WO2019227039A1

WO2019227039A1 - Compositions comprising antibodies to rabies virus and the uses thereof

Info

Publication number: WO2019227039A1
Application number: PCT/US2019/033995
Authority: WO
Inventors: Scott K. Dessain
Original assignee: Lankenau Institute For Medical Research
Priority date: 2018-05-24
Filing date: 2019-05-24
Publication date: 2019-11-28

Abstract

Anti-rabies antibodies, epitope-binding fragments, and compositions containing one or more of such antibodies or fragments are disclosed, as are uses of these compositions for treating, preventing or delaying the onset or severity of rabies virus infection.

Description

COMPOSITIONS COMPRISING ANTIBODIES TO RABIES VIRUS AND THE USES THEREOF

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED IN

ELECTRONIC FORM

Applicant hereby incorporates by reference the Sequence Listing material filed in electronic form herewith. This file is labeled "MLHl05PCT_20l90523_

SequenceListing_ST25.txt", prepared May 24, 2019 and is 36,864 bytes in size. BACKGROUND OF THE INVENTION

Rabies, being a major zoonotic disease, significantly impacts global public health. It is invariably fatal once clinical signs are apparent. The majority of human rabies deaths occur in developing countries. According to the CDC, more than 55,000 people, mostly in Africa and Asia, die from rabies every year - a rate of one person every ten minutes. India alone reports more than 50% of the global rabies deaths. Despite evidence that control of dog rabies through programs of animal vaccination and elimination of stray dogs can reduce the incidence of human rabies, exposure to rabid dogs is still the cause of over 90% of human exposures to rabies and of over 99% of human deaths worldwide. Because vaccines to prevent human rabies have been available for more than 100 years, most deaths from rabies occur in countries with inadequate public health resources and limited access to preventive treatment. These countries also have few diagnostic facilities and almost no rabies surveillance. The cost of these rabies prevention programs prohibits their full implementation in much of the developing world, and in even the most prosperous countries the cost of an effective dog rabies control program is a drain on public health resources.

The estimated annual expenditure for rabies prevention in the United States is over US$300 million, most of which is spent on dog vaccinations. An annual turnover of approximately 25% in the dog population necessitates revaccination of millions of animals each year, and reintroduction of rabies through transport of infected animals from outside a controlled area is always a possibility should control programs lapse. Cell culture rabies vaccines have become widely available in developing countries. Currently, rabies vaccines made from inactivated cell cultures include human diploid cell vaccine (Imovax Rabies) and Purified Chick Embryo Cell Vaccine (Rab Avert) and are well tolerated. Although it is a vaccine-preventable disease, effective rabies prevention in humans for post-exposure cases (i.e., category III bites) can require the combined administration of both rabies immunoglobulin (RIG) and vaccine. In still other instances, passive immunization with human anti-rabies immunoglobulin is valuable particularly in children and adults who have weakened immune systems or may not be good candidates for routine vaccinations for other reasons. It can be used with people who haven’t been vaccinated against a disease to which they’ve been exposed. For example, the passive rabies immunization (rabies immune globulin) is commonly used after a certain type of wild animal bites a child.

SUMMARY OF THE INVENTION

In one aspect, a recombinant, synthetic or monoclonal human antibody of an IgG class that binds to a rabies virus epitope, or a fragment of said antibody that binds a rabies virus epitope, is provided. The antibody or fragment comprises in one aspect, a heavy chain variable domain sequence that is an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 11, 3, 5, 7, or 1 or an amino acid sequence at least 80% identical to SEQ ID NO: 9, 11, 3, 5, 7, or 1. In another aspect, the antibody or fragment comprises a light chain variable domain sequence that is an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 12, 4, 6, 8 or 2 or an amino acid sequence at least 80% identical to these sequences. In still another embodiment, truncations and/or modifications of these sequences SEQ ID NO: 1-12 are described.

In still another aspect, the antibody or fragment comprises both heavy chain and light chain variable regions from among those SEQ ID Nos identified herein. In a further embodiment, the antibody comprises a heavy chain and light chain sequence of SEQ ID NOs: 9 and 10, referred to as antibody 8C5. In a further embodiment, the antibody comprises a heavy chain and light chain sequence of SEQ ID NOs: 11 and 12, referred to as antibody 10H5. In a further embodiment, the antibody comprises a heavy chain and light chain sequence of SEQ ID NOs: 3 and 4, referred to as antibody 4H3. In a further embodiment, the antibody comprises a heavy chain/light chain sequence of SEQ ID NOs: 5 and 6, referred to as antibody 7A2. In another embodiment, the antibody comprises a heavy chain and light chain sequence of SEQ ID NOs: 7 and 8, referred to as antibody 7E8. In a further embodiment, the antibody comprises a heavy chain and light chain sequence of SEQ ID NOs: 1 and 2, referred to as antibody 4C12.

In another aspect, a pharmaceutical composition for the prevention or treatment of rabies infection is provided that comprises at least one antibody or epitope-binding fragment or modification thereof described herein and a pharmaceutically acceptable carrier.

In another aspect, nucleic acid sequences encoding the antibody fragments, and constructs (e.g., vectors or plasmids) containing the coding sequences, as well as compositions containing the nucleic acid sequences, vectors, or plasmids are also provided.

In another aspect, a method for preventing rabies infection in an uninfected subject comprises administering an effective amount of a single antibody or epitope binding fragment or modification thereof as described herein. In another aspect, a method for preventing rabies infection in an uninfected subject comprises administering an effective amount of a mixture of antibodies or fragments described herein.

In another aspect, a method for preventing rabies infection in a subject suspected of having rabies infection comprises administering an effective amount of a single antibody or epitope binding fragment or modification thereof as described herein. In another aspect, a method for preventing rabies infection in a subject suspected of having rabies infection comprises administering an effective amount of a mixture of antibodies or fragments described herein.

In another aspect, a method for treating a subject infected with rabies virus comprises administering an effective amount of a single antibody or epitope binding fragment or modification thereof. In another aspect, a method for treating a subject infected with rabies virus comprises administering an effective amount of a mixture of antibodies or fragments as described herein.

Methods of generating the antibodies, using the nucleic acid sequences and formulating the pharmaceutical compositions are also provided.

Other aspects and advantages of these methods and compositions are described further in the following detailed description. BRIEF DESCRIPTION OF THE FIGURES

FIGs. 1A, 1B and 1C identify the heavy and light chain amino acid sequences of anti-rabies antibodies 4C12, 4H3, 7A2, 7E8, 8C5 and 10H5 with accompanying SEQ ID Nos and with the CDR sequences highlighted in each sequence. The symbols used in the figures are: HC = heavy chain; LLC = lambda light chain; KLC = kappa light chain; numbers in brackets denote the sequence length.

