Bispecific antibody and use thereof

Abstract

The invention is in the field of medical treatment and relates to a method for treating influenza virus infection. In particular, the present invention relates to methods for prophylactic and / or therapeutic treatment of influenza virus infection by means of the mucosal administration of bispecific antibodies, comprising at least one binding domain capable of specifically binding to hemagglutinin and at least one binding domain capable of specifically binding to neuraminidase. Also provided are methods of producing these bispecific antibodies and methods of using the same.

Description

[0001] P134948PC00 BISPECIFIC ANTIBODY AND USE THEREOF FIELD OF THE INVENTION The invention is in the field of medical treatment and relates to a method for treating influenza virus infection. The disclosure specifically relates to antibodies that have broad binding activity against the surface antigens hemagglutinin and neuraminidase of influenza A virus subtypes A1 and / or A2, and / or the hemagglutinin and neuraminidase of influenza virus B subtypes. BACKGROUND OF THE INVENTION Seasonal influenza virus epidemics cause 3 to 5 million severe cases of influenza worldwide and 650,000 deaths each year. Thus, the ongoing healthcare burden is inadequately addressed with current therapies, i.e., vaccines and antivirals. The inadequacy of these therapies has been largely due to current vaccines only being effective against a specific and very narrow spectrum of viral strains. The influenza virus also poses pandemic threats (e.g., influenza virus H5). Prophylactic and / or therapeutic administration of antibodies could represent a key tool in controlling transmission and infection severity of current and future strains of influenza virus. The great genetic variation within influenza viruses represents an obstacle to the delivery of broad protection against many if not all current and future strains. Four genera of Influenza virus are known to infect vertebrates: influenza A, influenza B, influenza C and influenza D. Influenza A and B cause seasonal influenza epidemics in humans. The elderly and the immunocompromised are at higher risk from severe influenza A, whereas children and adolescents are more susceptible to influenza B. Influenza C and D are mainly observed in animal reservoirs. Although they do not circulate widely in humans, influenza C is able to cause mild disease in humans; influenza D poses a zoonotic risk, especially to cattle workers. Influenza A and B contain two cell surface proteins: the hemagglutinin glycoprotein (HA) and neuraminidase (NA). HA binds to sialic acid on human target cells and contains the cell fusion machinery. NA cleaves off sialic acid residues from individual's cell receptors, which is necessary for egress by newly formed virions. The HA and NA surface proteins of influenza B differ phylogenetically from those of influenza A. Eighteen subtypes of Influenza virus A HA have been identified, which cluster into two groups. Group 1 comprises 12 HA subtypes (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18) and group A2 comprises 6 subtypes (H3, H4, H7, H10, H14 and H15). Eleven subtypes of Influenza virus A NA have been identified (N1-N11). Influenza B is divided into the Victoria lineage and the Yamagata lineage. Broad protection can be achieved by administration of antibodies targeting immunogenic sequences that are highly conserved within several strains of influenza virus. The human monoclonal antibody (mAb) CR9114 has been proven to protect from weight loss and lethality mice challenged with Influenza A1, A2 and B. CR9114 binds to a highly conserved immunogenic sequence in the stem region of hemagglutinin (HA). CR9114 neutralizes a wide spectrum of influenza A viruses in vitro. CR9114 protects against Influenza virus A mostly by preventing fusion of the viral envelope with the endocytic vesicular membrane. CR9114 fails at neutralizing influenza B strains in vitro. It is postulated that in vivo protection against Influenza B virus hinges on its ability to evoke immune system effector cells. CR9114 might deliver in vivo protection against Influenza B also by preventing egress of newly formed virions from infected cells. Despite not binding to NA, through steric hindrance, CR9114 is capable of inhibiting NA catalytic activity which is necessary for efficient viral egress. The human monoclonal antibody (mAb) 1G01 has been proven to protect from weight loss and lethality mice challenged with Influenza A1, A2 and B. 1G01 binds to a highly conserved immunogenic sequence in the NA and prevent newly formed virions from egressing infected cells.1G01 also evokes immune system effector cells. Influenza virus evolves rapidly with mutations occurring randomly in the viral genome, a phenomenon named “antigenic drift”. Non-synonymous mutations alter the antigen sequence, potentially leading to antibodies being unable to recognize the mutated epitope. Exposition to antibodies creates selection pressure against the targeted viruses. Viral mutants that are no longer recognized by antibodies survive and replicate and are defined as “escape mutants”. In the case of Influenza virus, even single mutations have been shown to potentially lead to antibody escape. Monotherapy with a single monoclonal antibody would pressure targeted antigens to cumulate mutations that lead to antibody escape. This calls for strategies to counter the emergence of escape mutants. Bispecific antibodies are artificial antibodies or antibody-constructs designed to bind to two different types of antigens or two different epitopes on the same antigen. The most common bispecific monoclonal antibody format is the (asymmetrical) trifunctional antibody, characterized by three unique binding sites: two fragment antigen binding (Fab) arms and the fragment crystallizable (Fc) domain. The Fab arms are the variable region of an antibody and confer specificity. In the case of a trifunctional bispecific antibody each Fab arm is formed by a heavy and light chain pair from a unique mAb and is designated to target one antigen (or antigenic sequence). The Fc region is designated to activate immune effector functions by binding to the Fcγ receptors on the surface of leukocytes; the Fc region also binds the neonatal Fc receptors, extending the half-life of the antibody. In the case of a trifunctional bispecific antibody, the Fc domain is made from the two heavy chains from each mAb. Therapeutic antibodies have the potential to target specific virions but have the unintended consequence of contributing towards the emergence of escape mutants. There is thus a need for an improved antibody therapy capable of targeting and suppressing the emergence of genetically diverse escape mutants. SUMMARY OF THE INVENTION The inventors have discovered methods for prophylactic and / or therapeutic treatment of influenza virus infection by means of the mucosal administration of bispecific antibodies, comprising at least one binding domain capable of specifically binding to hemagglutinin and at least one binding domain capable of specifically binding to neuraminidase. Also provided are methods of producing these bispecific antibodies and methods of using the same. The inventors have discovered that a bispecific antibody or antigen-binding fragment thereof, having complementarity-determining regions (CDR) as disclosed herein can advantageously be used in the treatment of influenza A virus subtype A2, and / or preferably influenza A virus subtype A1 and / or preferably influenza virus B subtypes infections. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of binding to influenza A virus subtype A2 hemagglutinin and neuraminidase, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of binding to influenza A virus subtype A1 hemagglutinin and neuraminidase, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of binding to the distinct phylogenetic lineages of influenza virus B hemagglutinin and neuraminidase, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of binding to influenza B virus hemagglutinin and neuraminidase in both Yamagata and Victoria lineages, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of binding to surface antigens hemagglutinin and neuraminidase of influenza A virus subtypes A1 and A2, and influenza virus B subtypes, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof, that is capable of simultaneously binding to surface antigens hemagglutinin and neuraminidase of influenza A virus subtypes A1 and A2, and influenza virus B subtypes, is disclosed. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, wherein the bispecific antibody or antigen-binding fragment comprises: (a) a first antigen-binding domain that binds to hemagglutinin , wherein the first antigen- binding domain comprises: a VH domain as described in SEQ ID NO: 007 comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 003, and a VL domain as described in SEQ ID NO: 008 comprising a LCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 006; and (b) a second antigen-binding domain that binds to neuraminidase , wherein the second antigen-binding domain comprises: a VH domain as described in SEQ ID NO: 023 comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 019, and a VL domain as described in SEQ ID NO: 024 comprising a LCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 022. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, wherein the bispecific antibody or the antigen-binding fragment thereof comprises: (i) a first polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 001, or the amino acid sequence having at least 1, or 2 amino acids different from SEQ ID NO: 001, (ii) a second polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 002, or the amino acid sequence having at least 1, 2, 3, 4, or 5 amino acids different from SEQ ID NO: 002, (iii) a third polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 003, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 003, (iv) a fourth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 004, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 004, (v) a fifth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 005, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 005, (vi) a sixth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 006, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 006, (vii) a seventh polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 017, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 017, (viii) an eighth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 018, or the amino acid sequence having at least 1, 2, 3, 4 or 5 amino acids different from SEQ ID NO: 018, (ix) a ninth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 019, or the amino acid sequence having at least 1, 2, 3, 4, 5, or 6 amino acids different from SEQ ID NO: 019, (x) a tenth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 020, or the amino acid sequence having at least 1, 2 or 3amino acids different from SEQ ID NO: 020, (xi) an eleventh polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 021, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 021, and (xii) a twelfth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 022, or the amino acid sequence having at least 1, 2 or 3 amino acids different from SEQ ID NO: 022. In a preferred embodiment, a bispecific antibody or antigen-binding fragment is disclosed, wherein the bispecific antibody comprises a first Fab fragment capable of specifically binding to hemagglutinin, a second Fab fragment capable of specifically binding to neuraminidase, and an Fc domain composed of a first and a second subunit which is capable of stable association. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, wherein any one of the antigen-binding domains is chimeric, fully human or humanized. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, wherein any one of the antigen-binding domains comprises a Fab fragment, a Fab(ab')2 fragment, a scFv-Fc fragment, or a scFv fragment. