Therapy for filovirus infection
Inventors
Lai, Jonathan R. • Koelhoffer, Jayne F. • Frei, Julia • Chandran, Kartik • Sidhu, Sachdev • Chen, Gang • Dye, JR., John M. • Zak, Samantha
Assignees
University of Toronto • Albert Einstein College of Medicine • Com Affiliation Inc • United States Department of the Army
Publication Number
US-10081669-B2
Publication Date
2018-09-25
Expiration Date
2034-05-30
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Abstract
The present invention addresses a need for improved treatments for Filovirus infections.
Core Innovation
The present invention provides isolated humanized anti-filovirus glycoprotein pre-fusion core antibodies designed to improve treatments for filovirus infections. These antibodies comprise a framework region having a sequence of 95% or greater identity to a human antibody framework region, which includes specific heavy and light chain complementarity-determining regions (CDRs) characterized by defined amino acid sequences. The invention also includes antigen-binding fragments of these antibodies and compositions comprising them, such as those with pharmaceutically acceptable carriers. Methods for treating or inhibiting filovirus infections in subjects by administering effective amounts of these antibodies or fragments are disclosed.
Filoviruses like Ebola virus (EBOV) and Marburg virus (MARV) cause severe human disease with high fatality rates, and there are currently no FDA-approved treatments. These viruses enter host cells via the glycoprotein (GP) spike, which undergoes conformational changes for membrane fusion. Antibodies that neutralize the prefusion GP core, blocking these conformational changes, can inhibit infection. The invention addresses the need for effective, human-compatible antibodies capable of neutralizing filoviruses by targeting conserved regions of the prefusion GP core, enhancing therapeutic potential against viruses such as EBOV Sudan strain and MARV.
Previous antibodies such as the murine 16F6 and human-derived KZ52 have demonstrated protective capability but present limitations such as murine origin or insufficient potency in non-human primate models. This invention builds on these findings by humanizing antibodies like 16F6 through grafting of murine CDRs onto optimized human antibody frameworks, generating humanized variants (e.g., hu16F6) with improved neutralization activity and therapeutic potential. Synthetic antibody engineering and phage display libraries enable the generation of antibodies with enhanced affinity, specificity, and human compatibility to address the critical gap in effective filovirus therapies.
Claims Coverage
The patent includes one primary independent claim focused on a humanized anti-filovirus glycoprotein pre-fusion core antibody with specific sequence features. The inventive features involve antibody structure, sequence identity, and functional use in inhibiting filovirus infection.
Humanized anti-filovirus glycoprotein antibody with specific heavy and light chain CDR sequences
An isolated humanized antibody containing a framework region with at least 95% identity to a human antibody framework region, comprising (a) a heavy chain CDR1 of GFAFNYYDMH (SEQ ID NO:1), heavy chain CDR2 of YINPGGGNTYYADSV (SEQ ID NO:2), and heavy chain CDR3 of QLYGNSFMDY (SEQ ID NO:3), and (b) a light chain sequence DIQMTQSPSSLSASVGDRVTITCQASQDVTTAVAWYQQKPGKAPKL (SEQ ID NO:12) with a light chain CDR1, light chain CDR2 LIYAASGRHKGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ (SEQ ID NO:13), and a light chain CDR3 comprising HYSTPLT (SEQ ID NO:5).
Antigen-binding fragment of the humanized anti-filovirus antibody
An antigen-binding antibody fragment derived from the humanized antibody described, retaining specific CDR sequences and binding activity against filovirus glycoprotein pre-fusion core.
Composition comprising the antibody or antigen-binding fragment
Formulations comprising the humanized anti-filovirus antibodies or their antigen-binding fragments, optionally including a pharmaceutically acceptable carrier to enable therapeutic administration.
Method of inhibiting Ebola virus infection using the antibody
Administration of an effective amount of the humanized antibody or an antigen-binding fragment thereof to inhibit infection by Ebola virus, specifically including use prior to exposure and directed to the Sudan strain of Ebola virus.
The independent claim provides a humanized antibody specifically defined by key CDR sequences with high identity to human frameworks, together with antigen-binding fragments, compositions for therapeutic use, and methods for inhibiting filovirus infection. These claims focus on the structural antibody features and their application in prevention or treatment of filovirus infections, particularly Ebola Sudan strain.
Stated Advantages
The humanized antibodies have improved neutralization potency against filoviruses.
The antibodies are compatible with human immune systems due to humanization, reducing immunogenicity.
Antibody-based therapy allows for effective post-exposure treatment and prophylaxis of filovirus infection.
The invention provides broad-spectrum protection by targeting conserved regions of the filovirus glycoprotein pre-fusion core.
Documented Applications
Treatment of filovirus infections in subjects using the humanized anti-filovirus glycoprotein antibodies or antigen-binding fragments.
Inhibition of filovirus infection in subjects by administering effective amounts of the humanized antibodies or fragments.
Use of antibodies prophylactically prior to exposure to Ebola virus, including the Sudan strain.
Use of antibodies as post-exposure therapy for filovirus infections.
Diagnostic applications involving detection of filovirus in samples using the antibodies.
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