FIGs. 2A, 2B, 2C and 2D provide the nucleotide sequences encoding the heavy and light chains of anti-rabies antibodies 4C12, 4H3, 7A2, 7E8, 8C5 and 10H5 with accompanying SEQ ID NOs and with the CDR-encoding sequences highlighted in each sequence. The symbols used in the figures are: HC = heavy chain; LLC = lambda light chain; KLC = kappa light chain; numbers in brackets denote the sequence length.

DETAILED DESCRIPTION OF THE INVENTION

As disclosed herein, a recombinant, synthetic and/or monoclonal antibody that binds to a rabies virus epitope, or a fragment of the antibody that binds a rabies virus epitope, is provided. In certain embodiments, the antibody is a human antibody. In certain embodiments, the antibody is a human antibody of an IGG class. In one embodiment, an anti-rabies antibody comprises a heavy chain variable domain sequence that is an amino acid sequence comprising SEQ ID NO: 9, 11, 3, or 5, or an amino acid sequence at least 80% identical thereto. In another embodiment an anti-rabies antibody comprises a heavy chain variable domain sequence that is an amino acid sequence comprising SEQ ID NO: 7 or 1 or an amino acid sequence at least 80% identical thereto. Such antibody or antigen-binding fragment(s) can also include a light chain variable domain sequence that is an amino acid sequence comprising SEQ ID Nos: 10, 12, 4, or 6 or an amino acid sequence at least 80% identical thereto. In another embodiment, such an antibody or antigen-binding fragment can also include a light chain variable domain sequence that is an amino acid sequence of SEQ ID NO: 8 or 2 or an amino acid sequence at least 80% identical thereto. Such antibodies or fragments useful for inclusion in passive immunization formulae for the treatment of post-exposure rabies subjects, among other uses.

Components Utilized in the Compositions and Methods

"Antibody" refers to a molecule that is capable of specifically complexing with, binding to, identifying or detecting an epitope of an antigen, e.g., a rabies virus epitope. Unless otherwise indicated, the term "antibody" includes, in addition to antibodies comprising two full-length heavy chains (each chain comprising a variable region and a constant region) and two full-length light chains (each chain comprising a variable region and a constant region), modifications, antigen or epitope binding fragments, as well as “antibody mimics” or“antibody equivalents” or muteins thereof. In one embodiment, an "antibody" refers to an intact immunoglobulin, such as an IgA, IgD, IgE, IgG, and IgM, or to an antigen binding portion thereof that competes with the intact antibody for specific binding, unless otherwise specified. In one embodiment, an intact antibody is an IgGl, IgG2, IgG3 or IgG4. Heavy and light chain variable domain sequences and CDRs may be selected from those described herein in Tables A through M and in the Figures and Sequence Listing, e.g., SEQ ID NOs: 1-24.

As used herein, an“antibody” or“antigen/epitope binding fragment” as described herein refers to an anti-rabies antibody or fragment thereof based upon the sequences defined herein. Such an antibody or fragment includes a monoclonal antibody, a synthetic antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, a multispecific binding construct that can bind two or more epitopes, a dual specific antibody, a bi-specific antibody, a multi-specific antibody, an affinity matured antibody, a single antibody chain or an scFv fragment, a diabody, a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs, an Fv construct, a disulfide-linked Fv, a Fab construct, a Fab' construct, a F(ab')₂ construct, an Fc construct, a monovalent or bivalent construct from which domains non- essential to monoclonal antibody function have been removed, a single-chain molecule containing one VL (variable region of light chain), one VH (variable region of heavy chain) antigen-binding domain, and one or two constant“effector” domains optionally connected by linker domains, a univalent antibody lacking a hinge region, a single domain antibody, a dual variable domain immunoglobulin (DVD-Ig) binding protein or a nanobody, or any recombinant versions thereof. Definitions and examples of these types of structures are found in the art and in, e.g., US Patent No. 9,902,772, incorporated by reference herein.

"Recombinant antibody" refers to an antibody that is expressed from a cell or cell line transfected with one or more expression vectors comprising a coding sequence of the antibody, where said coding sequence is not naturally associated with the cell or naturally occurred in the cell. Said cell may be termed as a host cell. In certain embodiments, the host cell may be a non-human cell or non-human cell line. In certain embodiments, the host cell may be a non-mammalian cell or cell line, for example, an insect cell or cell line, a yeast cell or cell line, or an E coli cell or cell line. In certain embodiments, the host cell may be a mammalian cell or cell line. In certain embodiments, the host cell may be a non human mammalian cell or cell line. In certain embodiments, the host cell may be a human cell or cell line, for example a human embryonic kidney 293 cells or a hybridoma cell or cell line. In one embodiment, a recombinant antibody has a glycosylation pattern that is different than the glycosylation pattern of an antibody having the same sequence if it were to exist in nature. In one embodiment, a recombinant antibody is expressed in a mammalian host cell which is not a human host cell. Notably, individual mammalian host cells have unique glycosylation patterns.

Methods for producing such antibodies are well-known in the art. Indeed, commercial vectors for certain antibody and antibody fragment constructs are available. The antibody may also be a protein (e.g., a fusion protein) comprising at least one antibody or antibody fragment. In a particular embodiment, the antibody comprises an Fc region. In particular embodiments, these anti-rabies antibodies and fragments thereof have a binding affinity (Ka) for a rabies virus epitope of at least 10³M. In other embodiments, the antigen binding proteins exhibit a Ka of at least 10³ M, at least 10⁴ M, at least 10⁵, or at least 10⁶.

As used herein, an“antibody mimic” or an“antibody equivalent” refers to a molecule (for example, an amino acid sequence, a protein, or a modified or conjugated version thereof). For example, affibodies, /. e.. a class of engineered affinity proteins, generally small (~6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given target, aptamers, polypeptide molecules that bind to a specific target, an affilin, an affitin, an affimer, an alphabody, an anticalin, an avimer, a DARPin (designed ankyrin repeat proteins), a Fynomer, a Kunitz domain peptide, a monobody, a peptabody and others known in the art.

As used herein, a“modification” of an amino acid sequence (e.g. , antibody or a fragment thereof) comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from, or substituted into the reference amino acid sequence, e.g., any of amino acid sequence encoding the variable light or heavy chains, and/or CDRs of antibodies 10H5 or 4H3 or 8C5 or 7A2 or 4C12 or 7E8. One such modification is the replacement of one amino acid in such a sequence, e.g., any of SEQ ID NO: 1 to 24, with a conservative amino acid. Other modifications include, for example, fusion proteins formed by fusing the heavy chain of a selected antibody into an Ig backbone. Still another modification includes an anti-rabies antibody that has been modified via conjugation to another chemical moiety (such as, for example, polyethylene glycol or albumin, e.g., human serum albumin), or a post-translational modification, such as phosphorylation, glycosylation, acylation, acetylation, formylation, alkylation, amidation, arginylation, polyglutamylation, polyglycylation, butyrylation, gamma- carboxylation, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester or phosphoramidate, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, S-sulfmylation, S-sulfonylation, succinylation addition of a succinyl group to lysine, and sulfation. In another embodiment, a modification of any of antibodies 10H5 or 4H3 or 8C5 or 7A2 or 4C12 or 7E8 is a single chain human antibody, having a variable domain region from a heavy chain and a variable domain region from a light chain and a peptide linker connecting the heavy chain and light chain variable domain regions.