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, wherein the bispecific antibody is bivalent, trivalent, tetravalent, hexavalent or multivalent. In a preferred embodiment, a nucleic acid molecule comprising a nucleic acid sequence is disclosed, wherein the nucleic acid encodes a bispecific antibody or antigen-binding fragment according to any embodiment as herein described. In a preferred embodiment, a nucleic acid sequence is disclosed, wherein the sequence comprises: (i) a first nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 001, or a first nucleic acid sequence encoding the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 001, (ii) a second nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 002, or a second nucleic acid sequence encoding the amino acid sequence having at least 1, 2, 3, 4, 5 amino acids different from SEQ ID NO: 002, (iii) a third nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 003, or a third nucleic acid sequence encoding the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 003, (iv) a fourth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 004, or a fourth nucleic acid sequence encoding the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 004, (v) a fifth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 005, or a fifth nucleic acid sequence encoding the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 005, (vi) a sixth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 006, or a sixth nucleic acid sequence encoding the amino acid sequence having at least 1, 2 or 3 amino acids different from SEQ ID NO: 006, (vii) a seventh nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 017, or a seventh nucleic acid sequence encoding the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 017, (viii) an eighth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 018, or an eighth nucleic acid sequence encoding the amino acid sequence having at least 1, 2, 3, 4, or 5 amino acids different from SEQ ID NO: 018, (ix) a nineth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 019, or a nineth nucleic acid sequence encoding the amino acid sequence having at least 1, 2, 3, 4, 5, or 6 amino acids different from SEQ ID NO: 019, (x) a tenth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 020, or a tenth nucleic acid sequence encoding the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 020, (xi) an eleventh nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 021, or an eleventh nucleic acid sequence encoding the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 021, and (xii) a twelfth nucleic acid sequence encoding the amino acid sequence as set forth in SEQ ID NO: 022, or a twelfth nucleic acid sequence encoding the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 022. In a preferred embodiment, a bispecific antibody or antigen-binding fragment is disclosed, and / or a nucleic acid molecule according to any described embodiment, for use as a medicament, is disclosed. In a preferred embodiment, a vector comprising one or more nucleic acids is disclosed, wherein the vector is suitable for the recombinant production of the bispecific antibody according to any embodiment as herein described. In a preferred embodiment, a host cell is disclosed, wherein the host cell comprises one or more vectors according to any embodiment as herein described. In a preferred embodiment, an immunoconjugate is disclosed, wherein the immunoconjugate comprises the bispecific antibody or antigen-binding fragment according to any embodiment as herein described. In a preferred embodiment, a pharmaceutical composition is disclosed, wherein the pharmaceutical composition comprises any combination of a bispecific antibody according to any embodiment as herein described. Preferably the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a preferred embodiment, a pharmaceutical composition is disclosed, wherein the pharmaceutical composition comprises any combination of nucleic acids according to any embodiment as herein described. Preferably the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a preferred embodiment, a pharmaceutical composition is disclosed, wherein the pharmaceutical composition comprises any combination of immunoconjugates according to any embodiment as herein described. Preferably the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In a preferred embodiment, a bispecific antibody or antigen-binding fragment thereof is disclosed, and / or a nucleic acid molecule according to any embodiment as herein described, for use as a medicament for the prophylactic and / or therapeutic treatment of an influenza infection. In a preferred embodiment, a method for treating or preventing influenza disease in a subject is disclosed, the method comprises administering to the subject an effective amount of the bispecific antibody or antigen-binding fragment according to any embodiment, the nucleic acids as herein described, the vectors as herein described, the host cells as herein described, the immunoconjugates as herein described, or the pharmaceutical compositions as herein described. In a preferred embodiment, the use of the bispecific antibody or antigen-binding fragment according to any embodiment as herein described, the nucleic acids as herein described, the vectors as herein described, the host cells as herein described, the immunoconjugates as herein described, or the pharmaceutical compositions as herein described, in the manufacture of a medicament for treating influenza disease in a subject, is disclosed. In a preferred embodiment, the intranasal administration of the bispecific antibody or antigen-binding fragment according to any embodiment as herein described, the nucleic acids as herein described, the vectors as herein described, the host cells as herein described, the immunoconjugates as herein described, or the pharmaceutical compositions as herein described, is disclosed. In a preferred embodiment, the oral inhalation of the bispecific antibody or antigen- binding fragment according to any embodiment as herein described, the nucleic acids as herein described, the vectors as herein described, the host cells as herein described, the immunoconjugates as herein described, or the pharmaceutical compositions as herein described, is disclosed. In a preferred embodiment, a Kit comprising the bispecific antibody or antigen-binding fragment according to any embodiment as herein described, the nucleic acids as herein described, the vectors as herein described, the host cells as herein described, the immunoconjugates as herein described, or the pharmaceutical compositions as herein described, is disclosed. Complementarity-determining regions Preferably, Complementarity Determining Regions (CDRs) are according to Kabat et al., (1991) as described in Sequences of Proteins of Immunological Interest. The variable binding regions comprise discrete, well-defined sub-regions known as CDRs and “framework regions” (FRs). The terms “complementarity determining region” and “CDR” refer to sequences of amino acids within antibody variable regions, which together confer the antigen specificity and / or binding affinity of the antibody, wherein consecutive CDRs (i.e., CDR1, CDR2 and CDR3) are separated from one another in primary structure by a framework region. There are three CDRs in each variable region (HCDR1, HCDR2, HCDR3; LCDR1, LCDR2, LCDR3; also referred to as CDRHs and CDRLs, respectively). Vehicles and routes of administration Preferred vehicles or carriers for administration to a human subject include any one of lipid or lipid-derived delivery vehicles, such as liposomes, solid lipid nanoparticles, oily suspensions, submicron lipid emulsions, lipid microbubbles, inverse lipid micelles, cochlear liposomes, lipid microtubules, lipid microcylinders, or lipid nanoparticles (LNP) or a nanoscale platform. Preferred techniques for designing appropriate mRNA and formulating mRNA-LNP and delivering the same include capping, codon optimization, nucleoside modification, purification of mRNA, incorporation of the mRNA into stable lipid nanoparticles (e.g., ionizable cationic lipid / phosphatidylcholine / cholesterol / PEG-lipid; ionizable lipid:distearoyl PC:cholesterol:polyethylene glycol lipid; chitosan), and subcutaneous, intramuscular, intradermal, intravenous, intraperitoneal, mucosal, intranasal, pulmonary and intratracheal administration of the same. Preferred routes of administration include mucosal and especially intranasal administration. Dosing Preferably, between 0.01 mg and 20 mg of the bispecific antibody or antigen-binding fragment is administered to an individual, more preferably between 0.1 mg and 20 mg of the bispecific antibody or antigen-binding fragment is administered to an individual. Binding Preferably the bispecific antibody or antigen binding fragment thereof binds influenza A virus subtype A1 hemagglutinin and neuraminidase at an EC50 in the range of from about 1 μg / ml to about 50 μg / ml of antibody. Preferably the bispecific antibody or antigen binding fragment thereof binds influenza A virus subtype A1 hemagglutinin and neuraminidase at an EC50 in the range of from about 0.001 μg / ml to about 50 μg / ml of antibody Preferably the bispecific antibody or antigen binding fragment thereof binds influenza A virus subtype A2 hemagglutinin and neuraminidase at an EC50 in the range of from about 1 μg / ml to about 50 μg / ml of antibody. Preferably the bispecific antibody or antigen binding fragment thereof binds influenza B virus subtypes hemagglutinin and neuraminidase at an EC50 in the range of from about 0.001 μg / ml to about 50 μg / ml of antibody. Preferably the bispecific antibody or antigen binding fragment thereof binds influenza B virus subtypes hemagglutinin and neuraminidase at an EC50 in the range of from about 1 μg / ml to about 50 μg / ml of antibody. Preferably the bispecific antibody or antigen binding fragment thereof binds influenza B virus subtypes hemagglutinin and neuraminidase at an EC50 in the range of from about 0.001 μg / ml to about 50 μg / ml of antibody. Timing and intervals Preferably, the bispecific antibody or antigen-binding fragment is administered at least once or at least twice per month. Vector Preferably, the nucleic acid as disclosed herein is comprised in the vector, and subsequently delivered to the subjects. By using the vector, repeated injections during a course of treatment may be prevented and / or decreased. Suitably, the vector can be viral vector or non-viral vector. Suitably, the vector as disclosed herein is selected from the group consisting of alphavirus, flavivirus, herpes simplex viruses (HSV), measles viruses, rhabdoviruses, retrovirus, Newcastle disease virus (NDV), poxviruses, picomavirus, lentivirus, adenoviral vectors or adeno-associated virus (AAV). Preferably the vector may be a recombinant vector. Preferably the vector may be an expression vector. Host cell Preferably, host cells that sustain in vitro replication of the vector as disclosed herein are derived from mammalian cell lines or insect cell lines, Preferably, the mammalian cell line includes 293 cells, COS cells, HeLa cells, or KB cells. Preferably, the insect cell line includes Se301, SeIZD2109, SeUCRl, Sf9, Sf900+, Sf21, BTI-TN-5B1-4, MG-I, Tn368, HzAmI, Ha2302, Hz2E5 or High Five cells. DESCRIPTION OF THE FIGURES Figure 1A. Survival after lethal challenge from Example 1A Kaplan-Meier survival curves for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups are shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 1B. Bodyweight change after lethal challenge from Example 1A Bodyweight change for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 1C. Median effective dose after lethal challenge from Example 1A Median effective dose for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Figure 2A. Survival after lethal challenge from Example 1A – Antibody according to the invention Kaplan-Meier survival curves for the intranasal administration of the bispecific antibody according to the invention in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of the bispecific antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups are shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 2B. Bodyweight change after lethal challenge from Example 1A – Antibody according to the invention Bodyweight change for the intranasal administration of the bispecific antibody according to the invention in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of the bispecific antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 2C. Median effective dose after lethal challenge from Example 1A – Antibody according to the invention Median effective dose for the intranasal administration of bispecific antibody according to the invention in a prophylactic efficacy study in BALB / c mice upon lethal A / Puerto Rico / 8 / 1934 (H1N1) influenza virus challenge. Animals were treated intranasally with a dose titration of the bispecific antibody according to the invention at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Figure 3A. Survival after lethal challenge from Example 3A Kaplan-Meier survival curves for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups are shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 3B. Bodyweight change after lethal challenge from Example 3A Bodyweight change for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 3C. Median effective dose after lethal challenge from Example 3A Median effective dose for the intranasal administration of Parental Antibody 1 (CR9114) in a prophylactic efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of Parental Antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Figure 4A. Survival after lethal challenge from Example 3A Kaplan-Meier survival curves for the intranasal administration of the bispecific antibody according to invention [LLC0010] in a pre-exposure efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups are shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 4B. Bodyweight change after lethal challenge from Example 3A Bodyweight change for the intranasal administration of the bispecific antibody according to invention in a pre-exposure efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 4C. Median effective dose after lethal challenge from Example 1A Median effective dose for the intranasal administration of the bispecific antibody according to invention in a pre-exposure efficacy study in BALB / c mice upon lethal B / Malaysia / 2506 / 2004 influenza virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS) Figure 5A. Survival after lethal challenge