ATF Polypeptide uPAR Binding Atherosclerosis Treatment
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Solution Overview
Problem
Current methods are inadequate in effectively treating atherosclerosis, as genetic depletion of uPA did not significantly affect atherosclerotic lesion formation in ApoE deficient mice, indicating a need for alternative therapeutic approaches targeting the uPA/uPAR pathway.
Innovation Solution
Administration of ATF polypeptides, either naturally occurring or synthetic, conjugated with agents like PEG or fused with albumin to extend half-life, which can bind to uPAR or induce an immune response, thereby blocking the uPA/uPAR interaction and inhibiting atherosclerosis progression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetic depletion of uPA is used to treat atherosclerosis, then the approach targets the uPA/uPAR pathway, but it does not significantly affect atherosclerotic lesion formation
Solution Approach 1:
The patent extracts and isolates the amino terminal fragment (ATF) of uPA, which contains the uPAR binding domain. By separating this functional domain from the full uPA protein, the invention creates a targeted therapeutic agent that specifically blocks uPA-uPAR interaction without requiring complete genetic depletion of uPA, thereby achieving effective treatment while maintaining broader therapeutic adaptability
Solution Approach 2:
The ATF polypeptide acts as an intermediary agent that competes with uPA for binding to uPAR. This mediator specifically blocks the pathological uPA-uPAR interaction in atherosclerotic lesions without affecting other physiological functions of full-length uPA, resolving the contradiction by providing selective inhibition through a intermediary molecule
2Reliability
If ATF polypeptides are administered to block uPA/uPAR interaction, then atherosclerosis progression is inhibited, but the half-life of the polypeptide in the patient is limited
Solution Approach 1:
The patent creates composite therapeutic agents by conjugating ATF polypeptides with long-circulating carriers such as polyethylene glycol (PEG) or fusing them with albumin. These composite structures combine the therapeutic functionality of ATF with the extended circulation properties of the carrier, thereby maintaining high therapeutic effectiveness while significantly extending the half-life of the polypeptide in the patient
Solution Approach 2:
The invention merges the uPAR-binding ATF domain with half-life extending moieties (PEG chains or albumin molecules). This combination allows the ATF polypeptide to maintain its ability to block uPA-uPAR interaction while gaining prolonged circulation time from the attached carrier, thus resolving the contradiction between therapeutic effectiveness and 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 use of ATF polypeptides and anti-uPAR antibodies effectively reduces atherosclerotic lesion formation by interrupting the uPA/uPAR interaction, providing a therapeutic approach to treat or prevent atherosclerosis.
Implementation Method 1
The amino terminal fragment (ATF) of uPA is responsible for binding to uPAR
Implementation Method 2
the polypeptides can be conjugated with polyethylene glycol (PEG)
Implementation Method 3
the polypeptides can be fused to albumin or other agents known to extend the half-life of polypeptides in vivo
Data Source
AI summary
The present application features methods and compositions for treating patients suffering from atherosclerosis or at risk for developing atherosclerosis. The treatment includes administering to the patient a pharmaceutical composition that includes an agent capable of blocking the interaction between uPA and its receptor uPAR, e.g., an ATF or a fragment thereof, an anti-uPA antibody, a uPAR or a fragment thereof, or an antibody that specifically binds to uPAR.