As used herein, an antibody construct (e.g., an antibody, an antibody heavy chain, an antibody light chain, or any fragment or modification thereof) comprises three

Complementarity-Determining Regions (CDRs, also known as HV, hypervariable regions, namely CDR1, CDR2, CDR3, from N-terminal to C-terminal, or 5’ to 3’ when corresponding nucleic acid sequence is referred to), and four framework regions (FRs, namely FR1, FR2, FR3 and FR4, from N-terminal to C-terminal, or 5’ to 3’ when corresponding nucleic acid sequence is referred to). See, e.g., Janeway, Charles A Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J (2001). Immunobiology: The Immune System in Health and Disease (5 ed.). New York: Garland Science. ISBN 0-8153-3642 -X, which is incorporated herein by its entirety. It would be understood that in the antibody construct, CDRs are arranged non-consecutively, not immediately adjacent to each other, and may be separated by an FR. As part of the variable chain in an antibody construct and T cell receptors generated by B-cells and T-cells respectively, CDRs are where an antigen specifically binds. FIGs 1 A to 2C, the incorporated Sequence Listing, and Tables A through M below depict several examples of antibody constructs via their amino acid sequences, nucleic acid coding sequences, and other regions. Framework regions (FRs) 1 to 3 and CDR 1 to 3 are also identified in the Sequence Listing. Additionally, V-region, D-region if available, and J-region from the perspective of V(D)J recombination are also noted in the Sequence Listing.

V(D)J recombination or rearrangement is a process by which T cells and B cells randomly assemble different gene segments - known as variable (V), diversity (D) and joining (J) genes (or regions, or segments, as used herein) - in order to generate unique receptors (known as antigen receptors) that can collectively recognize many different types of antigens. Briefly, the germ line (unrearranged) genomic DNA configuration of the immunoglobulin heavy chain locus comprises the tandem arrays of V, D, and J gene segments. A germ line kappa or lambda light chain locus comprises unrearranged V and J segments. Stepwise rearrangement of the germ line DNA results in the joining of a heavy chain D and J gene segment, followed by joining of a V segment to the D-J product, to generate the DNA encoding the heavy chain variable region. In the process of

rearrangement, the ends of the gene segments are subject to variable amounts of exonuclease digestion and randomized non-templated bases are added at the segment ends, to produce additional sequence diversity at the VDJ junctional region that encodes the complementarity-determining region 3 (CDR3), which is often the region of the antibody heavy chain that has the greatest impact on antigen specificity. A similar process of V and J gene rearrangement with diversification of the VJ junction occurs in the light chain locus, to produce the rearranged light chain gene. See, e.g., Boyd et al, High-Throughput DNA Sequencing Analysis of Antibody Repertoires Microbiology Spectrum. 2.

10.1 l28/microbiolspec.AID-00l7-20l4, which is incorporated herein by its entirety.

It would be understood by one of skill in the art that, the antibody constructs, fragments or modifications, and CDR described herein may be used in any embodiment, composition, reagent, or method, including those also described herein. It would also be understood that, an antibody, antibody construct, fragment or modification provided herein may comprise an FR or a non-CDR J-region, other than those identified provided in the incorporated Sequence Listing. Such an antibody, antibody construct, fragment or modification may have a binding affinity and/or specificity to its antigen at about 20%, about 40% , about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 97%, about 99%, about 100%, more than about 100%, about 200%, about 300%, or about 500% of that of any antibody construct described in Tables A-M or elsewhere in this specification. Conventional methods, including enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), MSD assay, and antibody phage display library, may be used to determine such binding affinity and/or specificity.

An "epitope" as used herein refers to the portion of a rabies virus protein or any naturally occurring or synthetic or recombinant amino acid sequence that is capable of specifically complexing with one or more of the antibodies 10H5 or 4H3 or 4C12 or 7E8 or 8C5 or 7A2, or fragments or modified antibodies, as described herein. An epitope can comprise non-contiguous portions of the molecule (e.g., in a polypeptide, amino acid residues that are not contiguous in the polypeptide's primary sequence but that, in the context of the polypeptide's tertiary and quaternary structure, are near enough to each other to be bound by an antigen binding protein). Specific embodiments of a rabies virus antibody are defined in detail below.

As used herein, "disease", "disorder" and "condition" are used interchangeably, to indicate an abnormal state in a subject. In one embodiment, the disease is infection by a rabies virus. In certain embodiments, the condition is a post-exposure suspected rabies infection. In certain embodiments, the condition is a pre-exposure suspected rabies infection.

“Patient” or“subject” as used herein means a male or female mammalian animal, including a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research. In one embodiment, the subject of these methods and compositions is a human. In one embodiment, the subject of these methods and compositions is a male or female human who has an existing rabies infection. In one embodiment, the subject of these methods and compositions is a patient suspected of or having rabies infection due to exposure to rabies virus. In one embodiment, the subject of these methods and compositions is a patient pre-exposure to rabies virus, e.g., a visitor to an environment wherein rabies virus is endemic.

The terms“percent (%) identity”,“sequence identity”,“percent sequence identity”, or“percent identical” in the context of amino acid sequences or nucleotide sequences refers to the residues in the two sequences which are the same when aligned for correspondence. Percent identity may be readily determined for amino acid sequences or nucleotide sequences over the full-length of a protein, polypeptide, or encoding region thereof, e.g., about 15 amino acids, about 150 amino acids, or a peptide fragment thereof or the corresponding nucleic acid sequence coding sequences. A suitable amino acid fragment may be at least about 4 amino acids in length and may be up to about 200 or up to about 700 amino acids or nucleotide fragments of from about 12 nucleotides to about 600 to 2100 nucleotides. Generally, when referring to“identity”,“homology”, or “similarity” between two different sequences,“identity”,“homology” or“similarity” is determined in reference to“aligned” sequences. “Aligned” sequences or“alignments” refer to multiple nucleic acid sequences or protein (amino acids) sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Alignments are performed using any of a variety of publicly or commercially available Multiple Sequence Alignment Programs. Sequence alignment programs are available for amino acid sequences, e.g., the“Clustal Omega”,“Clustal X”, “MAP”,“PIMA”,“MSA”,“BLOCKMAKER”,“MEME”, and“Match-Box” programs. Generally, any of these programs are used at default settings, although one of skill in the art can alter these settings as needed. Alternatively, one of skill in the art can utilize another algorithm or computer program which provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. See, e.g., (THOMPSON et al. 1999).