from Example 9 (Parental Antibody 1) Kaplan-Meier survival curves for the intranasal administration of the parental antibody 1 (CR9114) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the parental antibody 1 at day -1. At day 0, animals were intranasally infected with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups is shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 5B. Bodyweight change after lethal challenge from Example 9 (Parental Antibody 1) Bodyweight change for the intranasal administration of the parental antibody 1 (CR9114) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the parental antibody 1 at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 5C. Median effective dose after lethal challenge from Example 9 (Parental Antibody 1) Median effective dose for the intranasal administration of the parental antibody 1 (CR9114) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the parental antibody 1 (CR9114) at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Figure 6A. Survival after lethal challenge from Example 9 (Parental Antibody 2) Kaplan-Meier survival curves for the intranasal administration of 1G01 (Parental Antibody 2) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of 1G01 (Parental Antibody 2) at day -1. At day 0, animals were intranasally infected with a lethal dose of A / Puerto Rico / 8 / 1934 influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups is shown. Lines are nudged relative to the Y-axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 6B. Bodyweight change after lethal challenge from Example 9 (Parental Antibody 2) Bodyweight change for the intranasal administration of 1G01 (Parental Antibody 2) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of 1G01 (Parental Antibody 2) at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 7A. Survival after lethal challenge from Example 9 (Combination of parental Antibody 1 and parental Antibody 2) Kaplan-Meier survival curves for the intranasal administration of the combination of CR9114 (Parental antibody 1) and 1G01 (Parental Antibody 2) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were intranasally infected with a lethal dose of B / Malaysia / 2506 / 2004 influenza virus. A vehicle control group was included (PBS). Kaplan-Meier survival curves of the groups is shown. Lines are nudged relative to the Y- axis to improve visual representation. Asterisk indicates significance compared to control group. Figure 7B. Bodyweight change after lethal challenge from Example 9 (Combination of parental Antibody 1 and parental Antibody 2) Bodyweight change for the intranasal administration o of the combination of parental antibody 1 (CR9114) and 1G01 (Parental Antibody 2) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). Bodyweight change (%) relative to day 0 is shown. Error bars represent the mean with 95% confidence interval. If a mouse died / was euthanized during follow-up of the study, the last observed bodyweight was carried forward. Asterisk indicates significance compared to control group. Figure 7C. Median effective dose after lethal challenge from Example 9 (Combination of parental Antibody 1 and parental Antibody 2) Median effective dose for the intranasal administration of the combination of parental antibody 1 (CR9114) and 1G01 (Parental Antibody 2) in a pre-exposure efficacy study in H1N1 mouse model upon lethal influenza A / Puerto Rico / 8 / 1934 (H1N1) virus challenge. Animals were treated intranasally with a dose titration of the antibody according to invention at day -1. At day 0, animals were infected intranasally with a lethal dose of A / Puerto Rico / 8 / 1934 (H1N1) influenza virus. A vehicle control group was included (PBS). DETAILED DESCRIPTION OF THE INVENTION For the purpose of clarity and a concise description, features may be described herein as part of the same or separate embodiments, however, it will be appreciated that the disclosure includes embodiments having combinations of all or some of the features described. References to “method for treatment”, “treatment method”, “antibody for use” and “use of an antibody in the manufacture of a medicament” can be used interchangeably and embodiments disclosed in relation to any one of those aspects also applies in relation to said other aspects. In other words, they all refer to medical treatments involving an antibody as disclosed herein. Preferably a bispecific antibody or antigen-binding fragment as described herein is capable of neutralizing infection by influenza. As used herein, a “neutralizing bispecific antibody” is one that can neutralize, i.e., prevent, inhibit, reduce, impede, or interfere with, the ability of the influenza virus to initiate and / or perpetuate an infection in a host. The terms “neutralizing bispecific antibody” and “a bispecific antibody that neutralizes” or “bispecific antibodies that neutralize” are used interchangeably herein. The same applies for the described antigen-binding fragments, mutatis mutandis. Prophylactic treatment The term ‘prophylactic treatment’, as used herein, includes reference to a treatment for preventing infection of an individual with an influenza virus, or preventing symptoms after infection with an influenza virus, or preventing severe symptoms after known infection with an influenza virus with or without symptoms, or preventing hospitalization and death after infection with an influenza virus. Prevention of an infection is preferably performed by administration of an antibody as disclosed herein prior to influenza virus exposure i.e. pre-exposure prophylaxis. ‘Prophylactically’ therefore preferably means prior to virus exposure. Nonetheless, it may also involve administration after infection, for example for reducing the replication or spread, or increasing clearance of the virus i.e. post-exposure prophylaxis. Infected individuals may present with no symptoms. Alternatively, infected individuals may present with symptoms. Preferably, post-exposure prophylaxis involves administering a bispecific antibody or antigen-binding fragment as disclosed herein after influenza virus exposure to prevent symptomatic or asymptomatic disease. Preferably, post-exposure prophylaxis involves administering a bispecific antibody or antigen-binding fragment as disclosed herein after influenza virus exposure to prevent severe disease, in particular hospitalization. In a treatment method of the invention, prophylactic treatment involves administration of the bispecific antibody or antigen-binding fragment as disclosed herein against influenza virus at a point in time when the individual is not infected with influenza virus. Preferably, said bispecific antibody or antigen-binding fragment bind to a conserved epitope of the hemagglutinin and neuraminidase surface antigens of an influenza virion. In some embodiments, an individual in need thereof is not (yet) infected with an influenza virus. Therapeutic treatment The term ‘therapeutic treatment’, as used herein, includes reference to treatment of a viral infection (including influenza virus disease) after viral infection has taken place. A viral infection involves the entry of the body by the virus, and / or the replication of the virus in the body and / or the spreading of the virus to cells, tissues or locations in the body that were previously uninfected. A viral infection may cause one or more disease, but may also be latent, in other words may reside in the body without causing symptoms or disease. Influenza virus The term ‘influenza virus’, as used herein, includes reference to a negative-sense single- stranded RNA virus belonging to the family of Influenza viruses r to Influenza family as used herein. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of specifically binding to the hemagglutinin and / or neuraminidase of an influenza virus, in particular influenza A virus subtype A2, influenza A virus subtype A1 and / or influenza virus B of both the Yamagata and Victoria lineages. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of binding to the hemagglutinin and / or neuraminidase of an influenza virus, in particular, influenza A virus subtype A2, influenza A virus subtype A1 and / or influenza virus B of both the Yamagata and Victoria lineages. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of binding to the hemagglutinin and / or neuraminidase of an influenza virus, in particular, influenza A virus subtype A2, and / or influenza A virus subtype A1. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of binding to the hemagglutinin and / or neuraminidase of an influenza virus, in particular, influenza A virus subtype A2. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of neutralizing an influenza virus, in particular influenza A virus subtype A2, influenza A virus subtype A1 and / or influenza virus B of both Yamagata and Victoria lineages. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of neutralizing an influenza virus, in particular, influenza A virus subtype A1 and / or influenza A virus subtype A2. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of neutralizing an influenza virus, in particular, influenza A virus subtype A1 and / or influenza A virus subtype A2. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of neutralizing an influenza virus, in particular influenza A virus subtype A2. Preferably, a bispecific antibody or antigen binding fragment as disclosed herein is capable of neutralizing or inhibiting at least one or more, preferably two or more, preferably three or more, preferably four or more, even more preferably five or more influenza virus subtypes. Influenza virus infection The terms ‘influenza virus infection’, ‘flu virus infection’, and ‘flu’ as used herein, includes reference to the pathological or non-pathological, preferably pathological, entrance and residence of an influenza virus of any type in a human host. The infecting virus may replicate within the host, its cells or the cells of its microbiome. The infecting virus may or may not cause a disease, for example influenza. The infection may or may not be able to be detected by methods for virus infection detection known in the art. The infected individual may or may not be aware of the infection. Typical, but non-exclusive locations of the human body where, for example Influenza virus, may be located in an infected individual, are the respiratory system and / or cells thereof and / or the cardiovascular system and / or cells thereof. The term ‘influenza virus infection’, as used herein, further includes reference to the entrance and residence of a part of an influenza virus of any type that is able to cause viral replication in a human host. The term ‘influenza virus infection’ encompasses symptoms or disease following the infection, e.g. influenza. The term ‘as set forth in’ as used herein, includes reference to the amino acid sequence or nucleic acid sequence as disclosed herein that consists of one sequence as disclosed herein. Epitope An “epitope”, as used herein, includes reference to a moiety that is capable of binding to an antibody as disclosed herein with sufficiently high affinity to form a detectable antigen- antibody complex. The person skilled in the art is aware of how to measure the affinity of the epitope to the antibody, for example, by enzyme-linked immunosorbent assay (ELISA) assay. Also, antigen-antibody complex can be detected by an assay known by the person skilled in the art, such as Ouchterlony assay. Individual The term ‘individual’, as used herein, includes reference to a mammal preferably a human that is subject to, or a risk of suffering from viral infection. Infection may take place in any system, tissue or cell belonging to the host, including the host’s microbiome. Influenza virus infection and the disease influenza virus may occur in individuals of all age groups and sexes. Nonetheless, preferably, the individual is a human, in particular an elderly human such as a human that is at least 60, 65, 70, 75, 80, or at least 85 years old, or that has an increased risk of infection because of occupation or living environment. Preferably, the individual is at risk of suffering from severe illness, for example influenza, once infected. In preferred embodiments, the individual has an underlying disease such as (i) a respiratory disease such as asthma, COPD, chronic bronchitis and lung emphysema, (ii) cardiovascular disease such as cardiac arrhythmia or individuals that have received cardiac surgery, (iii) diabetes, (iv) renal failure and / or (v) a disease affecting the immune system, for instance immunocompromised individuals, or higher risk of viral infection because of occupation. The phrase ‘an individual’, as used herein, includes reference to a mammal such as a but not limited to a human that benefits from a specified therapy, for example, the phrase ‘an individual’ may encompass non-human primates (NHP), birds, pigs, dogs, cats, and horses. Preferably, the individual is a mammal, more preferably a human. Administering and Administration The terms ‘administering’ and ‘administration’, as used herein, include reference to the provision of one or more drug and optionally one or more adjuvant with the aim to treat, cure, reduce, or prevent a disease or its symptoms in an individual, or to promote the individual’s well-being. Preferred methods