Anti-ACE2 Antibodies for Broad Coronavirus Neutralization
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Solution Overview
Problem
Existing monoclonal antibodies targeting the spike proteins of coronaviruses are ineffective against a broad range of SARS-related coronaviruses due to high variability in spike proteins, making it difficult to develop potent neutralizing antibodies that can combat current and future coronavirus pandemics.
Innovation Solution
Development of monoclonal antibodies that target the Angiotensin-converting enzyme-2 (ACE2) receptor rather than the viral spike proteins, using ACE2-Fc fusion proteins expressed in Expi293 cells and immunized in AlivaMab mice to generate fully human anti-ACE2 antibodies that inhibit coronavirus infection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If monoclonal antibodies target the spike proteins of coronaviruses, then they can neutralize specific virus strains, but they fail to provide broad-spectrum protection against diverse SARS-related coronaviruses due to high spike protein variability
Solution Approach 1:
The patent introduces ACE2 as an intermediary target instead of directly targeting the viral spike protein. The antibodies bind to ACE2, which is a conserved host receptor used by all SARS-related coronaviruses for entry. This intermediary approach allows the antibodies to inhibit multiple virus strains simultaneously while maintaining effective neutralization, resolving the contradiction between broad-spectrum capability and strain-specific potency.
2Adaptability or versatility
If monoclonal antibodies are designed to bind to conserved regions of viral proteins, then broad-spectrum activity is achieved, but the antibodies may interfere with essential host functions
Solution Approach 1:
The patent applies local quality by targeting a specific local region on the ACE2 protein (the extracellular domain involved in viral binding) rather than the entire ACE2 protein or other essential domains. The antibodies bind to a localized epitope that is critical for viral entry but does not disrupt ACE2's enzymatic function. This localized targeting achieves broad-spectrum antiviral activity while minimizing harmful effects on host functions.
Solution Approach 2:
The patent uses Fc-fused ACE2 proteins as a copy or surrogate to generate antibodies. The Fc fusion protein replicates the extracellular domain structure of ACE2 without containing the enzymatic catalytic domain. Antibodies raised against this copy bind to the relevant epitopes on native ACE2 during infection, providing viral neutralization without interfering with ACE2's enzymatic activity, thus resolving the contradiction between cross-neutralization and host function preservation.
3Reliability
If existing anti-SARS-CoV-2 antibodies are used, then treatment and prophylaxis are effective against the original strain, but they become obsolete due to escape mutations in variants like omicron
Solution Approach 1:
The patent inverts the traditional approach by instead of having the virus mutate to escape antibodies, the antibodies adapt to bind a different target (ACE2) that the virus cannot easily mutate. By inverting the attack vector from spike protein to host receptor, the system achieves evolutionary stability and maintains effectiveness against diverse variants including omicron, resolving the contradiction between original strain effectiveness and variant resistance.
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 anti-ACE2 antibodies effectively inhibit coronavirus infection by binding to the ACE2 receptor, providing a broad-spectrum defense against SARS-related coronaviruses, including SARS-CoV-2 variants, without interfering with the enzymatic activity of ACE2.
Implementation Method 1
binds to the extracellular domain of a human ACE2 protein
Implementation Method 2
purified soluble recombinant forms of the monomeric (8×His tagged) and dimeric (Fc-fused) human ACE2 receptor extracellular domain
Implementation Method 3
binding of the human ACE2 protein by the antibody or antigen binding fragment thereof does not interfere with the enzymatic activity of the human ACE2 protein
Data Source
AI summary
The current disclosure is directed to antibodies which inhibit coronaviruses, methods of making such antibodies, and the uses of such antibodies for the treatment and prevention of infection caused by coronaviruses.