As used herein, the“conservative amino acid replacement” or“conservative amino acid substitutions” refers to a change, replacement or substitution of an amino acid to a different amino acid with similar biochemical properties (e.g. charge, hydrophobicity and size), which is known by practitioners of the art. Also see, e.g. FRENCH et al. 1983, and YAMPOLSKY et al. 2005. In certain embodiments, a CDR of the disclosed antibody or fragment thereof is free of conservative amino acid replacement.

As used herein, the term "immunologically specific" refers to proteins or polypeptides, particularly antibodies, that bind to one or more epitopes of a protein or compound of interest, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic biological molecules. The term "prevent" refers to the prophylactic treatment of a subject who is at risk of developing rabies when the treatment is administered pre-exposure to the virus or post exposure, resulting in a decrease in the probability that the subject will develop rabies.

The term "treat" as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, or reduction in severity of the infection and symptoms of rabies, etc.

It should be understood that while various embodiments in the specification are presented using“comprising” language, under various circumstances, a related

embodiment is also described using“consisting of’ or“consisting essentially of’ language. “Comprising” is a term meaning inclusive of other components or method steps. When“comprising” is used, it is to be understood that related embodiments include descriptions using the“consisting of’ terminology, which excludes other components or method steps, and“consisting essentially of’ terminology, which excludes any

components or method steps that substantially change the nature of the embodiment or invention.

With regard to the description of these inventions, it is intended that each of the compositions herein described, is useful, in another embodiment, in the methods of the invention. In addition, it is also intended that each of the compositions herein described as useful in the methods, is, in another embodiment, itself an embodiment of the invention.

It is to be noted that the term“a” or“an”, refers to one or more, for example,“a Target”, is understood to represent one or more Target(s). As such, the terms“a” (or“an”), “one or more,” and“at least one” is used interchangeably herein.

As used herein, the term“about” means a variability of plus or minus 10 % from the reference given, unless otherwise specified.

Unless defined otherwise in this specification, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and by reference to published texts, which provide one skilled in the art with a general guide to many of the terms used in the present application. Antibodies, Fragments and Methods of Producing Antibodies

The production of antibodies or fragments that specifically bind to a rabies epitope, can employ conventional techniques utilizing any of the amino acid sequences of the heavy chain and light chain variable regions SEQ ID Nos: 1 to 12, or the nucleotide sequences encoding same, i.e., SEQ ID Nos: 13 to 24, respectively or the other fragments of the antibodies identified in Tables A - M, including epitope binding fragments, or modifications thereof as described. In one embodiment, polyclonal antibody compositions are typically produced by immunizing a selected mammal, e.g., a primate, rodent, or human, with a peptide/ polypeptide composition containing a specific epitope. The selection of high titer, high affinity polyclonal antibodies can be monitored by standard techniques, such as with an enzyme-linked immunosorbent assay and surface plasma resonance. If desired, the polyclonal antibody molecules can be isolated from the mammal, e.g., from the whole blood, plasma or serum, and further purified from the plasma or serum of the immunized mammal by conventional techniques. Conventional harvesting techniques can include plasmapheresis, protein A and G chromatography, among others. Such polyclonal antibody compositions may themselves be employed as pharmaceutical compositions of this invention.

In another embodiment, monoclonal antibodies can be generated to any one of the epitopes by now conventional techniques, using antibody producing cells obtained from the immunized mammals and fused to non-IgG-producing myeloma cells to form hybridomas or from selection from activated immune B cells with extraction by known molecular biological techniques. These monoclonal antibodies can be further used to prepare other forms of antibodies, e.g., chimeric antibodies, humanized antibodies, human antibodies. Other antibody fragments or ligands can be produced by screening phage display libraries, antibody fragments and mixtures thereof. Techniques for generating these types of antibodies and ligands are well-known in the art and the ligands themselves may be generated using the disclosed amino acid sequences of the above-identified epitopes.³²·^{35 39}

Chimeric antibodies may similarly be developed using known techniques.

Chimeric antibodies are molecules in which different portions are derived from different animal species. Single chain antibodies may also be prepared by conventional methods, such as described in US Patent Nos. 4,946,778 and 4,704,692 using the variable portions of the polyclonal or monoclonal antibodies produced according to this invention.

Antibody fragments, such as the Fab, F(ab)2 and scFv fragments and libraries thereof may also be employed in generation of the selective anti-TNF monomer-specific antibodies or ligands as described herein.

The production of bi-specific antibodies or ligands that specifically bind to two or more selected epitopes, can employ conventional techniques. See, e.g., Homig N, Farber- Schwarz A.,“Production of bispecific antibodies: diabodies and tandem scFv.”, 2012, Methods Mol Biol., 907:713-27; Speiss, C. et al,” Bispecific antibodies with natural architecture produced by co-euiture of bacteria expressing two distinct half-antibodies, M 7, 2013, Nature Biotechnology, 31 :753-758; and Jonathan S Martin and Zhenping Zhu, “Recombinant approaches to IgG-like bispecific antibodies”, 2005 Acta Pharmacologica Sinica, 26: 649-658.

The availability of nucleic acid molecules encoding the heavy and light chains of the antibody also enables production of a recombinant antibody, fragment or modification using in vitro expression methods and cell-free expression systems known in the art. In vitro transcription and translation systems are commercially available, e.g., from Promega Biotech (Madison, WI) or Gibco-BRL (Gaithersburg, MD). The antibodies, epitope binding fragments or modifications thereof may also be produced by expression in a suitable prokaryotic or eukaryotic system. Similarly modifications may be inserted by use of a variety of CRISPR techniques and other related, e.g., zinc finger, methodologies for modifying amino acid and nucleotide sequences. Antibody recombinant engineering techniques are well-taught in the art including in publications, texts and reviews, such as Edwards, W. B., Xu, B., Akers, W., Cheney, P. P., Liang, K., Rogers, B. E., et al. (2008). Agonist-antagonist dilemma in molecular imaging: evaluation of a monomolecular multimodal imaging agent for the somatostatin receptor. Bioconjug. Chem. 19, 192-200; Roque, A. C., Lowe, C. R., and Taipa, M. A. (2004). Antibodies and genetically engineered related molecules: production and purification. Biotechnol. Prog. 20, 639-654; Smith, G. P. (1985). Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315-1317; Saeed, AFUH et al, Antibody Engineering for Pursuing a Healthier Future, Front. Microbiol., 28 March

2017; 8:495; Green, MR and Sambrook, J., 2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, all incorporated herein by reference. Antibody 8C5

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 9 and 10 (antibody 8C5), or sequences at least 80% (for example, about 85%, about 86%, about 87% about

88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 8C5. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 8C5. In certain

embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 8C5. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 9 and 10. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 9 and 10. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 9 and 10. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 9 and 10. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell.

