Filovirus antibody
Inventors
Lai, Jonathan R. • Koellhoffer, Jayne F. • Frei, Julia • Chandran, Kartik • Sidhu, Sachdev • Chen, Gang • Dye, John M. • Zak, Samantha
Assignees
University of Toronto • Albert Einstein College of Medicine • United States Department of the Army
Publication Number
US-10875907-B2
Publication Date
2020-12-29
Expiration Date
2034-05-30
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Abstract
The present invention addresses a need for antibodies useful for filovirus infections.
Core Innovation
The present invention provides isolated humanized antibodies that specifically target the filovirus glycoprotein pre-fusion core, particularly those against the Sudan strain of Ebola virus glycoprotein. These antibodies comprise a framework region having at least 95% sequence identity to a human antibody framework region and include defined complementarity determining regions (CDRs) in both heavy and light chains. The invention also encompasses antigen-binding fragments of these antibodies, compositions containing them, and methods for treating or inhibiting filovirus infections by administering the antibodies or fragments to subjects.
The problem addressed by the invention relates to the lack of effective treatments for filovirus infections, which include Ebola virus and Marburg virus, notable for their high mortality rates and pandemic potential. Specifically, existing neutralizing antibodies, such as KZ52, target the Ebola virus glycoprotein but exhibit limited protective efficacy, particularly in non-human primates. Moreover, some potent antibodies, like 16F6, are murine in origin and thus limited in therapeutic use. The invention fills the need for humanized antibodies with improved therapeutic potential by targeting conserved regions of the filovirus glycoprotein pre-fusion core to neutralize infection effectively.
The invention leverages synthetic antibody engineering and humanization techniques to produce antibodies with human-compatible frameworks grafted with CDRs from potent murine antibodies like 16F6, enabling recognition and neutralization of the filovirus glycoprotein pre-fusion core. These antibodies demonstrate strong neutralization of authentic Sudan strain Ebola virus and high binding affinity, potentially offering a therapeutic approach for filovirus infections that can be administered both pre- and post-exposure.
Claims Coverage
The claims include one independent claim that covers the core humanized antibody and several dependent claims covering sequences, fragments, recombinant nucleic acids, cells, compositions, and methods of treatment and inhibition for filovirus infections.
Humanized anti-Sudan strain Ebola virus glycoprotein pre-fusion core antibody
An isolated humanized antibody comprising a framework region with 95% or greater identity to a human antibody framework and specific heavy chain CDRs (SEQ ID NO:1 GFAFNYYDMF, NO:2 YIKPGGGNTYYADSV, NO:3 QLYGNSFFDY) and light chain CDRs (SEQ ID NO:4 DVTTA, NO:5 WASTR, NO:6 HYSTPLT) targeting the Sudan strain Ebola virus glycoprotein pre-fusion core.
Antigen-binding fragments of the antibody
Fragments such as Fab, Fab', F(ab')2, Fd, Fv, single-chain variable fragments, or CDR-containing fragments derived from the humanized antibodies that retain binding specificity to the filovirus glycoprotein pre-fusion core.
Recombinant nucleic acid and transformed cells
Nucleic acids encoding the heavy and light chain variable regions of the humanized antibody and cells transformed with these recombinant nucleic acids for the purpose of antibody production.
Pharmaceutical compositions
Compositions comprising the humanized antibodies or antigen-binding fragments formulated with pharmaceutically acceptable carriers suitable for administration.
Methods for treating and inhibiting filovirus infections
Methods comprising administering an effective amount of the humanized antibody or antigen-binding fragment to a subject to treat or inhibit filovirus infection, including administration both prior to and after exposure to the filovirus, specifically the Sudan strain Ebola virus.
Neutralizing antibody property
The antibody or antigen-binding fragment is characterized as a neutralizing antibody that interferes with filovirus infection.
The claims collectively cover humanized antibodies with defined CDR sequences targeting the Sudan strain Ebola virus glycoprotein pre-fusion core, their fragments, methods to produce them recombinantly, pharmaceutical compositions containing them, and their use to treat or inhibit filovirus infections with neutralizing activity.
Stated Advantages
Provides improved therapeutic agents for filovirus infections by offering humanized antibodies with enhanced neutralization potency against the Sudan strain Ebola virus.
Humanized antibodies have reduced immunogenicity compared to murine antibodies, increasing their suitability for clinical use.
Antibody phage display and synthetic engineering enable the generation of humanized antibodies without the need for immunization, which can enhance production efficiency and specificity.
The antibodies target conserved, functionally relevant epitopes on the filovirus glycoprotein pre-fusion core, which may contribute to broad and effective neutralization.
Documented Applications
Therapeutic treatment of filovirus infection, specifically infection by Sudan strain Ebola virus.
Inhibiting filovirus infection prophylactically by administering antibodies prior to exposure.
Post-exposure treatment of filovirus infection in subjects already exposed.
Use of recombinant nucleic acids and transformed non-human cells for antibody production.
Formulation of pharmaceutical compositions containing the antibodies or fragments for administration.
Diagnostic kits comprising the antibodies for detecting filovirus presence in samples.
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