Identification of antibodies specific for at least two different lyssaviruses
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-9809643-B2
Publication Date
2017-11-07
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 a fatal but preventable disease that remains a significant endemic burden in developing countries, with approximately 55,000 deaths annually worldwide. Post-exposure prophylaxis (PEP) typically involves wound washing, vaccination, and administration of rabies immunoglobulin (RIG), but the availability of RIG is extremely limited in many regions. Additionally, the safety concerns of equine and human-derived RIGs limit their usage, highlighting the need for alternative treatments.
The invention discloses a method of identifying monoclonal antibodies or antigen-binding fragments that specifically bind a plurality of lyssaviruses, including rabies virus and other related lyssaviruses such as Mokola virus and West Caucasian bat virus. This method uses a naïve human antibody phage display library screened against recombinant viruses or glycoproteins from multiple lyssaviruses to select phage clones that bind at least two different lyssavirus glycoproteins or viruses. Identified antibodies can be used for post-exposure rabies prophylaxis or treatment of clinical rabies.
This approach addresses the limitations of current human monoclonal antibody selections, which depend on the diversity of viral antigens used to immunize human donors and tend to neutralize only rabies virus genotype 1. The disclosed method uses a naïve antibody phage library to identify broadly neutralizing antibodies that bind multiple lyssaviruses, thereby potentially improving the breadth and efficacy of rabies prophylaxis and treatment.
Claims Coverage
The claims include one independent claim, which defines a monoclonal antibody or antigen-binding fragment that specifically binds at least two different lyssaviruses or their glycoproteins.
Isolated monoclonal antibody or antigen-binding fragment that binds at least two lyssaviruses
An isolated monoclonal antibody, or antigen-binding fragment, comprising a variable heavy (VH) domain with complementarity determining regions (CDR1, CDR2, CDR3) encoded by the nucleotide sequences of SEQ ID NO: 44, that specifically binds at least two different lyssaviruses or glycoproteins thereof.
Specific lyssavirus targets for antibody binding
The antibody specifically binds at least two lyssaviruses selected from rabies virus (RABV), Mokola virus (MOKV), West Caucasian bat virus (WCBV), Lagos bat virus (LBV), and Duvenhage virus (DUVV).
Inclusion of variable light domain
The antibody optionally comprises a variable light (VL) domain derived from a rabies virus-specific antibody.
Antibody isotype and humanization
The antibody can be an IgG isotype and may be a human or humanized antibody.
Antigen-binding fragment formats
The antigen-binding fragment can take the form of a Fab, Fab', F(ab')2, single chain Fv protein (scFv), or disulfide stabilized Fv protein (dsFv).
Sequence identity and nucleotide sequence encoding antibody domains
The VH domain of the antibody or fragment is encoded by a nucleotide sequence at least 95% identical to SEQ ID NO: 44 and includes the VH domain CDRs encoded by SEQ ID NO: 44; the nucleotide sequence encoding the VH domain may be SEQ ID NO: 44 itself.
Isolated immunoconjugate with fusion partner
An isolated immunoconjugate comprising the monoclonal antibody and a fusion partner such as an effector molecule, a label, or a heterologous polypeptide.
Pharmaceutical compositions including the antibody
Compositions comprising the monoclonal antibody or antigen-binding fragment and a pharmaceutically acceptable carrier, optionally combined with an additional monoclonal antibody specific for RABV or RABV glycoprotein.
The claims cover isolated monoclonal antibodies and antigen-binding fragments binding multiple lyssaviruses or their glycoproteins, defined by specific VH domain sequences and CDRs, various antibody formats, and compositions including immunoconjugates and pharmaceutical formulations for therapeutic use.
Stated Advantages
Human monoclonal antibodies can be produced in a cost-effective manner compared to RIG.
Use of human monoclonal antibodies reduces the likelihood of adverse immune reactions compared to equine RIG.
The antibodies identified exhibit broad lyssavirus neutralizing activity, potentially overcoming the limited cross-reactivity of current anti-rabies immunoglobulins.
Broader neutralization enables treatment and post-exposure prophylaxis against multiple lyssaviruses beyond genotype 1 rabies virus.
The use of naïve antibody phage display libraries circumvents biases from immunized donors enhancing antibody diversity and breadth.
Documented Applications
Use of identified monoclonal antibodies or antigen-binding fragments for post-exposure rabies prophylaxis.
Treatment of clinical rabies in subjects.
Administration to subjects bitten by potentially rabid animals, including injection directly into wounds and adjacent tissue.
Use in pharmaceutical compositions with carriers for systemic or local administration.
Combining monoclonal antibodies with rabies vaccines to enhance prophylaxis.
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