Engineered Polypeptides with Albumin Binding Domain
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Solution Overview
Problem
There is a need for polypeptides with extended half-lives to effectively treat metabolic diseases such as lipodystrophy, dyslipidemia, obesity, and diabetes, 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) in combination with a biologically active hormone domain (HD), such as leptin, to enhance binding affinity to albumin, leading to increased duration of action and reduced renal clearance and degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If existing polypeptide treatments are used, then therapeutic effect is achieved, but duration of action is insufficient and dosing frequency is high
Solution Approach 1:
The patent uses albumin as an intermediary carrier molecule. The engineered polypeptide contains an albumin-binding domain that binds to serum albumin with high affinity, creating a circulating complex. This intermediary association protects the therapeutic polypeptide from rapid renal clearance and proteolytic degradation, extending its half-life from hours to days without requiring frequent dosing
Solution Approach 2:
The patent creates a composite polypeptide structure combining two functional domains: a therapeutic hormone domain (e.g., leptin, insulin, GLP-1) and an albumin-binding domain (ABD). This composite design allows the molecule to simultaneously deliver therapeutic effect and achieve prolonged circulation by binding to the abundant serum albumin reservoir, resolving the contradiction between efficacy and duration
2Duration of action of stationary object
If polypeptide half-life is extended through albumin binding, then duration of action increases, but molecular complexity increases
Solution Approach 1:
The patent segments the polypeptide into distinct functional modules: a therapeutic hormone domain and an albumin-binding domain connected by a linker peptide. This segmentation allows independent optimization of each domain's function while maintaining overall molecular stability. The modular design achieves extended half-life through the ABD component without compromising the therapeutic activity of the hormone domain
Solution Approach 2:
The albumin-binding domain serves multiple functions simultaneously: it extends circulation half-life, protects the therapeutic polypeptide from degradation, and facilitates reversible binding to the therapeutic target. This multi-functionality reduces the need for additional separate components, managing molecular complexity while achieving extended duration of action
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 prolonged biological activity, with a duration of action of at least 3 days in rodent models, translating to a week or longer in humans, and show efficacy in reducing food intake, body weight, and improving metabolic parameters.
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
AI summary
Compounds are provided having inter alia good duration of action, high potency and/or convenient dosing regimens including once weekly administration. 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 lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease or diabetes (including type I and type II). Additional diseases and disorders which can be treated by the compounds and methods described herein include nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X and Huntington's Disease.