Therapy for filovirus infection
Inventors
Lai, Jonathan R. • Koellhoffer, 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-9346875-B2
Publication Date
2016-05-24
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 invention provides isolated humanized antibodies that target the filovirus glycoprotein pre-fusion core, specifically comprising framework regions with at least 95% sequence identity to human antibody frameworks and certain defined complementarity-determining regions (CDRs) in the heavy and light chains. These antibodies bind to the conserved GP1-GP2 prefusion core of filovirus glycoproteins and neutralize the virus by inhibiting fusion-associated conformational changes required for viral entry into host cells.
The problem addressed is the lack of FDA-approved treatments for filovirus infections such as Ebola virus (EBOV) and Marburg virus (MARV), which cause high mortality hemorrhagic fevers with rapid disease progression and dysregulation of the host immune response. Existing neutralizing antibodies like KZ52 and 16F6 have limitations related to neutralization potency or non-human origin, limiting their therapeutic utility. Therefore, there is a need for improved antibody-based therapeutics that can effectively treat or prevent filovirus infections post-exposure or prophylactically.
Claims Coverage
The patent presents one independent claim detailing an isolated humanized antibody targeting filovirus glycoprotein pre-fusion core, followed by dependent claims and related methods and compositions. Main inventive features focus on antibody structure, sequences, compositions, and therapeutic methods.
Humanized antibody targeting filovirus glycoprotein pre-fusion core
An isolated humanized antibody comprising a framework region with ≥95% identity to a human antibody framework region, containing heavy chain CDR1 with GFAFNYYDM/I/LH (SEQ ID NO:1), heavy chain CDR2 with YINPGGGNTYYADSV (SEQ ID NO:2), heavy chain CDR3 with QLYGNSFMDY (SEQ ID NO:3), and a light chain sequence including CDR3 comprising HYSTPLT (SEQ ID NO:5). The light chain also comprises specified sequences DIQMTQSPSSLSASVGDRVTITCK/R/QASQDVTTAVAWYQQKPGKAPKL (SEQ ID NO:12) and LIYAASRLHNGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ (SEQ ID NO:14).
Specific heavy and light chain sequences for the antibody
The antibody's heavy chain comprises sequences such as EVQLVESGGGLVQPGGSLRLSCAASGFAFNYYDIHWVRQAPGKGLE (SEQ ID NO:6), WVAYINPGGGNTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTA (SEQ ID NO:9), and VYYCARQLYGNSFMDYWGQGTLVTV (SEQ ID NO:10). The light chain includes sequence HYSTPLTFGQGTKVFI (SEQ ID NO:16).
Composition comprising the humanized antibody or antigen-binding fragment
A composition is provided that includes the described humanized antibody or an antigen-binding fragment thereof, optionally combined with a pharmaceutically acceptable carrier.
Methods for treating or inhibiting filovirus infection using the antibody
Methods to inhibit or treat filovirus infection (specifically Ebola virus, including the Sudan strain) in a subject by administering an effective amount of the humanized antibody or its antigen-binding fragment, either prior to or after exposure to the virus, leveraging defined heavy and light chain CDR sequences for efficacy.
The claims collectively cover isolated humanized antibodies targeting the filovirus glycoprotein pre-fusion core with defined CDR sequences, their compositions for pharmaceutical use, and methods of treatment or inhibition of filovirus infections including Ebola virus, emphasizing structural specificity and therapeutic applications.
Stated Advantages
Antibody-based EBOV therapy is feasible, protective, and can be administered post-exposure.
Humanized antibodies provide improved therapeutic relevance compared to murine antibodies like 16F6 due to reduced immunogenicity.
Synthetic antibody engineering allows identification of antibodies with enhanced neutralization potency and tailored properties.
The method permits prophylactic and acute treatment of filovirus exposure, potentially increasing patient survival by reducing viral load and permitting effective immune response.
Documented Applications
Treatment of filovirus infections in subjects using humanized anti-filovirus glycoprotein pre-fusion core antibodies or their antigen-binding fragments.
Prophylactic administration of the antibodies prior to exposure to filovirus to inhibit infection.
Post-exposure therapy to inhibit or treat filovirus infection after exposure, especially Ebola virus including the Sudan strain.
Use of antibody compositions comprising the humanized antibodies and pharmaceutically acceptable carriers for therapeutic administration.
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