Identification of antibodies specific for lyssaviruses and methods of their use
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10400031-B2
Publication Date
2019-09-03
Expiration Date
2031-10-18
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Abstract
Described herein is a method of identifying a monoclonal antibody (or antigen-binding fragment thereof) that specifically binds a plurality of lyssaviruses for use in post-exposure rabies prophylaxis or in the treatment of clinical rabies. The method includes using a naïve antibody phage display library to screen for phage clones that bind whole recombinant rabies virus or cells expressing glycoprotein from multiple lyssaviruses (such as RABV, MOKV and WCBV) and/or specifically bind recombinant glycoprotein from different lyssaviruses.
Core Innovation
Rabies is an invariably fatal disease that can be prevented with prompt and proper post-exposure treatment, which currently includes wound cleansing followed by administration of vaccine and anti-rabies virus immunoglobulin (RIG). However, availability of RIG is limited, especially in developing countries, and existing RIG products, whether human or equine derived, have associated limitations such as risk of anaphylactic shock or blood-born pathogen transmission.
The invention addresses the problem that current post-exposure prophylaxis relies on RIG or monoclonal antibodies generated from immunized humans, which mainly neutralize genotype 1 rabies virus and have limited cross-reactivity against other lyssavirus genotypes. There is a need for broadly neutralizing antibodies that can target multiple lyssaviruses, improving treatment and prophylaxis effectiveness.
The disclosed invention provides a method of identifying monoclonal antibodies or antigen-binding fragments that specifically bind to multiple different lyssaviruses by screening a naïve human antibody phage display library against recombinant viruses or glycoproteins from various lyssaviruses such as rabies virus (RABV), Mokola virus (MOKV), West Caucasian bat virus (WCBV), Lagos bat virus (LBV), and Duvenhage virus (DUVV). This approach circumvents the limitations of diversity in antibodies derived from immunized donors.
The identified antibodies exhibit specificity to at least two different lyssaviruses or their glycoproteins. Such antibodies, including their variable heavy (VH) domains encoded by nucleotide sequences substantially identical to SEQ ID NOs: 1-110, can be used for therapeutic and prophylactic applications against rabies caused by multiple lyssavirus genotypes. The invention also contemplates expression of these antibodies from vectors and their use in compositions for clinical application.
Claims Coverage
The patent contains one independent claim and multiple dependent claims covering novel monoclonal antibodies and their uses.
Broadly lyssavirus-specific monoclonal antibodies
An isolated monoclonal antibody, or antigen-binding fragment thereof, that specifically binds at least two different lyssaviruses or their glycoproteins, comprising a variable heavy (VH) domain with complementarity determining regions (CDR1, CDR2, CDR3) encoded by nucleotide sequences of SEQ ID NOs: 45-110.
Specific lyssavirus selection
The at least two lyssaviruses targeted are selected from rabies virus (RABV), Mokola virus (MOKV), West Caucasian bat virus (WCBV), Lagos bat virus (LBV), and Duvenhage virus (DUVV).
Antibody structure and type
The antibody may comprise a variable light (VL) domain from a rabies virus-specific antibody, and can be an IgG, human antibody, or humanized antibody. The antigen-binding fragment includes Fab, Fab′, F(ab)′2, single chain Fv protein (scFv), or disulfide stabilized Fv protein (dsFv).
Sequence identity of VH domain
The VH domain may be encoded by a nucleotide sequence at least 95% identical to SEQ ID NOs: 102-110, encoding the corresponding CDRs.
Immunoconjugates and fusion partners
Isolated immunoconjugates comprising the antibody and a fusion partner, which may be an effector molecule, label, or heterologous polypeptide.
Pharmaceutical compositions and combinations
Compositions comprising the monoclonal antibodies with pharmaceutically acceptable carriers or in combination with monoclonal antibodies specific for RABV or RABV glycoprotein.
Therapeutic method
A method of treating rabies by administering the monoclonal antibody or antigen-binding fragment to a subject, providing therapeutic benefit.
The claims cover isolated antibodies broadly binding multiple lyssaviruses via specified VH domain sequences, their immunoconjugates, pharmaceutical compositions, and their therapeutic use for rabies treatment.
Stated Advantages
Broad neutralization of multiple lyssavirus genotypes beyond genotype 1, overcoming limitations of existing immunoglobulins and monoclonal antibodies.
Reduced likelihood of adverse immune responses compared to equine or human RIG, improving safety.
Cost-effective production of cell-cultured human monoclonal antibodies.
Potential for improved efficacy in post-exposure prophylaxis and treatment of clinical rabies due to broader lyssavirus coverage.
Documented Applications
Post-exposure rabies prophylaxis by administering antibodies that specifically bind multiple lyssaviruses to subjects exposed to potentially rabid animals.
Treatment of clinical rabies in subjects diagnosed with rabies through administration of isolated monoclonal antibodies or antigen-binding fragments.
Use of antibodies in compositions for systemic or local administration, including administration at wound sites.
Generation of expression vectors encoding the antibodies and production in host cells, facilitating therapeutic antibody production.
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