Soluble ACE2 Variants with Albumin-Binding Domain for Viral Decoy Therapy
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Solution Overview
Problem
Current treatments for coronavirus infections, particularly those caused by SARS-CoV-2, lack effective prophylactic and therapeutic options that can provide sustained protection and enzymatic activity, as existing soluble ACE2 variants have short durations of action and limited ability to bind to the viral receptor.
Innovation Solution
Development of soluble ACE2 variants, such as hACE2(1-618)-ABD, which are smaller in molecular size and fused with an albumin-binding domain (ABD) to extend their duration of action and enhance binding capacity to the SARS-CoV-2 receptor, thereby acting as decoys to intercept viral entry and maintain enzymatic activity in the body.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If soluble ACE2 variants are used to treat coronavirus infection, then binding to viral receptor and enzymatic activity are achieved, but duration of action is short
Solution Approach 1:
The patent creates fusion proteins by combining soluble ACE2 variants with exogenous polypeptides (such as Fc domains from antibodies or albumin-binding domains). This composite structure allows the ACE2 variant to maintain its binding capacity to SARS-CoV-2 while the fused exogenous polypeptide extends the half-life and duration of action in plasma and organs through mechanisms like reduced renal clearance and enhanced stability.
2Weight of moving object
If ACE2 variants are made smaller in molecular size, then glomerular filtration is improved, but duration of action in plasma is reduced
Solution Approach 1:
The patent fuses smaller ACE2 variants (such as hACE2(1-618) which is amenable to glomerular filtration) with exogenous polypeptides that have extended half-lives. The fusion protein structure allows the small ACE2 portion to be efficiently filtered and redistributed while the larger exogenous portion (like Fc domain or ABD) protects it from rapid degradation and extends plasma half-life, achieving both small effective size and prolonged duration of action.
Solution Approach 2:
The exogenous polypeptide acts as an intermediary carrier that binds to the small ACE2 variant and mediates its extended circulation. The Fc domain or ABD serves as a bridge between the small ACE2 molecule and the host's immune system or albumin, enabling prolonged half-life without requiring the ACE2 molecule itself to be large.
3Duration of action of moving object
If exogenous polypeptide is fused to extend duration of action, then half-life in plasma is increased, but molecular size increases
Solution Approach 1:
The patent uses compact exogenous polypeptides such as the albumin-binding domain (ABD) from streptococcal protein G or Fc domains from IgG antibodies. These domains provide substantial half-life extension (from hours to days) while adding minimal molecular weight compared to full-length antibodies or other large carriers, achieving an optimal balance between size 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 hACE2(1-618)-ABD variant demonstrates prolonged activity, effectively neutralizing SARS-CoV-2 infection in human kidney organoids and providing sustained enzymatic function, potentially offering improved preventative and therapeutic benefits with less frequent dosing.
Implementation Method 1
variants of ACE2... that comprise a binding site for the SARS-CoV-2 receptor binding domain
Implementation Method 2
the exogenous polypeptide portion of the fusion polypeptide extends the duration of action of the ACE2 variant by increasing the half-life of the ACE2 variant in plasma and organs
Implementation Method 3
The variants of ACE2 preferably are soluble
Data Source
AI summary
The present disclosure provides various insights relating to treatment of viral infection with soluble ACE2 variants, specifically including soluble human ACE2 (hACE2) variants. For example, the present disclosure teaches that decoy activity, which may intercept virus-receptor interactions, and ACE2 enzymatic activity can provide separate contributions to therapeutic efficacy; among other things, the present disclosure provides particular therapeutic regimens (e.g., relating to treatment of particular patient populations and/or to dosing regimens, combination therapies, etc.) for certain soluble ACE2 variants. Still further, the present disclosure provides certain particular ACE2 variants and methods of making and/or using them, including in accordance with particular therapeutic regimens.