of administration of the antibody as disclosed herein include mucosal administration, preferably intranasal administration and oral inhalation. An individual in need thereof The phrase ‘an individual in need thereof’, as used herein, includes reference to a mammal such as a human that benefits from a specified therapy. A treatment method of the invention may be used prophylactically, the exhibition of symptoms or indications for influenza virus infection are not required. Individuals that are especially in need of the method or antibody for use of the invention, are individuals with an elevated risk of influenza virus infection, individuals with an elevated risk of developing severe symptoms (illness), for example influenza, and / or individuals with an elevated risk of dying from influenza. The person skilled in the art is aware of the risk factors for an elevated risk of influenza virus infection, an elevated risk of developing severe symptoms of influenza virus infection, and an elevated risk of dying from influenza virus infection. Antibody The term ‘antibody’, as used herein, includes reference to an intact immunoglobulin, including monoclonal antibodies, such as chimeric, humanized or human monoclonal antibodies, or to a binding molecule comprising an antigen-binding domain (such as heavy chain CDRs 1-3 of a variable domain) of an antibody as disclosed herein or an antibody that competes with an antibody as disclosed herein for specific binding to the binding partner of the immunoglobulin. Preferably a bispecific antibody or antigen-binding fragment as described herein is capable of preventing and / or neutralizing an influenza infection in an in vitro model of infection and / or in an in vivo animal model of infection and / or in a human. Preferably, the bispecific antibody, or antigen-binding fragment, is human, humanized, or chimeric. In other words, functional fragments of antibodies are also encompassed by the term ‘antibody’. Functional fragments as disclosed herein may comprise or consist of parts of or full length of the polypeptide sequence of the intact immunoglobulin, while the functional fragments are capable of binding to the immunoglobulin with sufficient affinity. Suitably, the functional fragments as disclosed herein comprise the amino acid sequences of a CDR sequence comprising SEQ ID NO: 001. Preferably wherein the first antibody (arm) comprises CDR sequences comprising any one or more of SEQ ID NO: 001, SEQ ID NO: 002, or SEQ ID NO.: 003, and the second antibody (arm) comprises CDR sequences comprising any one or more of SEQ ID NO: 017, SEQ ID NO: 018, or SEQ ID NO.: 019. More preferably, wherein the heavy chain on the first antibody (arm) comprises CDR sequences comprising any one or more of SEQ ID NO: 001, SEQ ID NO: 002, or SEQ ID NO.: 003, the light chain on the first antibody (arm) comprises any functional humanized CDR sequences; the second antibody (arm) comprises heavy chain CDR sequences comprising any one or more of SEQ ID NO: 017, SEQ ID NO: 018, or SEQ ID NO.: 019, and the light chain on the second antibody (arm) comprises CDR sequences comprising any one or more of SEQ ID NO: 020, SEQ ID NO: 021, or SEQ ID NO.: 022. Antibodies are generally Y-shaped proteins. Within the antibody, constant domain and variable domains are generally present. The variable domain facilitates antigen binding. An antibody generally comprises two heavy chains and two light chains. Both the heavy chains and the light chains are partially constant and partially variable. Antibodies occur in a few classes: IgA, IgD, IgE, IgG and IgM. Preferably, the antibody of the invention is of the IgG, preferably IgG1, class. Some classes may be further subdivided into subclasses or isotypes. For example, the IgG class is subdivided into the subclasses IgG1, IgG2, IgG3 and IgG4. Preferably, the antibody of the invention is of the IgG, preferably IgG1, class. Antigen-binding regions, or antigen-binding fragments of an antibody, which are encompassed by the term ‘antibody’ and which are therefore part of the present invention, may include, for example, Fab, F(ab’), F(ab’)2, dAb, Fv, Fd, CDR fragments, diabodies, triabodies, tetrabodies, single-chain antibodies (scFv), scFv-Fc, bivalent single-chain antibodies such as tandem di-scFv and diabody, trivalent single-chain antibodies such as tandem tri-scFv and triabody, tandem single-domain antibodies, Fab-scFv bispecific antibodies, single-chain phage antibodies, (poly)peptides and variants thereof that contain at least a fragment of an immunoglobulin that is sufficient to confer specific antigen binding to the (poly)peptide, etc. The above fragments may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins or they may be genetically engineered by recombinant DNA techniques. The above fragments may be recombinantly expressed in a mammalian cell system. The methods for production of antibodies and antigen-binding fragments are well-known to a person skilled in the art. The bispecific antibody or antigen-binding fragment may be conjugated or unconjugated. The bispecific antibody or antigen-binding fragment may be conjugated, linked, or otherwise physically or functionally associated with an effector moiety or tag, such as inter alia an enzyme, a liposome, a radioactive substance, a fluorophore, a toxic substance. The bispecific antibody or antigen-binding fragment may be stabilized, multimerized, humanized or otherwise manipulated. Antibodies may be neutralizing, which includes reference to inhibition of a virus as measured by an in vitro neutralization assay, for instance in terms of viral entry and / or viral replication in the individuals as disclosed herein. Neutralization can for example be achieved by inhibiting the attachment or adhesion of the virus to the cell surface, or by inhibition of the fusion of viral and cellular membranes following attachment of the virus to the target cell or by inhibiting viral egress from cells. Neutralization does not specify the method of neutralization. Preferably, the antibody is cross-neutralizing, which includes reference to the ability of the antibodies of the invention to bind and neutralize a set of different molecules, preferably different molecules of different subtypes belonging to the Influenza family. Preferably, the bispecific antibody or antigen-binding fragment of the invention as disclosed herein can cross-neutralize influenza virus, in particular Influenza virus. Antibodies comprise complementarity determining regions situated on the variable domains of the heavy chain and the light chain. The CDRs contribute to a large extent to the antigen binding site. Three CDRs can be distinguished, namely CDR1, CDR2 and CDR3. As each CDR can be located on either the light chain or the heavy chain, there are generally six CDRs for each antigen receptor that collectively contact the antigen: the light chain CDR1, the light chain CDR2, the light chain CDR3, the heavy chain CDR1, the heavy chain CDR2 and the heavy chain CDR3. The CDRs of type CDR3 are the most variable. The CDRs can be specific for linear epitopes, discontinuous epitopes, or conformational epitopes of proteins or protein fragments, either as present on the protein in its native conformation or, in some cases, as present on the proteins as denatured or activated. Epitopes may also consist of or comprise post-translational modifications of proteins. Antibodies of the invention that are of particular interest, are antibodies comprising CDRs that recognize influenza virus antigens, such as the hemagglutinin and neuraminidase surface antigens of an influenza virion. The bispecific antibody or antigen- binding fragment thereof as disclosed herein binds to a conserved epitope at the base of the hemagglutinin and neuraminidase surface antigens of an influenza virion. The epitope of the bispecific antibody or antigen-binding fragment thereof as disclosed herein uses light and heavy chain CDR loops. Suitably, the bispecific antibody or antigen-binding fragment thereof of the present invention is capable of binding to two different targets, such as hemagglutinin and neuraminidase, simultaneously. Hence, the bispecific antibody or antigen-binding fragment thereof of the present invention may further reduce and / or prevent new virus variants or different virus variants from egressing and / or replicating. The bispecific antibody or antigen-binding fragment thereof as disclosed herein can be used in isolated or non-isolated form. Preferably, the compositions of the invention comprise a single anti-influenza virus bispecific antibody or antigen-binding fragment thereof as disclosed herein. Furthermore, the bispecific antibody as disclosed herein can be used alone or in a mixture comprising the antibody (or variant, fragment or bispecific thereof) as disclosed herein, and / or with other antibodies that bind to an influenza virus and have an influenza virus inhibiting effect. In other words, the antibody as disclosed herein can be used in combination, e.g., as a pharmaceutical composition or co-administration of compositions comprising two or more antibodies that specifically bind influenza virus. For example, antibodies having different, but complementary activities can be combined in a single therapy to achieve a desired therapeutic or prophylactic effect, but alternatively, antibodies having identical activities can also be combined in a single therapy to achieve a desired prophylactic or therapeutic effect. Optionally, the mixture further comprises at least one other therapeutic agent. Preferably, the bispecific antibody as disclosed herein is a human antibody. Framework regions Antibodies also comprise framework regions, generally four framework regions (FR1, FR2, FR3 and FR4) on each of the variable heavy chain domain and variable light chain domain. The CDRs are situated between the framework regions (preferably in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) and both the CDRs and framework regions together define a heavy chain variable domain (or region) and light chain variable domain (or region) which may also be referred to as an antigen-binding region or domain. IgG antibody The term ‘IgG antibody’, as used herein, includes reference to an antibody comprising two antigen-binding sites. IgG is the most common antibody in human serum. Heavy chains of IgG antibodies are of type γ, which can be subdivided in γ1, γ2, γ3 and γ4. Preferably, the antibodies described herein are γ1 heavy chains. Light chains of IgG antibodies are of type λ or κ. Preferably, the antibodies described herein are λ light chains. Preferably, the antibody is an IgG antibody, preferably an IgG1 antibody. IgA antibody The term ‘IgA antibody’, as used herein, includes reference to an antibody comprising two to four antigen-binding sites. IgA is the most abundant antibody in mucosal secretions. An IgA antibody can be produced in monomeric, dimeric or secretory form, with two or four antigen-binding sites, respectively, and can exist as an IgA1 or IgA2 isotype. [Heavy chains of IgA antibodies are of type α, which can be subdivided in α1 and α2. Light chains of IgA antibodies are of type λ or κ. Preferably, the antibody is an IgA antibody. IgM antibody The term ‘IgM antibody’, as used herein, includes reference to an antibody comprising ten to twelve antigen-binding sites. An IgM antibody can be produced in pentameric or hexameric form. Heavy chains of IgM antibodies are of type µ. Light chains of IgM antibodies are of type λ or κ. Preferably, the antibody is an IgM antibody. Anti-Influenza virus antibody The term ‘anti-influenza virus antibody’, as used herein, includes reference to an antibody as disclosed herein, i.e. a bispecific antibody or antigen-binding fragment thereof that can be used in a treatment method of the invention. Preferably, the anti-influenza virus bispecific antibody or antigen-binding fragment thereof of the invention is able to treat different subtypes of influenza virus. For the avoidance of doubt, the term ‘anti-influenza virus antibody’, can be used interchangeably with ‘influenza virus antibody’. A composition In a preferred embodiment, an antibody disclosed herein is the sole active ingredient in a composition administered for treatment, e.g., the antibody is provided in a composition as the sole active ingredient. In a preferred embodiment, the active ingredients comprise a bispecific antibody or antigen-binding fragment thereof as disclosed herein, e.g., the bispecific antibody or antigen-binding fragment thereof is provided either as a composition as the sole active ingredient in a composition administered for treatment or in a combination with another antibody. Preferably, the composition of the invention is a water-based composition such as an aqueous liquid. Preferably, the composition of the invention further comprises one or more salts, for example sodium chloride. The composition of the invention may further comprise one or more buffering agents, for example sodium acetate. The composition of the invention may further comprise one or more carbohydrates, such as sucrose, or other active ingredients, such as other antibodies, neuraminidase inhibitors, endonuclease inhibitors, and adjuvants such as oils, cytokines, emulsifiers, or combinations thereof. The pH of the composition of the invention can be