In another aspect, such antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 21 and 22 (8C5), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto.

Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 21 and 22. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 21 and 22. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 21 and 22. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 21 and 22.

Fragments of antibody 8C5 heavy chain nucleotide sequence SEQ ID NO: 21 and amino acid sequence SEQ ID NO: 9 include those sequences identified in Table A below:

Fragments of antibody 8C5 light chain nucleotide sequence SEQ ID NO: 22 and amino acid sequence SEQ ID NO: 10 include those sequences identified in Table B below:

Antibody 10H5

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 11 and 12

(antibody 10H5), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 10H5. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 10H5. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 10H5. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 11 and 12. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 11 and 12. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 11 and 12. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 11 and 12. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell.

In another aspect, antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 23 and 24 (10H5), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 23 and 24. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 23 and 24. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 23 and 24. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 23 and 24.

Fragments of antibody 10H5 heavy chain nucleotide sequence SEQ ID NO: 23 and amino acid sequence SEQ ID NO: 11 include those sequences identified in Table C below:

Fragments of antibody 10H5 light chain nucleotide sequence SEQ ID NO: 24 and amino acid sequence SEQ ID NO: 12 include those sequences identified in Table D below:

Antibody 4H3

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 3 and 4 (antibody 4H3), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 4H3. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 4H3. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 4H3. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 3 and 4. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 3 and 4. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 3 and 4. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 3 and 4. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell

In another aspect, antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 15 and 16 (4H3), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 15 and 16. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 15 and 16. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 15 and 16. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 15 and 16.

Fragments of antibody 4H3 heavy chain nucleotide sequence SEQ ID NO: 23 and amino acid sequence SEQ ID NO: 11 include those sequences identified in Table E below:

Fragments of antibody 4H3 light chain nucleotide sequence SEQ ID NO: 16 and amino acid sequence SEQ ID NO: 4 include those sequences identified in Table F below:

Antibody 7A2

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 5 and 6 (antibody 7A2), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 7A2. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 7A2. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 7A2. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 5 and 6. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 5 and 6. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 5 and 6. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 5 and 6. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell.

In another aspect, antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 17 and 18 (7A2), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 17 and 18. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 17 and 18. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 17 and 18. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 17 and 18.

Fragments of antibody 7A2 heavy chain nucleotide sequence SEQ ID NO: 17 and amino acid sequence SEQ ID NO: 5 include those sequences identified in Table G below:

Fragments of antibody 7A2 light chain nucleotide sequence SEQ ID NO: 4 and amino acid sequence SEQ ID NO: 16 include those sequences identified in Table H below:

Antibody 7E8

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 7 and 8 (antibody 7E8), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 7E8. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 7E8. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 7E8. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 7 and 8. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 7 and 8. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 7 and 8. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 7 and 8. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell.

In another aspect, antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 19 and 20

(7E8), or sequences at least 80% (for example, about 85%, about 86%, about 87% about

88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 19 and 20. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 19 and 20. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 19 and 20. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 19 and 20.

Fragments of antibody 7E8 heavy chain nucleotide sequence SEQ ID NO: 17 and amino acid sequence SEQ ID NO: 5 include those sequences identified in Table I below:

Fragments of antibody 7E8 light chain nucleotide sequence SEQ ID NO: 20 and amino acid sequence SEQ ID NO: 8 include those sequences identified in Table J below:

Antibody 4C12

Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of SEQ ID NO: 1 and 2 (antibody 4C12), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the heavy chain of antibody 4C12. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or all three CDRs of the light chain of antibody 4C12. In certain embodiments, antibodies or fragments that bind to one or more rabies epitopes comprise any one or two or three or four or five or all six CDRs of antibody 4C12. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 85% identical to SEQ ID NO: 1 and 2. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 90% identical to SEQ ID NO: 1 and 2. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 95% identical to SEQ ID NO: 1 and 2. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence consisting of sequences at least 99% identical to SEQ ID NO: 1 or 2. In certain embodiments, provided herein is a nucleic acid sequence encoding the antibodies or fragments thereof as described. In certain embodiments, the nucleic acid sequence is suitable for expression the antibodies or fragments thereof in a host cell.

In another aspect, antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by nucleotide sequences consisting of SEQ ID NO: 13 and 14 (4C12), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 85% identical to SEQ ID NO: 13 and 14. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 90% identical to SEQ ID NO: 13 and 14. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 95% identical to SEQ ID NO: 13 and 14. Antibodies or fragments that bind to one or more rabies epitopes include, in one embodiment a heavy chain variable domain and/or light chain variable domain sequence encoded by sequences at least 99% identical to SEQ ID NO: 13 and 14.

Fragments of antibody 4C12 heavy chain nucleotide sequence SEQ ID NO: 13 and amino acid sequence SEQ ID NO: 1 include those sequences identified in Table K below:

Fragments of antibody 4C12 light chain nucleotide sequence SEQ ID NO: 14 and amino acid sequence SEQ ID NO: 2 include those sequences identified in Table L below:

The antibody and antibody fragment thereof that bind to one of more rabies epitopes may comprise at least one domain from the antibodies described above. For example, the antibody or antibody fragment may comprise at least one, two, three, four, five, or all six CDR domains of the anti-rabies antibodies 8C5, or 10H5 or 4H3 or 7A2. In another embodiment, the antibody or antibody fragment may comprise one or more CDR domains of 4C12 or 7E8. In a particular embodiment, the antibody or antibody fragment comprises at least one or both of the CDR3 domains. Table M illustrates the amino acid and nucleotide sequences encoding the CDRs of the rabies antibodies described herein.

The antibodies and antibody constructs may be further modified from those exemplified. In a particular embodiment, the domains of the antibody or antibody fragment have at least 90%, 95%, 97%, 99%, or 100% homology or identity with the domains present in the anti-rabies monoclonal antibody 8C5, or 10H5 or 4H3 or 7A2, or 4C12 or 7E8, and illustrated in the sequences identified in FIGs 1A-2D, the Sequence Listing, and as shown in Tables A through M. The domains in Tables A-M may be longer or shorter than the domains identified in the tables by about 1, 2, 3, 4, or 5, amino acids, particularly 1 or 2 amino acids, at the N terminus and/or C-terminus of the domain. The domains may be encoded by nucleotide sequences longer or shorter than the domains identified in Tables A through M below by about 3, 6, 9, 12, or 15 nucleotides, particularly 3 or 6 nucleotides, at the 5’ terminus and/or 3’ terminus of the sequence encoding a domain.

