Monoclonal antibody capable of binding to specific discontinuous epitope occurring in AD1 region of human cytomegalovirus GB glycoprotein, and antigen-binding fragment thereof
Inventors
Takada, Kenzo • Kurino, Rika • Torashima, Takashi
Assignees
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Publication Number
US-8492529-B2
Publication Date
2013-07-23
Expiration Date
Abstract
The present invention provides a pharmaceutical composition for human cytomegalovirus HCMV causative of various disease states, the composition comprising a monoclonal antibody and an antigen-binding fragment thereof that specifically binds to the AD1 region of glycoprotein gB and that has excellent neutralizing capacity. The present invention provides: a monoclonal antibody and an antigen-binding fragment thereof having an excellent neutralizing capacity and cell-to-cell infection blocking capacity and specifically binding to a discontinuous sequence occurring in the HCMV AD1 region; a pharmaceutical composition comprising the antibody or the fragment thereof; and the like.
Core Innovation
The invention relates to a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to the AD1 region of human cytomegalovirus (HCMV) glycoprotein gB. The disclosed antibody EV2038 and its antigen-binding fragments are characterized by defined heavy chain and light chain CDR amino acid sequences, and the binding is associated with a discontinuous epitope in the AD1 region of gB.
The antibody is extensively defined in sequence terms. The heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO:13, heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO:14, and heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:15. The light chain CDR1, CDR2, and CDR3 comprise the amino acid sequences of SEQ ID NO:16, SEQ ID NO:17, and SEQ ID NO:18, respectively, with additional disclosure of heavy/light variable regions by specified SEQ ID NOs.
Functional performance and epitope mapping are reported for the AD1-binding antibody. The patent summary describes strong neutralization and cell-to-cell infection blocking activity. Epitope mapping using deletion mutants, Western blot, and peptide array identifies residues in the AD1 region, and variant effects are described with identified requisite residues for AD1 binding, including a proline at a CDR-H3 position 125.
Claims Coverage
The claims provided include one independent claim directed to the antibody/antigen-binding fragment defined by specific CDR amino acid sequences. The dependent claims further specify additional sequence constraints and a pharmaceutical composition and treatment uses.
AD1-binding monoclonal antibody defined by heavy and light chain CDR sequences
A monoclonal antibody or an antigen-binding fragment thereof that specifically binds to the AD1 region of HCMV glycoprotein gB, comprising heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:13, heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:14, heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:15, light chain CDR1 comprising the amino acid sequence of SEQ ID NO:16, light chain CDR2 comprising the amino acid sequence of SEQ ID NO:17, and light chain CDR3 comprising the amino acid sequence of SEQ ID NO:18.
Antibody with specified heavy and light variable region sequences
An antibody (or an antigen-binding fragment) in which the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:10 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:12.
IgG1/lambda class and subclass specification
The antibody (or an antigen-binding fragment) has the IgG1/λ class/subclass.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the antibody or antigen-binding fragment according to claim 1 together with a pharmaceutically acceptable carrier.
Treatment of HCMV infection by administering a pharmaceutical composition
A method for treating a human cytomegalovirus (HCMV) infection by administering to a subject a pharmaceutical composition containing the antibody or antigen-binding fragment together with a pharmaceutically acceptable carrier.
Treatment limited to congenital CMV infection
The method is further limited to where the HCMV infection is a congenital cytomegalovirus (CMV) infection.
Across the claim set, the core inventive coverage is an AD1-region gB-binding monoclonal antibody or antigen-binding fragment defined by specified heavy and light chain CDR sequences, further constrained by specified variable-region sequences and an IgG1/λ class/subclass, with pharmaceutical composition and treatment method claims including congenital CMV infection.
Stated Advantages
Strong neutralization via plaque/infection blocking IC50 values against multiple HCMV strains.
Cell-to-cell infection blocking activity with at least 50% inhibition at low concentrations.
Documented Applications
Preventing or treating HCMV-related diseases, including reactivation in immunodeficiency, congenital CMV transmission outcomes, and newborn/infant infections.
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