between 4 and 8, more preferably the pH is around 5.5. Preferably the pH is around 7.4. Mucosal composition The term ‘mucosal composition’, as used herein, refers to any pharmaceutical formulation that may be topically applied to a mucosal surface and delays or resists the mucosal flushing or removal action. The term ‘mucosal composition’, may be used in reference to a route of administration in which an antibody, as disclosed herein, is provided into the nasal cavity, oropharyngeal region or upper respiratory tract, preferably through the nostrils, as part of a prophylactic and / or therapeutic treatment as disclosed herein. Mucosally The mucosa comprises membranes that line cavities in the human body, covering internal organs, and consist of one or more layers of epithelial cells and loose connective tissue, which may produce mucus. The term ‘mucosally’, as used herein, may also be referred to as ‘mucosal administration’, and includes reference to a route of administration in which a drug is prophylactically and / or therapeutically provided to the mucosa, for example, mucosa found in the nose, mouth, lungs, vagina, rectum or stomach. The mucous membrane lubricates and protects these organs and cavities from abrasive particles and bodily fluids, as well as invasive pathogens. Preferably, the bispecific antibody or antigen-binding fragment thereof of the invention are administered mucosally. Intranasally The term ‘intranasally’, as used herein, may also be referred to as ‘nasal administration’, and includes reference to a route of administration in which a drug is provided into the upper respiratory tract and / or lower respiratory tract, preferably through the nostrils, as part of a prophylactic and / or therapeutic treatment as disclosed herein. Preferably, the administration provides for drug in the nasal cavity. The back section of the nasal cavity is also referred to as the pharynx. Nasal administration preferably provides for delivery of antibodies as disclosed herein in the mucous membrane lining the nasal cavity. Intranasal administration can be performed using, for instance, a nasal spray or nose drops. In some embodiments, the drug is delivered to the nasal cavity via the oral route. For example, RetroNose uses a breath-actuated pressurised metered-dose inhaler (pMDI) to administer drugs through the buccal cavity during the nasal expiratory phase. Such methods allow the drug particles to enter the nasal cavities through the pharynx. Preferably, the bispecific antibody or antigen-binding fragment thereof of the invention are administered intranasally. With intranasal administration, a drug is provided through the nostrils to the upper respiratory tract as part of a prophylactic and / or therapeutic treatment as disclosed herein. Preferably, the administration provides for drug in the nasal cavity. Nasal administration can either be a form of topical administration or systemic administration, as the drugs thus locally delivered can go on to have either local or systemic effects. In the present case, with antibodies as disclosed herein, nasal administration is preferably a form of topical administration. Intranasal administration as disclosed herein may be done using a medicament in liquid form, preferably in the form of drops or nasal spray. The aqueous liquid may comprise adjuvants. These adjuvants may for example be salts, oils, cytokines, emulsifiers, buffering agents, carbohydrates and combinations thereof. Intranasal administration may also be done using a medicament in solid form, such as powders. Oral inhalation The term ‘oral inhalation’, as used herein, may also be referred to as ‘mouth inhalation’, and includes reference to a route of administration in which a drug is provided through the mouth to the upper and / or lower respiratory tract such as lungs, as part of a prophylactic and / or therapeutic treatment of the invention. Oral inhalation may for example be applied for drugs in their powdered form and drugs in the form of liquid droplets or aerosols. Preferably, the bispecific antibody or antigen-binding fragment thereof of the invention are administered by oral inhalation. With oral inhalation, a drug is provided through the mouth to the respiratory tract, preferably lower respiratory tract such as lungs, as part of a prophylactic and / or therapeutic treatment of the invention. As described further herein, oral inhalation also includes nasal drug delivery (also referred to as nasal drug delivery via the oral route). Oral inhalation may for example be applied for drugs in their powdered form and drugs in the form of liquid droplets or aerosols. Oral inhalation may include the use of an inhaler. The inhaler may be involved in the achievement of the dose that was determined. The drug that is administered by oral inhalation may reach the lung but may also partially be cleared out by exhalation. Administration by oral inhalation as disclosed herein may be done using a medicament comprising aerosols in powdered (solid) or liquid form. Powdered aerosols comprising particles smaller than 3 µm in diameter will primarily reach the respiratory region of the lung, and will therefore be absorbed better than larger particles. The medicament may comprise adjuvants. These adjuvants may for example be salts, oils, cytokines, emulsifiers, buffering agents, carbohydrates and combinations thereof. Oropharyngeal administration The term ‘oropharyngeal administration’, as used herein, may also be referred to as delivery to the part of the pharynx that lies between the soft palate and the hyoid bone and includes reference to a route of administration in which a drug is provided via either the mouth or nasal passages as part of a prophylactic and / or therapeutic treatment. Oropharyngeal administration may, for example, be used for drugs in their powdered form and drugs in the form of liquid droplets or aerosols. Preferably, the bispecific antibody or antigen-binding fragment thereof of the invention are administered by oropharyngeal administration. Prior to The term ‘prior to’, as used herein, includes reference to the administration of a bispecific antibody or antigen-binding fragment thereof before an individual has been exposed to, or is infected with, an influenza virus. Preferably, the bispecific antibody or antigen-binding fragment thereof as disclosed is administered to an individual up to 24 hours prior to influenza virus exposure, for example between zero and 24 hours before the individual has been exposed to said influenza virus. Preferably, the bispecific antibody or antigen-binding fragment thereof as disclosed is administered to an individual up to 48 hours prior to influenza virus exposure, for example between zero and 48 hours before the individual has been exposed to said influenza virus. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 2 days or more prior to influenza virus exposure. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 3 days or more prior to influenza virus exposure. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 4 days, or more prior to influenza virus exposure. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 5 days or more prior to influenza virus exposure. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 6 days or more prior to influenza virus exposure. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered 7 days or more prior to influenza virus exposure. Dosage The term ‘dosage’ as used herein, refers to the amount of bispecific antibody or antigen- binding fragment thereof to be given at a particular time (e.g., over the course of a 24- hour, 12-hour, 30-minute period, etc.). A dose refers to a single dosing episode, whether the dose is a unit dosage form or multiple unit dosage forms taken together (e.g., ingestion of two or more pills, receiving two or more nasal administrations). A dosage includes reference to a pharmaceutical dosage form wherein the medicament is packaged for administration as, e.g., a single-unit dose or multiple-unit dose. A dosage may also be administered as, e.g., one or more drops of an antibody-comprising composition (e.g., nasal drops) or one or more sprays of an antibody-comprising composition (e.g., nasal sprays). Preferably, a suitable dosage of a bispecific antibody or antigen-binding fragment thereof as disclosed herein contains a dose of between 0.01 mg and 20 mg, preferably 0.1 mg and 15 mg, more preferably around 0.5 mg and 10 mg or even around 1 mg, e.g. when the dosage is for intranasal administration. Such dosages are also referred to as “flat dosages” or “nominal dosages” in contrast to dosages based on the weight of the patient. Flat dosages have the advantage that the medicament can be packaged in a single-unit dose, for example. A single dose of an antibody according to the present invention can provide protection from influenza virus infection for several days and may be provided “on demand” or “as needed”. For example, an individual may administer antibody before leaving the house or before coming into contact with other individuals. In order to provide long-lasting protection, the antibody may be administered on a regular basis. For example, the bispecific antibody or antigen-binding fragment thereof is administered once, or at least once per month. In a preferred embodiment, the antibody is administered once, or at least once per week, e.g., twice weekly. In a preferred embodiment, the bispecific antibody or antigen-binding fragment thereof is administered once, or at least once per day. As is clear to a skilled person, less antibody may be administered when the antibody is administered more frequently (e.g., daily). In a preferred embodiment, between 0.01 mg to 20 mg of bispecific antibody or antigen-binding fragment thereof is administered per week (e.g., once or twice weekly or daily). The invention also provides a composition formulated for intranasal administration and / or oral inhalation comprising a bispecific antibody or antigen-binding fragment thereof as disclosed herein, preferably in a single dose unit between 0.1 mg to 20 mg, preferably 0.5 mg to 15 mg or preferably 1 mg to 12.5 mg. A kit comprising the bispecific antibody of the invention The present invention provides a kit comprising the bispecific antibody or antigen-binding fragment thereof as disclosed herein, wherein the kit further comprises at least one pharmaceutically acceptable excipient. For the purpose of prophylactic and / or therapeutic treatment of influenza infection as disclosed herein, at least one compound may conveniently be combined into a kit. Thus, the term "kit" as disclosed herein, includes the antibody as disclosed herein and at least one compound for prolonging the prophylactic and / or therapeutic effect of the antibody in a human subject, for prolonging the shelf life of the bispecific antibody or antigen-binding fragment thereof as disclosed herein, and / or for maintaining the quality of the antibody, and means for retaining the antibody and at least one compound. Human subjects, for the purpose of prophylactic and / or therapeutic treatment can readily follow the labels and / or instructions to apply the bispecific antibody or antigen-binding fragment thereof and the compound. Use in a method for treatment The present invention relates inter alia to an antibody as disclosed herein, for use in a method for treatment of influenza virus infection in an individual, more specifically the bispecific antibody or antigen-binding fragment thereof can be used in a method for the prophylactic and / or therapeutic treatment of influenza virus infection in an individual. Complementarity-determining regions (CDRs) Preferably, the CDR regions are identified according to Kabat et al. (1991) as described in Sequences of Proteins of Immunological Interest. In a preferred embodiment, the binding interaction of the binding molecules, preferably the bispecific antibody, and the hemagglutinin is mediated exclusively by heavy chain variable sequences. In a preferred embodiment, the binding interaction of the binding molecules, preferably the bispecific antibody, and the neuraminidase is mediated exclusively by light and heavy chain variable sequences. The bispecific antibody or antigen-binding fragment thereof as disclosed herein may be capable of specifically binding to an influenza virus that is in attenuated or inactivated form or that is viable, and / or in an infective form. The bispecific antibody or antigen-binding fragment thereof as disclosed herein is also capable of specifically binding to one or more fragments of the influenza virus. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred heavy chain CDR1 sequence comprising SEQ ID NO: 001. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred heavy chain CDR2 sequence comprising SEQ ID NO: 002. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred heavy chain CDR3 sequence comprising SEQ ID NO: 003. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred light chain CDR1 sequence comprising SEQ ID NO: 004. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred light chain CDR2 sequence comprising SEQ ID NO: 005. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a preferred light chain CDR3 sequence comprising SEQ ID NO: 006. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR1 of SEQ ID NO: 009. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR2 of SEQ ID NO: 010. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR3 of SEQ ID NO: 011. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR4 of SEQ ID NO: 012. In a preferred embodiment, the heavy chain variable domain of said bispecific antibody or antigen-binding fragment thereof comprises - a heavy chain framework region FR1 of SEQ ID NO: 009, a heavy chain framework region FR2 of SEQ ID NO: 010, a heavy chain framework region FR3 of SEQ ID NO: 011, and / or a heavy chain framework region FR4 of SEQ ID NO: 012, preferably all said heavy chain heavy chain framework regions FR1 to FR4. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR1 of SEQ ID NO: 013. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR2 of SEQ ID NO: 014. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR3 of SEQ ID NO: 015. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR4 of SEQ ID NO: 016. In a preferred embodiment, the light chain variable domain of said bispecific antibody or antigen-binding fragment thereof comprises - a light chain framework region FR1 of SEQ ID NO: 013, a light chain framework region FR2 of SEQ ID NO: 014, a light chain framework region FR3 of SEQ ID NO: 015, and / or a light chain framework region FR4 of SEQ ID NO: 016, preferably all said light chain framework regions are FR1 to FR4. In treatment methods of the invention, the heavy chain variable domain (VH) of the bispecific antibody comprising a first arm comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 003, and a light chain variable domain (VL) comprising a LCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 006. In treatment methods of the invention, the heavy chain variable domain (VH) of the bispecific antibody comprises a second arm comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 019, and a light chain variable domain (VL) comprising a LCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 022. Preferably, a antibody or antigen-binding fragment thereof as disclosed herein comprises a first arm having a heavy chain variable domain having the sequence of SEQ ID NO: 007 having at most 15, preferably 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably having 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions. Preferably, a antibody or antigen-binding fragment thereof as disclosed herein comprises a first arm having a light chain variable domain having the sequence of SEQ ID NO: 008 having at most 15, preferably 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably having 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions. Preferably, a antibody or antigen-binding fragment thereof as disclosed herein comprises a second arm having a heavy chain variable domain having the sequence of SEQ ID NO: 023 having at most 15, preferably 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably having 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions. Preferably, a antibody or antigen-binding fragment thereof as disclosed herein comprises a second arm having a light chain variable domain having the sequence of SEQ ID NO: 024 having at most 15, preferably 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably having 0, 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR1 of SEQ ID NO: 025. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR2 of SEQ ID NO: 026. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR3 of SEQ ID NO: 027. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a heavy chain framework region FR4 of SEQ ID NO: 028. In a preferred embodiment, the heavy chain variable domain of said bispecific antibody or antigen-binding fragment thereof comprises - a heavy chain framework region FR1 of SEQ ID NO: 025, a heavy chain framework region FR2 of SEQ ID NO: 026, a heavy chain framework region FR3 of SEQ ID NO: 027, and / or a heavy chain framework region FR4 of SEQ ID NO: 028, preferably all said heavy chain heavy chain framework regions FR1 to FR4. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR1 of SEQ ID NO: 029. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR2 of SEQ ID NO: 030. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR3 of SEQ ID NO: 031. A bispecific antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable domain that further comprises at least a light chain framework region FR4 of SEQ ID NO: 032. In a preferred embodiment, the light chain variable domain of said bispecific antibody or antigen-binding fragment thereof comprises - a light chain framework region FR1 of SEQ ID NO: 029, a light chain framework region FR2 of SEQ ID NO: 030, a light chain framework region FR3 of SEQ ID NO: 031, and / or a light chain framework region FR4 of SEQ ID NO: 032, preferably all said light chain framework regions are FR1 to FR4. Preferably, said amino acid insertions, deletions, substitutions in respect of either the heavy chain variable domain and / or the light chain variable domain are not in the CDRs. Bispecific frameworks LLC0010- Bispecific antibody according to the invention Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH- CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein the constant domains CL and CH1 from the second arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 033 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 034, and (b.) a second arm which comprises a heavy chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 035 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 036, wherein the constant domains CL and CH1 from the second arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 033 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 034, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, and (b.) a second arm which comprises a heavy chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 035 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 036, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein the constant domains CL and CH1 from the second arm are replaced by each other. LLC0021 – Bispecific antibody according to the invention Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH- CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein the constant domains CL and CH1 from the first arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 037 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 038, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 039 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 040, wherein the constant domains CL and CH1 from the first arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 037 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 038, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 039 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 040, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, wherein the constant domains CL and CH1 from the first arm are replaced by each other. LLC0022 – Bispecific antibody according to the invention Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH- CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein domains VL-CL and VH-CH1 from the second arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 033 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 034, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 041 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 042, wherein domains VL-CL and VH-CH1 from the second arm are replaced by each other. Preferably, a bispecific antibody or an antigen-binding fragment thereof is disclosed, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 033 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 034, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2 and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO.: 041 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO.: 042, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, wherein domains VL-CL and VH-CH1 from the second arm are replaced by each other. SEQUENCES CDRs and framework regions defined herein are based on the Kabat numbering scheme as described in Sequences of Proteins of Immunological Interest (Kabat et al., 1991). Heavy chain CR9114 (Parental Antibody 1) CDR1 region SEQ ID NO.: 001 NYAIS Heavy chain CR9114 (Parental Antibody 1) CDR2 region SEQ ID NO.: 002 GISPIFGSTAYAQKFQG Heavy chain CR9114 (Parental Antibody 1) CDR3 region SEQ ID NO.: 003 HGNYYYYSGMDV Light chain CR9114 (Parental Antibody 1) CDR1 region SEQ ID NO.: 004 SGSDSNIGRRSVN Light chain CR9114 (Parental Antibody 1) CDR2 region SEQ ID NO.: 005 SNDQRPS Light chain CR9114 (Parental Antibody 1) CDR3 region SEQ ID NO.: 006 AAWDDSLKGAV Heavy chain CR9114 (Parental Antibody 1) variable domain SEQ ID NO.: 007 QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMGGISPIFGS TAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGNYYYYSGMDVWGQ GTTVTVSS Light chain CR9114 (Parental Antibody 1) variable domain SEQ ID NO.: 008 QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSNDQRPSV VPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGGGTQLTVL Heavy chain CR9114 (Parental Antibody 1) FR1 region SEQ ID NO.: 009 QVQLVQSGAEVKKPGSSVKVSCKSSGGTSN Heavy chain CR9114 (Parental Antibody 1) FR2 region SEQ ID NO.: 010 WVRQAPGQGLDWMG Heavy chain CR9114 (Parental Antibody 1) FR3 region SEQ ID NO.: 011 RVTISADIFSNTAYMELNSLTSEDTAVYFCAR Heavy chain CR9114 (Parental Antibody 1) FR4 region SEQ ID NO.: 012 WGQGTTVTVSS Light chain CR9114 (Parental Antibody 1) FR1 region SEQ ID NO.: 013 QSALTQPPAVSGTPGQRVTISC Light chain CR9114 (Parental Antibody 1) FR2 region SEQ ID NO.: 014 WYQQFPGTAPKLLIY Light chain CR9114 (Parental Antibody 1) FR3 region SEQ ID NO.: 015 VVPDRFSGSKSGTSASLAISGLQSEDEAEYYC Light chain CR9114 (Parental Antibody 1) FR4 region SEQ ID NO.: 016 FGGGTQLTVL Heavy chain 1G01 (Parental Antibody 2) CDR1 region SEQ ID NO.: 017 DYAMS Heavy chain 1G01 (Parental Antibody 2) CDR2 region SEQ ID NO.: 018 GLNWNGDITAYTDSVKG Heavy chain 1G01 (Parental Antibody 2) CDR3 region SEQ ID NO.: 019 TSSWGDYTRGPEPKITWYFDL Light chain 1G01 (Parental Antibody 2) CDR1 region SEQ ID NO.: 020 RASQGIDGYLA Light chain 1G01 (Parental Antibody 2) CDR2 region SEQ ID NO.: 021 AASLLQS Light chain 1G01 (Parental Antibody 2) CDR3 region SEQ ID NO.: 022 QHLDSYPLFT Heavy chain 1G01 (Parental Antibody 2) variable domain SEQ ID NO.: 023 EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSGLNWNG DITAYTDSVKGRFTVSRDNAKNSLYLHINSPKPEDTALYYCARTSSWGDYTRGPEPKI TWYFDLWGRGTLVTVSS Light chain 1G01 (Parental Antibody 2) variable domain SEQ ID NO.: 024 DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAASLLQSGVP SRFSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLFTFGPGTKVDIK Heavy chain 1G01 (Parental Antibody 2) FR1 region SEQ ID NO.: 025 EVQLVESGGRALRPGGSLRLSCAASGFKFD Heavy chain 1G01 (Parental Antibody 2) FR2 region SEQ ID NO.: 026 WVRQVPGKGLEFVS Heavy chain 1G01 (Parental Antibody 2) FR3 region SEQ ID NO.: 027 RFTVSRDNAKNSLYLHINSPKPEDTALYYCAR Heavy chain 1G01 (Parental Antibody 2) FR4 region SEQ ID NO.: 028 WGRGTLVTVSS Light chain 1G01 (Parental Antibody 2) FR1 region SEQ ID NO.: 029 DIQLTQSPSFLSASVGDRITITC Light chain 1G01 (Parental Antibody 2) FR2 region SEQ ID NO.: 030 WYQQRPGKAPNLLIY Light chain 1G01 (Parental Antibody 2) FR3 region SEQ ID NO.: 031 GVPSRFSGSGYGTEFTLTISSLQPEDFATYYC Light chain 1G01 (Parental Antibody 2) FR4 region SEQ ID NO.: 032 FGPGTKVDIK LLC0010 Heavy Chain of CR9114 arm SEQ ID NO.: 033 QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMGGISPIFGS TAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGNYYYYSGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LLC0010 Light Chain of CR9114 arm SEQ ID NO.: 034 QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSNDQRPSV VPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGGGTQLTVLGQPKA APSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS LLC0010 Heavy Chain of 1G01 arm SEQ ID NO.: 035 EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSGLNWNG DITAYTDSVKGRFTVSRDNAKNSLYLHINSPKPEDTALYYCARTSSWGDYTRGPEPKI TWYFDLWGRGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGECDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK LLC0010 Light Chain of 1G01 arm SEQ ID NO.: 036 DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAASLLQSGVP SRFSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLFTFGPGTKVDIKSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LLC0021 Heavy Chain of CR9114 arm SEQ ID NO.: 037 QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMGGISPIFGS TAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGNYYYYSGMDVWGQ GTTVTVSGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKA GVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LLC0021 Light Chain of CR9114 arm SEQ ID NO.: 038 QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSNDQRPSV VPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGGGTQLTVLSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC LLC0021 Heavy Chain of 1G01 arm SEQ ID NO.: 039 EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSGLNWNG DITAYTDSVKGRFTVSRDNAKNSLYLHINSPKPEDTALYYCARTSSWGDYTRGPEPKI TWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK LLC0021 Light Chain of 1G01 arm SEQ ID NO.: 040 DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAASLLQSGVP SRFSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLFTFGPGTKVDIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC LLC0022 Heavy Chain of CR9114 arm SEQ ID