Monoclonal anti-claudin 1 antibodies for the inhibition of hepatitis C virus infection
Inventors
Baumert, Thomas • Schuster, Catherine • Thompson, John • Grunert, Fritz
Assignees
Genovac GmbH • Institut National de la Sante et de la Recherche Medicale INSERM • Universite de Strasbourg
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Publication Number
US-8518408-B2
Publication Date
2013-08-27
Expiration Date
Abstract
The present invention provides monoclonal antibodies that specifically bind to the extracellular domain of human Claudin-1 on the cell surface, thereby inhibiting HCV entry into susceptible cells and preventing HCV infection of these cells; and hybridoma cell lines which produce such monoclonal antibodies. Also provided are reagents that comprise such antibodies, and pharmaceutical compositions comprising such antibodies. Methods of treating or preventing HCV infection by administration of an inventive monoclonal antibody, or a pharmaceutical composition thereof are also described.
Core Innovation
The disclosure relates to anti-CLDN1 monoclonal antibodies that bind the extracellular domain of human Claudin-1 (Claudin 1) and inhibit hepatitis C virus (HCV) entry and infection. The antibodies are described as secreted by hybridoma cell lines deposited at the DSMZ on Jul. 29, 2008 under specified accession numbers.
The invention further identifies a conserved Claudin 1 first extracellular loop motif involved in antibody binding. The conserved motif is W(30)-GLW(51)-C(54)-C(64), and binding to the Claudin 1 extracellular domain is linked to functional inhibition of HCV.
Functional data are reported for inhibition of HCVcc/HCVpp across major genotypes and patient-derived quasispecies. Mechanism studies indicate that the antibodies reduce E2 association with permissive cells and disrupt CD81–Claudin-1 co-receptor interactions, including via FRET analysis, and thereby reduce HCV cell-to-cell transmission and viral spread.
The disclosure also covers prophylactic and therapeutic use, including prevention of post–liver transplantation recurrence. It further covers assessment of tolerability via in vitro toxicity assays and non-therapeutic diagnostic/prognostic uses for Claudin 1 in cancers, including with antibody-detectable conjugates and kits.
Claims Coverage
The independent claims are clm-00002 and clm-00006. Across these, the claims define Claudin 1 extracellular domain binding monoclonal antibodies derived from DSMZ-deposited hybridoma cell lines and extend coverage to antibody epitope defined by a conserved Claudin 1 motif, and to engineered antibodies via CDR-derived variants. Additional coverage in the dependent claims includes functional inhibition of HCV entry/viral processes and Claudin 1 detection kit use with a detectable moiety, as reflected in the provided claim summaries.
DSMZ-deposited Claudin 1 extracellular domain binding monoclonal antibody
A monoclonal antibody secreted by a hybridoma cell line deposited at the DSMZ on Jul. 29, 2008 under an Accession Number selected from DSM ACC2931–DSM ACC2938, or a biologically active fragment thereof that binds Claudin 1 extracellular domain.
CDR-derived antibody from DSMZ-deposited hybridoma
A monoclonal antibody comprising the complementary determining regions (CDRs), or portions thereof, derived from a monoclonal antibody secreted by a hybridoma cell line deposited at the DSMZ on Jul. 29, 2008 under an Accession Number selected from DSM ACC2931–DSM ACC2938, or a biologically active fragment thereof that binds Claudin 1 extracellular domain.
Epitope on first extracellular loop defined by conserved motif
The monoclonal antibody (or biologically active fragment) binds an epitope in the Claudin 1 first extracellular loop defined by the conserved motif W(30)-GLW(51)-C(54)-C(64).
Non-human primate Claudin 1 binding specificity
The monoclonal antibody (or biologically active fragment) does not bind rodent Claudin 1 but instead binds non-human primate Claudin 1.
Inhibition of HCV entry and/or spread via Claudin 1 or E2/virion interactions
The monoclonal antibody (or biologically active fragment) inhibits HCV envelope glycoprotein E2 or infectious virion binding to HCV permissive cell lines, CD81–Claudin-1 association, and/or HCV cell-to-cell transmission and viral dissemination.
Humanized, de-immunized, or chimeric antibody format
The monoclonal antibody or biologically active fragment is humanized, de-immunized, or chimeric.
Therapeutic administration to treat HCV infection or HCV-related disease
A method of treating hepatitis C virus (HCV) infection or an HCV-related disease by administering an effective amount of a monoclonal antibody or a biologically active fragment to a subject in need thereof.
Claudin 1 detection kit with detectable-moiety-conjugated antibody
A detection kit for Claudin 1 in a biological sample that includes a monoclonal antibody (or biologically active fragment) attached to a detectable moiety.
Taken together, the independent claims center on monoclonal antibodies (and biologically active fragments) that bind the Claudin 1 extracellular domain and are derived from specified DSMZ-deposited hybridoma cell lines, with additional claim coverage specifying an epitope in the Claudin 1 first extracellular loop via the conserved motif W(30)-GLW(51)-C(54)-C(64), possible non-human primate binding specificity, and engineered CDR-derived formats. The dependent claim summaries further extend coverage to HCV entry/spread inhibition functions, therapeutic administration for HCV infection or HCV-related disease, and Claudin 1 detection kits using a detectable moiety.
Stated Advantages
Inhibits HCV entry and infection by interfering with Claudin 1 extracellular domain interactions.
Reduces HCV envelope glycoprotein E2 association and disrupts CD81–Claudin 1 co-receptor interactions.
Reduces HCV cell-to-cell transmission and viral spread.
Prevents post–liver transplantation recurrence (prophylactic/therapeutic use).
Supports assessment of tolerability via in vitro toxicity assays.
Provides non-therapeutic diagnostic/prognostic detection of Claudin 1 in cancers using antibody-detectable conjugates and kits.
Documented Applications
Therapeutic prophylactic/therapeutic use to treat hepatitis C virus (HCV) infection or an HCV-related disease, including prevention of post–liver transplantation recurrence.
Reduction of HCV cell-to-cell transmission and viral dissemination as an application of Claudin 1-targeting antibodies.
In vitro toxicity assay-based tolerability assessment for the antibodies.
Diagnostic/prognostic use for Claudin 1 in cancers using antibody-detectable conjugates and a detection kit with a detectable moiety.
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