In certain embodiments, the CDR of an antibody can be determined by one of skill in the art, for example, via various databases, software or algorithms. See, www.imgt.org/. In certain embodiments, the CDRs are illustrated in FIGs. 1A-1C and 2A-2D as well as in Tables A-M. In certain embodiments, the CDRs comprises one or two or three or four or five or six more or less amino acids at the N-terminal side and/or C-terminal side of the CDRs as illustrated in FIGs. 1A-1C and 2A-2D and/or in Tables A-M. In certain embodiments, the CDRs are shifted toward the N-terminal side or the C-terminal side by one or two or three or four or five or six or seven or eight or nine or ten amino acid(s) compared to the ones as illustrated in FIGs. 1A-1C and 2A-2D and/or in Tables A-M.

In one embodiment of a modification, the antibodies may be humanized. In a particular embodiment, the selected sequences of the heavy or light chains of any of the antibodies disclosed herein (or a portion thereof) are inserted into the backbone of an antibody or antibody fragment construct. For example, the variable light domain and/or variable heavy domain of the antibodies described herein may be inserted into another antibody construct. Still another embodiment comprises a fully human Fab antibody fragment having a heavy chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 1, 3, 5, 7, 9 or 11; or having a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10 or 12, or combinations thereof. Still other modifications of the antibodies are single chain antibodies having a heavy chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 1, 3, 5, 7, 9 or 11, and a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10 or 12, and combinations thereof, with a peptide linker connecting the heavy and light chains. These same combinations can be generated by use of the corresponding chain encoding nucleotide sequences SEQ ID NOs: 13-24, or sequences having at least 80, 85, 90, 95 or 99% identity thereto.

In still another embodiment, the antibody comprises a heavy chain CDR sequence and light chain CDR sequence selected from the group consisting of the heavy chain variable domain CDR sequence and the light chain variable domain CDR sequences of SEQ ID Nos: 25 to 84 as illustrated in Table M.

Still other antibody modifications employing the SEQ ID Nos disclosed herein, e.g., as taught by the techniques referenced in above-cited US Patent No. 9,902,772, incorporated by reference herein.

In yet another aspect, a pharmaceutical composition for the prevention or treatment of rabies infection comprises at least one antibody or epitope-binding fragment as described above and a pharmaceutically acceptable carrier. In one embodiment, the composition contains one or more of antibodies 10H5 or 4H3 or 8C5 or 7A2 or 4C12 or 7E8, as described above. In another embodiment, the composition contains a fragment or other of the above-noted modifications of one or more of these antibodies. In still another embodiment, the pharmaceutical composition comprises one of more of a heavy chain variable domain sequence of SEQ ID Nos: 1, 3, 5, 7, 9, or 11, or a sequence having at least

80%, at least 85%, at least 90%, at least 95% or at least 99% identity to one of the sequences; or having a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10 or 12, or combinations thereof. Other pharmaceutical compositions can be generated by use of the corresponding chain encoding nucleotide sequences SEQ ID NOs: 13-24, or sequences having at least 80, 85, 90, 95 or 99% identity thereto, e.g., for delivery in vectors, viruses and the like.

Still another pharmaceutical composition contains a mixture of two or more of the antibodies or epitope binding antibody fragments as described above and a

pharmaceutically acceptable carrier. In one embodiment, the composition contains two or more of antibodies 8C5 or 10H5 or 4H3 or 7A2 as described above. In one embodiment, the composition contains antibodies 7A2 and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5 and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5 and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5 and 4H3, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3 and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3 and 8C5, or modifications or fragments thereof.

In other embodiments the compositions contain additionally antibodies or epitope binding antibody fragments of 4C12 or 7E8. In one embodiment, the composition contains antibodies 10H5 and 4C12, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5 and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3 and 4C12, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3 and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12 and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12 and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12 and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 7E8 and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 7E8 and 7A2, or modifications or fragments thereof.

In one embodiment, the composition contains three or more of antibodies 10H5 or 4H3 or 8C5 or 7A2, as described above. In another embodiment 4C12 or 7E8 may also be introduced. In one embodiment, the composition contains antibodies 10H5, 4H3, and

8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 8C5, and 72A, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 72A, 4H3, and 10H5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 8C5, 4H3, and 10H5, or modifications or fragments thereof.

Other combinations include compositions containing antibodies 7E8, 4H3, and 4C12, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 8C5, 4H3, and 4C12, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 7A2, 4H3, and 4C12, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 7A2, 4H3, and 10H5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H3, 4H3, and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12, 7E8, and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12, 7E8, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 8C5, 7E8, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 7E8, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12, 8C5, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 7E8, and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 7E8, and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 7E8, and 8C5, or modifications or fragments thereof.

In one embodiment, the composition contains four antibodies 10H5, 4H3, 8C5 and

7A2, as described above. In other embodiments, 4C12 or 7E8 could be added. In one embodiment, the composition contains antibodies 10H5, 4H3, 4C12 and 8C5, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 4C12 and 7E8, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 4C12 and 7A2, or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, 7E8, and 8C5 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, 7E8, and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 7E8, 8C5, 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 7E8, and 8C5 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 7E8, and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 4C12, 7E8, and 8C5 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 4C12, 7E8, and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 4C12, 8C5, and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 7E8, 8C5 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4C12, 7E8, 8C5 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 8C5 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, 8C5 and 7A2 or modifications or fragments thereof.

In one embodiment, the composition contains five or more of antibodies 10H5 or 4H3 or 4C12 or 7E8 or 8C5 or 7A2, as described above. In one embodiment, the composition contains antibodies 10H5, 4H3, 4C12, 7E8 and 8C5 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 4C12, 7E8 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4H3, 7E8, 8C5 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 10H5, 4C12, 7E8, 8C5 and 7A2 or modifications or fragments thereof. In one embodiment, the composition contains antibodies 4H3, 4C12, 7E8, 8C5 and 7A2 or modifications or fragments thereof. In still another embodiment, a pharmaceutical composition contains an effective amount of all six antibodies, or modifications or fragments thereof. In these compositions, the antibodies, fragments or modifications are present in an amount effective to bind a selected rabies epitope and neutralize the effect of the viral infection.

In another embodiment, the composition contains a fragment or other of the above-noted modifications of one or more of these antibodies. In still another

embodiment, the pharmaceutical composition comprises one of more of a heavy chain variable domain sequence of SEQ ID NOs 1, 3, 5, 7, 9 or 11, one of more of a light chain variable domain sequence of SEQ ID NOs 2,4,6,8,10 or 12, or a sequence having at least 80%, at least 85%, at least 90% or at least 95% identity to one of these sequences, or a fragment or modification thereof.