NO.: 033 QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMGGISPIFGS TAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGNYYYYSGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LLC0022 Light Chain of CR9114 arm SEQ ID NO.: 034 QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSNDQRPSV VPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGGGTQLTVLGQPKA APSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS LLC0022 Heavy Chain of 1G01 arm SEQ ID NO.: 041 DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAASLLQSGVP SRFSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLFTFGPGTKVDIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVC TLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL VSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK LLC0022 Light Chain of 1G01 arm SEQ ID NO.: 042 EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSGLNWNG DITAYTDSVKGRFTVSRDNAKNSLYLHINSPKPEDTALYYCARTSSWGDYTRGPEPKI TWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSC EXAMPLES The bispecific antibody is tested in vitro for binding and functional assays against a variety of influenza A and B strains. Binding affinity is tested in an enzyme-linked immunosorbent assay (ELISA) assay against a number of neuraminidase (NA) and hemagglutinin (HA) antigens, including H1N1, H3N2, H5N1, H7N9 and influenza B Victoria and Yamagata strains. The single parental antibodies are tested in comparison to the bispecific antibody. The bispecific antibody is tested against all strains listed in the range of 0.00002-100 nM compared to the individual control antibodies CR9114 and 1G01. The bispecific antibody is tested for functional activity in a neutralization assay against different influenza strains including H1N1 Michigan, H3N2 Hong Kong, B Florida and B Brisbane influenza strains by binding specifically to the hemagglutinin and neuraminidase surface antigens of an influenza virion, a binding region shared with bispecific antibodies of the present invention. The bispecific antibody is tested for neutralizing activity in the range of 0.0051- 100 µg / ml compared to the individual control antibodies CR9114 and 1G01. Moreover, the bispecific antibody and the parental antibodies are tested for the ability to inhibit neuraminidase enzymatic activity. One common assay is the enzyme-linked lectin assay (ELLA). The assay measures the ability of neuraminidase to cleave sialic acid residues from a substrate, and the removal of sialic acid exposes a galactose residue. ELLA measures the amount of galactose that is available after cleavage and is specific for neuraminidase inhibition via binding or steric hindrance. Another option is the NA-Star assay which is insensitive to steric hindrance and uses a small soluble chemiluminescent substrate and therefore distinguishes antibodies that directly inhibit the enzymatic activity of neuraminidase by binding close to the enzymatic site. Viral egress inhibition assay is performed to assess the effect of the bispecific antibody to prevent viral particle release. Thus, a susceptible cell line is infected with virus, and then antibody is added to block viral egress, the number of infected particles in the cell supernatant is assessed. This assay can detect both direct blockage of the active site as well as through steric hindrance. The bispecific antibody is tested in one or multiple of these assays against H1N1, H3N2 and influenza B Victoria and Yamagata strains in the range of 0.005-100 µg / ml compared to the individual control antibodies CR9114 and 1G01. After the in vitro assessments, in vivo studies are performed. There are several methods to generate Y-shaped bispecific antibodies. One method is the DuoBody® technology (Denmark, Genmab A / S). The technology uses a controlled Fab- arm exchange redox reaction of two parental homodimeric antibodies to generate a bispecific antibody. The parental mAbs are produced separately and then combined via the reduction of the hinge region disulfide bonds, accompanied by "knobs into holes" (KiH) technology, as disclosed below, for heterodimer formation. Another method is the IgG-like dual-variable-domain format (DVD-Ig), which is a tetravalent IgG-like molecule, designed by attaching Variable Light (VL) and Variable Heavy (VH) domains to the N termini of the same domain of another binding specificity antibody. Moreover, there are several methods to align the heavy chains correctly and / or the light chains of the antibodies when generating Y-shaped bispecific antibodies. One example for aligning the heavy chains is the KiH technology. Correct heavy chain pairing can be achieved by introducing large amino acid side chains into the CH3 domain of one heavy chain that fit into a corresponding cavity in the CH3 domain of the other heavy chain, Aligning the correct light chains is achieved by the technology called CrossMab, which only allows for the pairing of corresponding heavy and light chains and therefore achieves a higher rate of correctly assembled bispecific antibodies. Another variation of this method includes the replacement of the VH domain by VL domain (CrossMabVH-VL) or the interchange of CH1 and CL (CrossMabCH1-CL), both resulting in CrossMab formats. Example 1: Intranasal administration of the bispecific in the treatment of influenza A1. The objective of this study is to compare the prophylactic efficacy of a single dose of a bispecific antibody having a first antigen-binding domain (first arm) that binds to hemagglutinin, the antigen-binding domain having a VH domain with a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH domain having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022, with that of a single dose of each parental antibody: CR9114 or 1G01 (Parental 1 or Parental 2) administered intranasally (IN) against challenge with influenza A1 virus. Materials & methods Preparation The test item is a bispecific human monoclonal antibody as described above produced in HEK293 cells (referred to herein as Test Antibody). The virus strain tested is Influenza virus A1, which is stored at -75°C ± 10°C under temperature monitoring and restricted access. Animals The animal species and breed is Mouse (Mus musculus), BALB / c AnNCrl, SPF at a weight of ~ 16-20 g on the day of arrival at the facility. Mice are used at the age of 6-8 weeks on the day of arrival at the facility and are exclusively female. Animals are randomly allocated to treatment groups. Potable water from the public supply is available ad libitum from water bottles. The animals have free access to feed (RMH-B from Altromin, Germany). Mice are maintained between a minimum and maximum temperature of 20.9°C and 21.4°C and at relative humidity percentage between 35 and 42%, under artificial lighting with 12 hours light and 12 hours dark. Study design The dose level of Test Antibody applied in the current example is based on previous parental antibody efficacy data. Mice, 6-8 weeks of age at the time of arrival, are transported to the animal Facility and allocated to experimental groups according to Table 1. Mice are given a period of 3-6 days for acclimatization. Table 1. Treatment schedule Test group mAb IgG Admin. route DoseDay of (mg / kg) admin.No. of Animals1 Parental 1 IN 0.001-15 -1 6-10 2Parental 1 IN0.001-15 -16-103Parental 1 IN0.001-15 -16-104 Parental 1 IN 0.001-15 -1 6-10 5 Parental 2IN0.001-15 -1 6-10 6Parental 2 IN0.001-15 -16-107 Parental 2 IN 0.001-15 -1 6-10 8 Parental 2 IN 0.001-15 -1 6-10 9 Bispecific IN 0.001-15 -1 6-10 10 BispecificIN0.001-15 -16-1011 BispecificIN0.001-15 -16-1012 Bispecific IN 0.001-15 -1 6-10 13 Bispecific IN 0.001-15 -1 6-10 14 BispecificIN0.001-15 -16-1015 Placebo PBSIN- -16-10The mice are treated via the intranasal route of administration with compositions comprising either parental antibodies or the bispecific antibody at dose ranges between 0.001 and 15 mg / kg. On Day 0, all mice are challenged with a lethal dose of Influenza A1 virus and observed for clinical signs and weight loss until the end of the study at day 21. Antibody administration The monoclonal antibody (mAb) of the Test Antibody preparation is stored at -75°C ± 10°C upon arrival. The appropriate dose, according to the treatment schedule (Table1), is formulated assuming an average weight of the mice of 20 g. On the day of administration, the material is kept on ice during transfer to the animal facility. Just prior to dosing, the material is drawn into a syringe, allowed briefly to warm to room temperature and then injected. The animals are anesthetized by inhalation with isoflurane and receive the indicated dose by intranasal inoculation of 0.030 mL divided between both nostrils using a pipette tip. Virus administration The virus material is stored at -75°C ± 10°C and defrosted prior to administration. Once defrosted, the material is diluted in cold PBS and kept on ice until administration to the mice. The animals are anesthetized by inhalation with isoflurane and each animal receives approximately 30 µL of virus by intranasal inoculation using a pipette tip. Unused material is returned on ice to the lab for back titration along with the material that was kept on ice in the lab during inoculation of the animals. Laboratory analysis Laboratory analyses are performed in class II biological safety cabinets. Inoculum is returned to the lab and the actual dose of the virus administered was verified by titrating eight replicate samples on MDCK cells. Virus titres (TCID50 / mL) are determined by the method of Reed and Münch. Clinical monitoring General health observations are performed on each animal from the day of arrival until the end of the study at least once daily (during normal servicing procedures). Clinical signs are scored from day -1 until the end of the study on day 21 using a scoring system (0=no clinical signs; 1=rough coat; 2=rough coat, less reactive during handling; 3=rough coat, rolled up, labored breathing, less reactive during handling; 4=rough coat, rolled up, labored breathing, inactive in response to manipulation / handlings). Animals are inspected twice a day as long as they received a score of 3 and were euthanized when they received a score of 4 (humane end point). Each animal is weighed daily beginning one day prior to infection (day -1). Calibrated weighing scales are used. Terminal investigations At the end of the study, on day 21, mice are euthanized by CO2 asphyxiation. Gross necropsy is not performed. Data analysis and statistical methods Repeated body weight and clinical score measurements in the challenge phase are summarized as a single outcome per animal using an Area Under the Curve (AUC) approach where missing values for any animals that died before day 21 are imputed with a last-observation-carried-forward method. Body weight data is expressed as the change relative to the day 0 measurement. The AUC is defined as the summation of the area above and below the day 0 measurement. Survival proportions at day 21, survival times, change in bodyweight (using the Area Under the Curve) and clinical scores (using the Area Under the Curve) are summarized by group. Survival dose response curves are analyzed using Probit regression. For each mAb, the median effective dose is estimated and the differences between parental and bispecific antibodies tested for statistical significance. Statistical analysis is performed using R and statistical significance is set at α = 0.05. Example 1A: Intranasal administration of the bispecific in the treatment of influenza A1. The objective of this study was to compare the prophylactic efficacy of a single dose of a Bispecific Antibody having a first antigen-binding domain (first arm) that binds to hemagglutinin, the antigen-binding domain having a VH with a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022, with that of a single dose of CR9114 (Parental Antibody 1) as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 administered intranasally (IN) against challenge with influenza H1N1 (A1) virus. Study Set-up The test item was a Bispecific Antibody as described above produced in HEK293 cells and formulated in PBS. The Bispecific Antibody was compared to CR9114 (Parental Antibody 1), also produced in HEK293 cells and formulated in 20 mM Sodium acetate, 75mM NaCl, 5% Sucrose, pH 5.5. On Day -1, 122 adult female BALB / c mice at a weight of ~ 20 g (6-8 weeks) on the day of arrival at the facility were weighed and randomly assigned to experimental groups that produced similar group mean bodyweight values. Antibodies were administered intranasally in a volume of 35 ^l split between the nares with a pipette tip based on an assumed bodyweight of 20g on D-1 to treatment groups (n=8) or vehicle control group (n=10) according to Table 1A. On Day 0, animals were challenged intranasally with a dose of ~ 50 TCID50 of A / Puerto Rico / 8 / 1934 (H1N1) (PR8) in a volume of 35 ^l split between the nares. A sample of the inoculum was taken and used to confirm the infectious titer by a TCID50 assay. Animals were monitored daily until D21 for clinical signs of ill-health and bodyweights were recorded daily and percentage change in weight compared with pre-infection (Day 0) weight. Animals were terminated if their bodyweight loss, clinical score, or combination of both, exceeded humane endpoints. Table 1A. Treatment schedule Test Admin. Dose Day of