as those containing hydrophobic residues that bind to albumin's hydrophobic pockets). These parameter changes in the molecular structure directly result in extended half-life and duration of action without requiring complex overall structural redesign.
3Duration of action of moving object
If renal clearance is decreased to extend duration of action, then polypeptide remains in circulation longer, but risk of accumulation and immunogenicity increases
Solution Approach 1:
The patent uses human albumin, a naturally abundant and biocompatible protein, as the binding partner. By copying the natural albumin structure and utilizing its endogenous binding sites, the engineered polypeptide mimics a self-tolerated molecule, thereby reducing the risk of immunogenicity while achieving prolonged circulation through decreased renal clearance.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered polypeptides demonstrate a prolonged duration of action, with effects lasting up to several days, providing robust glycemic control, body weight reduction, and improved patient compliance through oral delivery, while maintaining therapeutic efficacy similar to exendin-4.
Implementation Method 1
engineered polypeptides which incorporate an albumin binding domain in combination with a biologically active peptide... because the engineered polypeptides described herein can bind albumin, the compounds can be sequestered (e.g., bound to albumin) while in the circulation
Data Source
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AI summary
Compounds are provided having inter alia good duration of action, high potency and/or convenient dosing regimens including oral administration, and reduced immunogenicity. The compounds are engineered polypeptides which incorporate an albumin binding domain in combination with one or more biologically active polypeptides. Also provided are pharmaceutical compositions and methods of treatment for diseases and disorders including obesity and overweight, diabetes, dyslipidemia, hyperlipidemia, Alzheimer's disease, fatty liver disease, Short Bowel Syndrome, Parkinson's disease, and cardiovascular disease.