Human monoclonal antibody specific for the F protein of respiratory syncytial virus (RSV)
Inventors
Koch, Holger • Urwyler, Simon • Rudolf, Michael • Truong, Vu
Assignees
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Publication Number
US-10081671-B2
Publication Date
2018-09-25
Expiration Date
Abstract
This invention is directed to an antibody construct or fragment thereof derived from an RSV-infected human, such that the antibody construct binds with specificity to RSV fusion protein antigenic region II/A with an affinity of greater than 1×10−9M. Preferably, the antibody construct is capable of neutralizing RSV strains, including at least one RSV strain that is resistant to palivizumab. The invention further relates to nucleic acids encoding the antibody construct or portions thereof, and cell lines expressing the antibody. This invention further relates to methods for producing said antibody construct, and to the use of said antibody construct for treating or preventing infection of a patient by RSV having a normal or mutated version of F protein.
Core Innovation
The invention relates to fully human monoclonal antibody AR201 (KBRV201) that binds to the respiratory syncytial virus (RSV) fusion (F) protein antigenic region II/A. The disclosure states that the antibody shows binding affinity greater than 1×10^-29 M and neutralizes palivizumab-resistant and palivizumab-sensitive RSV strains. The document provides a rationale that RSV F protein fusion and antigenic region II/A act as a functional target for the antibody.
The background framing addresses limitations associated with palivizumab and motavizumab, including resistance and escape, and links the proposed antibody target to improved strain recognition. The disclosure states that the antibody is designed to recognize strains broadly and to exhibit neutralization activity that is stronger in comparison to palivizumab in neutralization assays described in the document. The document also discusses identification of escape mutations in the palivizumab epitope region.
The disclosure further characterizes the antibody as an antibody construct or antibody fragment comprising heavy chain variable region and light chain variable region with specified heavy- and light-chain CDR1, CDR2, and CDR3 amino acid sequences. The antibody is disclosed with glycoengineering to produce glycans lacking fucose and xylose, and the disclosure describes Fc engineering for FcRn binding for longer half-life. The document also includes expression and characterization of binding affinity and neutralization activity.
Claims Coverage
The provided claim set includes three independent claims for a cell, an antibody or antibody fragment, and an expression vector. Each independent claim centers on defined heavy-chain and light-chain CDR sets, and the antibody claim additionally requires a glycan composition constraint.
A cell producing an antibody construct or antibody fragment with specified heavy- and light-chain CDR sequences
A cell comprising a first cDNA encoding a heavy chain variable region with CDR1 (GASINLYD), CDR2 (GYISGST), and CDR3 (ARDVGWGPQYYYGLDV), and a second cDNA encoding a light chain variable region with CDR1 (HSVQSTS), CDR2 (GGS), and CDR3 (QQSDRSPPIT), wherein the cell produces an antibody construct or antibody fragment comprising the heavy chain variable region and the light chain variable region, wherein the cell is other than a beta lymphocyte.
An antibody or antibody fragment with specified heavy- and light-chain CDR sequences and glycans lacking fucose and xylose
An antibody or antibody fragment comprising at least a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises CDR1 (GASINLYD), CDR2 (GYISGST), and CDR3 (ARDVGWGPQYYYGLDV), and wherein the light chain variable region comprises CDR1 (HSVQSTS), CDR2 (GGS), and CDR3 (QQSDRSPPIT), wherein the antibody or antibody fragment comprises glycans lacking fucose and xylose.
An expression vector encoding the specified heavy- and light-chain variable regions
An expression vector comprising a first nucleic acid encoding a heavy chain variable region and a second nucleic acid encoding a light chain variable region, wherein the heavy chain variable region encoded by the first nucleic acid sequence comprises CDR1 (GASINLYD), CDR2 (GYISGST), and CDR3 (ARDVGWGPQYYYGLDV), and wherein the light chain variable region encoded by the second nucleic acid sequence comprises CDR1 (HSVQSTS), CDR2 (GGS), and CDR3 (QQSDRSPPIT).
Across the independent claims, the core claim coverage is directed to an antibody construct or fragment defined by specific heavy-chain CDR1/2/3 amino acid sequences and specific light-chain CDR1/2/3 amino acid sequences, with a non-beta-lymphocyte cell producing the construct, and with an expression vector providing the encoding nucleic acids; the antibody claim additionally requires glycans lacking fucose and xylose.
Stated Advantages
Neutralization of palivizumab-resistant and palivizumab-sensitive RSV strains.
Broad strain recognition of RSV strains.
Stronger plaque reduction neutralization reductions versus palivizumab (as characterized in the document).
Glycoengineering to produce glycans lacking fucose and xylose.
Optional FcRn-binding Fc mutations for longer half-life.
Documented Applications
Cotton rat RSV challenge model for prophylaxis/protection.
Assessment of binding affinity and RSV neutralization, including stronger plaque reduction compared to palivizumab and testing across reference and clinical isolates.
Identification of palivizumab epitope escape mutations in palivizumab epitope region (escape mutation identification described in the document).
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