Pre-fusion RSV F Protein Antibodies Targeting Antigenic Site VIII
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Solution Overview
Problem
Current RSV vaccines and treatments face challenges due to antigenic diversity of the RSV G protein and the limited efficacy and high cost of monoclonal antibodies like palivizumab, while the pre-fusion conformation of the F protein is difficult to target effectively for broad protection against RSV infection.
Innovation Solution
Development of antibodies with clone-paired heavy and light chain CDR sequences that recognize the pre-fusion RSV F protein, specifically targeting antigenic site VIII, which is unique and effective against both RSV subgroups A and B, and can be administered as monoclonal antibodies or included in vaccine formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies like palivizumab are used for prophylactic treatment, then protection against RSV infection is provided, but the cost is high and efficacy is moderate
Solution Approach 1:
The patent changes the target antigen parameter from the conventional post-fusion F protein conformation to the pre-fusion F protein conformation. This parameter change enables the development of antibodies (like D25 and AM14) that bind to unique epitopes only present in the pre-fusion state, achieving broader neutralization efficacy against both RSV subgroups A and B while potentially reducing costs through more effective prophylaxis
2Reliability
If antibodies target the RSV G protein, then neutralizing antibodies are induced, but antigenic diversity among RSV strains makes broad protection difficult
Solution Approach 1:
The patent targets the F protein instead of the G protein, as the F protein is highly conserved across RSV strains and subgroups. The pre-fusion F protein structure contains conserved epitopes (such as the antigenic site Ø recognized by D25 and the quaternary-dependent site recognized by AM14) that are universal across RSV strains, enabling broad-spectrum neutralizing antibodies to protect against both subgroups A and B
3Reliability
If antibodies target the post-fusion F conformation, then neutralizing antibodies are produced, but the pre-fusion conformation is lost and unique epitopes are unavailable
Solution Approach 1:
The patent employs stabilization techniques to maintain the pre-fusion F protein conformation before antibody binding occurs. By using stabilized pre-fusion F protein constructs as immunogens or targets, the patent preserves the unique pre-fusion epitopes (such as antigenic site Ø and the quaternary-dependent site) that are lost in the post-fusion conformation, enabling the production of antibodies that specifically recognize and neutralize the virus in its native pre-fusion state
Solution Approach 2:
The patent changes the conformational state parameter of the F protein from post-fusion to pre-fusion. This parameter change is achieved through molecular stabilization techniques that lock the F protein in its pre-fusion conformation, making the unique pre-fusion epitopes accessible and enabling the development of antibodies with enhanced neutralization capacity
4Reliability
If site II mAbs are used for treatment, then potent neutralization is achieved, but non-neutralizing mAbs at nearby site VII compete for binding and reduce protective effect
Solution Approach 1:
The patent extracts the binding competition problem by targeting a completely different antigenic site (antigenic site Ø or the quaternary-dependent site) that is spatially and functionally separate from site II and site VII. By selecting epitopes that do not overlap with known non-neutralizing antibody binding sites, the patent eliminates the harmful binding competition effect while maintaining potent neutralization
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
These antibodies provide potent neutralization of RSV by targeting a novel epitope on the pre-fusion F protein, offering broad protection and potential for use in both treatment and prevention of RSV infections, with the ability to bind to metapneumovirus fusion protein as well.
Implementation Method 1
contacting a sample from said subject with an antibody or antibody fragment having clone-paired heavy and light chain CDR sequences from Tables 3 and 4, respectively; and detecting human respiratory syncytial virus in said sample by binding of said antibody or antibody fragment to a Human respiratory syncytial virus antigen in said sample
Data Source
AI summary
The present disclosure is directed to antibodies binding to human respiratory syncytial virus F protein, including both neutralizing and non-neutralizing antibodies, and methods for use thereof.