In still another embodiment, the pharmaceutical composition comprises an additional anti-rabies antibody other than those described herein, or an antibody fragment or an antibody or antibody fragment that binds another virus. Still other agents which may be included in a pharmaceutical composition as described herein, particularly a composition to impart passive immunity to rabies virus include, without limitation, one or more additional immunostimulatory antibodies, such as an anti -PD- 1 antibody, an anti- PD-L1 antibody and/or an anti-CTLA-4 antibody. The antibody can be linked to the agent (as an immuno-complex) or can be administered separately from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, such as the rabies vaccines made from inactivated cell cultures. Desirably the passive immunity provided by use of the antibodies can reduce severity of the infection while the immune system is responding to the inactivated vaccine.

Suitable pharmaceutical carriers or excipients for such compositions include. for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an antibody, fragment or modification thereof is administered. "Pharmaceutically acceptable" indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described, for example, in "Remington's Pharmaceutical Sciences" by E.W. Martin. In general, the pharmaceutically acceptable carrier of the composition is selected from the group of diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. The compositions can include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). The compositions can also be incorporated into particulate preparations of polymeric compounds such as polylactic acid, poly glycolic acid, etc., or into liposomes or nanoparticles. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of the pharmaceutical composition described herein.

In yet another aspect, the antibodies, fragments and modifications of the anti-rabies antibodies described herein are useful in methods for preventing rabies infection in an uninfected subject comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments. In another aspect, a method for treating a subject suspected of having rabies infection comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments as described herein. In another aspect, a method for treating a subject infected with rabies virus comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments as described herein. In another aspect, a method for identifying a subject infected with rabies virus comprises applying a single antibody or epitope binding fragment or a mixture of antibodies or fragments as described herein to a biological sample of the subject (for example, a blood sample, a serum sample, or a saliva sample).

In one embodiment, the antibody comprises any of antibodies 10H5 or 4H3 or

4C12 or 7E8 or 8C5 or 7A2, or fragments or modifications thereof. In another embodiment, the antibody comprises any of the heavy chain sequences of SEQ ID NOs:

1,3, 5, 7, 9 or 11, an epitope binding fragment or a modification thereof. In another embodiment, the antibody comprises any of the light chain sequences of SEQ ID NOs: 2,

4, 6, 8, 10 or 12, an epitope binding fragment or a modification thereof. In yet another embodiment, the antibody is selected from HC/LC pairs of SEQ ID NOs: 1 and 2, 3 and 4, 5 and 6, 7 and 8, 9 and 10, 11 and 12, or fragments or modifications thereof.

In one embodiment, the antibody and antibody fragment may comprise at least one domain from one or more of the anti -rabies virus monoclonal antibodies 10H5 or 4H3 or 4C12 or 7E8 or 8C5 or 7A2. See FIGs. 1 A through 2D for the sequences of the heavy, chain, light chains and encoding nucleic acid sequence of these above referenced antibodies. These exemplified sequences can be used to generate the same antibodies or modifications or fragments thereof.

For example, the antibody or antibody fragment may comprise at least one, two, three, four, five, or all six complementarity-determining region (CDR) domains of the anti-rabies virus monoclonal antibodies 10H5 or 4H3 or 8C5 or 7A2. In another embodiment, the antibody or antibody fragment may comprise CDRs from antibodies 4C12 or 7E8. See Table M above for the CDRs and CDR encoding sequences of antibody 10H5 or 4H3 or 8C5 or 7A2 or 4C12 or 7E8. In a particular embodiment, the antibody or antibody fragment comprises at least one or both of the CDR3 domains. In a particular embodiment, the domains of the antibody or antibody fragment have at least 90%, 95%, 97%, 99%, or 100% homology or identity with the domains present in the anti -rabies virus monoclonal antibody 10H5 or 4H3 or 4C12 or 7E8 or 8C5 or 7A2. The domains may be longer or shorter than the domains depicted in Tables A through K by about 1, 2, 3, 4, or 5, amino acids, particularly 1 or 2 amino acids, at the N-terminus and/or C-terminus of the domain.

Suitable routes of administering the antibody compositions described herein (e.g., human monoclonal antibodies, multi-specific and bispecific molecules and immune- conjugates, fragments or modifications) are in vivo and in vitro are well known in the art and can be selected by those of ordinary skill. In one embodiment, the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous).

Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.

In general, regulatory agencies require that a protein reagent to be used as a therapeutic is formulated so as to have acceptably low levels of pyrogens. Accordingly, therapeutic formulations will generally be distinguished from other formulations in that they are substantially pyrogen free, or at least contain no more than acceptable levels of pyrogen as determined by the appropriate regulatory agency (e.g., FDA).

Therapeutic compositions may be administered with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be parenteral (e.g., intravenous, subcutaneous), oral, or topical, or intravenous, or by inhalation, as non- limiting examples. In addition, any gene therapy technique, using nucleic acids encoding the polypeptides of the invention, may be employed, such as naked DNA delivery, recombinant genes and vectors, cell-based delivery, including ex vivo manipulation of patients' cells, and the like. The concentration of the compound in the formulation varies depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.

The invention is now described with reference to the following examples. These examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these examples but rather should be construed to encompass any and all variations that become evident as a result of the teaching provided herein.

EXAMPLE 1 - RABIES VIRUS ANTIBODIES NEUTRALIZATION

A small aliquot of all antibodies was adjusted to 0.9 mg/ml with PBS and then diluted 5-fold (1:5 dilution) to be used in the assay. Six (6) purified rabies monoclonal antibodies were: 7A2: 3.5 mg/ml, 10H5: 4 mg/ml, 7E8: 0.9 mg/ml,

4H3: 8 mg/ml, 8C5: 8 mg/ml and 4C12: 6 mg/ml.

The assay involved the following steps:

1. 50 pl of serial three-fold dilutions of rabies monoclonal antibody test articles and WHO reference serum (2 IU/ml), all starting from 1:5 dilutions, were prepared in 96-well plates.

2. 5 TCID50 of CVS-l 1 viruses was added to each antibody dilution and incubated in 5% C02 incubator at 37°C for 60 min.

3. After incubation, 35 mΐ of BHK-21 cells (5 x 105 cells/ml) were added into each well. Additional cells were added to new wells without monoclonal antibodies or reference serum as negative controls. The samples were transferred in duplicate to 60 well mini titrate plate (Nunc, Denmark). The culture plates were incubated in C02 incubator at 37°C for 20 hrs.

4. The culture wells were fixed with 80% cold acetone for 20 minutes, air dried for 1 hour, and then stained with FITC-labeled anti rabies antibody (FITC Anti- Rabies Monoclonal Globulin, Fujirebio diagnostics, Inc., Malvern, PA) as described by manufacturer’s instructions. Monoclonal antibody titers were determined by the dilution at 50% fluorescent focus reduction in the infected cell cultures compared with the negative control under a fluorescent microscope. Values were compared with the WHO reference serum and were expressed in international units as IU/ml or IU/mg.

The monoclonal antibody titers were reported in Table L below:

When tested in other mouse neutralization tests, antibodies 4H3, 10H5 and 8C5 had 100% neutralization against a challenge rabies virus strain CVS and 100, 90 and 100%, respectively, neutralization against the Pasteur rabies virus strain.

Each and every patent, patent application, and publication, including publications listed herein and US Provisional Patent Application No. 62/676,045, filed May 24, 2018, and publicly available peptide sequences cited throughout the disclosure, is expressly incorporated herein by reference in its entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention are devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims include such embodiments and equivalent variations. (Sequence Listing Free Text)

The following information is provided for sequences containing free text under numeric identifier <223>.

Claims

WHAT IS CLAIMED IS:

1. A recombinant, synthetic or monoclonal human antibody or antibody construct that binds to a rabies virus epitope, or a fragment of said antibody that binds a rabies virus epitope, said antibody comprising at least one:

(a) a heavy chain variable domain sequence that is at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs. 9, 11, 3, or 5; and

(b) a light chain variable domain sequence that is at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 12, 4, or 6.

2. The antibody or epitope binding fragment according to claim 1, wherein said antibody is a chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, a multi-specific binding construct that can bind two or more targets, a dual specific antibody, a bi-specific antibody or a multi-specific antibody, or an affinity matured antibody.

3. The antibody or epitope binding fragment according to claim 1, wherein said fragment is a single-domain antibody (sdAb), a single antibody chain or an scFv fragment, a diabody, a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs, an Fv construct, a disulfide-linked Fv, a Fab construct, a Fab' construct, a F(ab')2 construct, a monovalent or bivalent construct from which domains non-essential to monoclonal antibody function have been removed, a single-chain molecule containing one VL, one VH antigen-binding domain, and one or two constant“effector” domains optionally connected by linker domains, a univalent antibody lacking a hinge region, a single domain antibody, a dual variable domain immunoglobulin (DVD-Ig) binding protein or a nanobody, an aptamer, an affibody, an affilin, an affitin, an affimer, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, or a monobody.

4. The antibody or epitope binding fragment according to claim 1, wherein the antibody comprises a heavy chain and light chain variable domain sequence selected from the group consisting of SEQ ID NO: 9 and SEQ ID NO: 10.

5. The antibody or epitope binding fragment according to claim 1, wherein the antibody comprises a heavy chain and light chain variable domain sequence selected from the group consisting of SEQ ID NO: 11 and SEQ ID NO: 12.

6. The antibody or epitope binding fragment according to claim 1, wherein the antibody comprises a heavy chain and light chain variable domain sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4.

7. The antibody or epitope binding fragment according to claim 1, wherein the antibody comprises a heavy chain and light chain variable domain sequence selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO: 6.

8. A recombinant or monoclonal human antibody of an IgG class that binds to a rabies virus epitope, or a fragment of said antibody that binds a rabies virus epitope, said antibody having

(b) a light chain variable domain sequence that is at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 12, 4 or 6.

9. The antibody or epitope binding fragment according to any one of claims 2 to 8, which is an IgG.

10. The antibody or epitope binding fragment according to claim 9, which is an IgGl isotype.

11. The antibody or epitope binding fragment according to any one of claims 1 to 10, that comprises one or more of the CDRs or is encoded by one or more of the CDR encoding regions of Table M .

12. A recombinant, synthetic or monoclonal human antibody of an IgG class that binds to a rabies virus epitope, or a fragment of said antibody that binds a rabies virus epitope, said antibody comprising:

(a) a nucleotide sequence encoding a heavy chain variable domain sequence that is at least 80% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs. 21, 23, 15 or 17; and

(b) a nucleotide sequence encoding a light chain variable domain sequence that is at least 80% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 22, 24, 16 or 18.

13. The antibody or epitope binding fragment according to claim 12, wherein the antibody comprises a heavy chain and light chain variable domain sequence encoded by SEQ ID NO: 21 and SEQ ID NO: 22 or sequences at least 80% identical thereto.

14. The antibody or epitope binding fragment according to claim 12, wherein the antibody comprises a heavy chain and light chain variable domain sequence encoded by SEQ ID NO: 23 and SEQ ID NO: 24 or sequences at least 80% identical thereto.

15. The antibody or epitope binding fragment according to claim 12, wherein the antibody comprises a heavy chain and light chain variable domain sequence encoded by SEQ ID NO: 15 and SEQ ID NO: 16 or sequences at least 80% identical thereto.

16. The antibody or epitope binding fragment according to claim 12, wherein the antibody comprises a heavy chain and light chain variable domain sequence encoded by SEQ ID NO: 17 and SEQ ID NO: 18 or sequences at least 80% identical thereto.

17. An antigen binding fragment thereof comprising one or more CDR selected from the amino acid sequences or encoding nucleotide sequences of Table M.

18. The fragment according to claim 17, comprising a heavy chain CDR set SEQ ID NO: 65-67, SEQ ID NO: 35-37, SEQ ID NO: 45-47, or SEQ ID NO: 75-77.

19. A pharmaceutical composition for the prevention or treatment of rabies infection comprising at least one antibody or epitope-binding fragment of claim 1 or a nucleic acid sequence encoding at least one antibody or epitope-binding fragment of claim 1, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, comprising a mixture of antibodies or epitope binding antibody fragments of SEQ ID NO: 3, 4, 5, 6, 9, 10, 11 or 12

21. The pharmaceutical composition according to claim 20, comprising two or more of said antibodies or fragments.

22. The pharmaceutical composition according to claim 21, further comprising an additional anti-rabies antibody or antibody fragment or an antibody or antibody fragment that binds another virus.

23. A method for preventing rabies infection in an uninfected subject comprising administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments, or a composition comprising said antibody or fragment of claim 1.

24. The method according to claim 23, wherein said single antibody or epitope binding fragment or a mixture of antibodies or fragments, or a composition is that of any one of claims 2 to 22.

25. A method for treating a subject infected with rabies virus comprising administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments, or a composition of claim 1.

26. A method for treating a subject infected with rabies virus comprising administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments, or a composition of any one of claims 2 to 22.

27. A single antibody or epitope binding fragment or a mixture of antibodies or fragments of claim 1, or a composition comprising an antibody or fragment of claim 1, or a composition comprising nucleic acid sequences encoding an antibody or fragment of claim 1, for use in preventing rabies infection in an uninfected subject or for treating a subject infected with rabies virus.

28. A single antibody or epitope binding fragment or a mixture of antibodies or fragments, or a composition of any one of claims 2 to 26, or a composition comprising nucleic acid sequences encoding an antibody or fragment of claim 1, for use in preventing rabies infection in an uninfected subject or for treating a subject infected with rabies virus.