No. of mAb IgG group route (mg / kg) admin. Animals 1 IN 0.19 -1 8 2 IN 0.1 -1 8 3 Parental IN 0.048 -1 8 4 Antibody 1 IN 0.024 -1 8 5 IN 0.012 -1 8 6 IN 0.006 -1 8 7 IN 5 -1 8 8 IN 1.67 -1 8 9 IN 0.56 -1 8 10 Bispecific IN 0.185 -1 8 11 Antibody IN 0.062 -1 8 12 IN 0.021 -1 8 13 IN 0.007 -1 8 14 IN 0.002 -1 8 Vehicle IN 10 15 - -1 control Data analysis and statistical methods Survival proportions at Day 21 and change in bodyweight (using the Area Under the Curve) were compared to the control group using Fisher’s exact test, and Welch's t-test, respectively. Survival proportions at Day 21 were used to estimate the survival dose response curve using Probit regression. The model was used to estimate the median effective dose and determine the ratio between the Bispecific Antibody and CR9114 (Parental Antibody 1). Group wise comparisons to the vehicle control group were adjusted according to Bonferroni for two treatment comparisons against control followed with a stepwise approach for each treatment group (starting with the highest dose and conditionally testing the lower dose if the previous dose was statistically significant). Results The vehicle control group showed 0% survival with a median survival time of 6 days. It was observed that prophylactic intranasal treatment with ≥ 0.007 mg / kg of the Bispecific Antibody and ≥ 0.006 mg / kg of CR9114 (Parental Antibody 1) provided a statistically significant increase in survival compared to control group (See Figure 1A and Figure 2A). While the minimal effective doses were similar between the Bispecific Antibody and CR9114 (Parental Antibody 1), the Bispecific Antibody at 0.007 mg / kg resulted in 87.5% survival and CR9114 (Parental Antibody 1) at 0.006 mg / kg in 50% survival. Regarding bodyweight loss, an intranasal dose of ≥ 0.007 mg / kg of the Bispecific Antibody and ≥ 0.012 mg / kg of CR9114 (Parental Antibody 1) provided a statistically significant reduction in bodyweight loss compared to the vehicle group (See Figure 1B and 2B). Therefore, the Bispecific Antibody requires a lower minimal effective dose and doses >0.002 result in lower body weight loss compared to the CR9114 (Parental Antibody 1) at comparable doses. The intranasal median effective dose was comparable for the Bispecific Antibody and the CR9114 (Parental Antibody 1), as depicted in Table 2A, no significant difference in ED50 was observed (See Figure 1C and 2C), based on the ratio of the Bispecific Antibody over the Parental Antibody being 0.84 with a 95% confidence interval including 1 (0.37- 1.94). Table 2A: Estimated ED50s (in mg / kg, rounded to three decimals). Treatment ED50 (mg / kg, 95% confidence interval (CI.)) Parental Antibody 1 0.006 (0.004 – 0.011) Bispecific Antibody 0.005 (0.003 – 0.010) The results of this study demonstrated that, in this Influenza H1N1 PR8 mouse model, the prophylactic intranasal administration of the Bispecific Antibody according to the invention at doses ≥ 0.007 mg / kg (as indicated in Table 1A) provides significant increase in survival and a reduction in body weight loss compared to the control group. While the median effective dose determined for the Bispecific Antibody was not significantly different to that for CR9114 (Parental Antibody 1), reduced bodyweight loss was observed for the Bispecific Antibody. Moreover, literature suggests an expected drop in avidity (which refers to the ability of the antibody as a whole to bind to the epitope and not specifically each Fab, which would be referred to as "affinity") due to monovalency of the Bispecific Antibody and the retained potency in vivo indicates that binding two epitopes on influenza A1 can compensate for this. Example 2: Intranasal administration of the bispecific in the treatment of influenza A2. The objective of this study is to compare the prophylactic efficacy of a single dose of a bispecific antibody having a first antigen-binding domain (first arm) that binds to hemagglutinin, the antigen-binding domain having a VH domain with a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH domain having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022, with that of a single dose of each parental antibody: CR9114 or 1G01 (Parental 1 or Parental 2) administered intranasally (IN) against challenge with influenza A2 virus. Materials & methods Preparation The test item is the described bispecific human monoclonal antibody as described above produced in HEK293 cells (referred to herein as Test Antibody). The virus strain tested was Influenza virus A2, which is stored at -75°C ± 10°C under temperature monitoring and restricted access. Animals The animal species and breed is Mouse (Mus musculus), 129X1 / SvJ, SPF at a weight of ~ 16-20 g on the day of arrival at the facility. Mice are used at the age of 6-8 weeks on the day of arrival at the facility and are exclusively female. Animals are randomly allocated to treatment groups. Potable water from the public supply is available ad libitum from water bottles. The animals have free access to feed (RMH-B from Altromin, Germany). Mice are maintained between a minimum and maximum temperature of 20.9°C and 21.4°C and at relative humidity percentage between 35 and 42%, under artificial lighting with 12 hours light and 12 hours dark. Study design The dose level of Test Antibody applied in the current example is based on previous parental antibody efficacy data. Mice, 6-8 weeks of age at the time of arrival, are transported to the animal Facility and allocated to experimental groups according to Table 2. Mice are given a period of 3-6 days for acclimatization. Table 2. Treatment schedule Test group mAb IgG Admin. route DoseDay of (mg / kg) admin.No. of Animals1 Parental 1 IN 0.001-15 -1 6-10 2Parental 1 IN0.001-15 -16-103Parental 1 IN0.001-15 -16-104 Parental 1 IN 0.001-15 -1 6-10 5 Parental 2IN0.001-15 -1 6-10 6 Parental 2 IN 0.001-15 -1 6-10 7 Parental 2 IN 0.001-15 -1 6-10 8Parental 2 IN0.001-15 -16-109 BispecificIN0.001-15 -16-1010 Bispecific IN 0.001-15 -1 6-10 11 Bispecific IN 0.001-15 -1 6-10 12 BispecificIN0.001-15 -16-1013 BispecificIN0.001-15 -16-1014 Bispecific IN 0.001-15 -1 6-10 15 Placebo PBS IN - -1 6-10 The mice are treated via the intranasal route of administration with compositions comprising either parental antibodies or the bispecific antibody at dose ranges between 0.001 and 15 mg / kg. On Day 0, all mice are challenged with a lethal dose of Influenza A2 virus and observed for clinical signs and weight loss until the end of the study at day 21. Antibody administration The monoclonal antibody (mAb) of the Test Antibody preparation is stored at -75°C ± 10°C upon arrival. The appropriate dose, according to the treatment schedule (Table2), is formulated assuming an average weight of the mice of 20 g. On the day of administration, the material is kept on ice during transfer to the animal facility. Just prior to dosing, the material is drawn into a syringe, allowed briefly to warm to room temperature and then injected. The animals are anesthetised by intraperitoneal injection of a mixture of ketamine / xylazine and receive the indicated dose by intranasal inoculation of 0.1 mL divided between both nostrils using a pipette tip. Virus administration The virus material is stored at -75°C ± 10°C and is defrosted prior to administration. Once defrosted, the material is diluted in cold PBS and kept on ice until administration to the mice. The animals are anesthetized by intraperitoneal injection of a mixture of ketamine / xylazine and each animal receives approximately 50 µL of virus by intranasal inoculation using a pipette tip. Unused material is returned on ice to the lab for back titration along with the material that is kept on ice in the lab during inoculation of the animals. Laboratory analysis Laboratory analyses are performed in class II biological safety cabinets. Inoculum is returned to the lab and the actual dose of the virus administered is verified by titrating eight replicate samples on MDCK cells. Virus titres (TCID50 / mL) are determined by the method of Reed and Münch. Clinical monitoring General health observations are performed on each animal from the day of arrival until the end of the study at least once daily (during normal servicing procedures). Clinical signs are scored from day -1 until the end of the study on day 21 using a scoring system (0=no clinical signs; 1=rough coat; 2=rough coat, less reactive during handling; 3=rough coat, rolled up, labored breathing, less reactive during handling; 4=rough coat, rolled up, labored breathing, inactive in response to manipulation / handlings). Animals are inspected twice a day as long as they received a score of 3 and are euthanized when they received a score of 4 (humane end point). Each animal is weighed daily beginning one day prior to infection (day -1). Calibrated weighing scales are used. Terminal investigations At the end of the study, on day 21, mice were euthanized by cervical dislocation. Gross necropsy is not performed. Data analysis and statistical methods Repeated body weight and clinical score measurements in the challenge phase is summarized as a single outcome per animal using an Area Under the Curve (AUC) approach where missing values for animals that died before day 21 are imputed with a last-observation-carried-forward method. Body weight data is expressed as the change relative to the day 0 measurement. The AUC is then defined as the summation of the area above and below the day 0 measurement. Survival proportions at day 21, survival times, change in bodyweight (using the Area Under the Curve) and clinical scores (using the Area Under the Curve) is summarized by group. Survival dose response curves were analyzed using Probit regression. For each mAb, the median effective dose is estimated and the differences between parentals and bispecific antibody tested for statistical significance. Statistical analysis is performed using R and statistical significance is set at α = 0.05. Example 3: Intranasal administration of the bispecific in the treatment of influenza B. The objective of this study is to compare the prophylactic efficacy of a single dose of each parental antibody (Parental 1 or Parental 2) with that of a single dose of a bispecific antibody having a first antigen-binding domain (first arm) that binds to hemagglutinin, the antigen-binding domain having a VH domain with a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH domain having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL domain having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022, administered intranasally (IN) against challenge with influenza B virus. Materials & methods Preparation The test item is the bispecific human monoclonal antibody as described above produced in HEK293 cells (referred to herein as Test Antibody). The virus strain tested was Influenza virus B, which is stored at -75°C ± 10°C under temperature monitoring and restricted access. Animals The animal species and breed is Mouse (Mus musculus), BALB / c AnNCrl, SPF at a weight of ~ 16-18 g on the day of arrival at the facility. Mice are used at the age of 6-8 weeks on the day of arrival at the facility and are exclusively female. Animals are randomly allocated to treatment groups. Potable water from the public supply is available ad libitum from water bottles. The animals have free access to feed (RMH-B from Altromin, Germany). Mice are maintained between a minimum and maximum temperature of 20.9°C and 21.4°C and at relative humidity percentage between 35 and 42%, under artificial lighting with 12 hours light and 12 hours dark. Study design The dose level of Test Antibody applied in the current example is based on previous parental antibody efficacy data. Mice, 6-8 weeks of age at the time of arrival, are transported to the animal Facility and allocated to experimental groups according to Table 3. Mice are given a period of 3-6 days for acclimatization. Table 3. Treatment schedule Test group mAb IgG Admin. route DoseDay of (mg / kg) admin.No. of Animals1 Parental 1 IN 0.001-15 -1 6-10 2Parental 1 IN0.001-15 -16-103Parental 1 IN0.001-15 -16-104 Parental 1 IN 0.001-15 -1 6-10 5 Parental 2IN0.001-15 -1 6-10 6Parental 2 IN0.001-15 -16-107 Parental 2 IN 0.001-15 -1 6-10 8 Parental 2 IN 0.001-15 -1 6-10 9 BispecificIN0.001-15 -16-1010 BispecificIN0.001-15 -16-1011 Bispecific IN 0.001-15 -1 6-10 12 Bispecific IN 0.001-15 -1 6-10 13 Bispecific IN 0.001-15 -1 6-10 14 BispecificIN0.001-15 -16-1015 Placebo PBSIN- -16-10The mice are treated via the intranasal route of administration with compositions comprising either parental antibodies or the bispecific antibody at dose ranges between 0.001 and 15 mg / kg. On Day 0, all mice were challenged with a lethal dose of Influenza B virus and observed for clinical signs and weight loss until the end of the study at day 21. Antibody administration The monoclonal antibody (mAb) of the Test Antibody preparation is stored at -75°C ± 10°C upon arrival. The appropriate dose, according to the treatment schedule (Table1), is formulated assuming an average weight of the mice of 20 g. On the day of administration, the material is kept on ice during transfer to the animal facility. Just prior to dosing, the material is drawn into a syringe, allowed briefly to warm to room temperature and then injected. The animals are anesthetized by intraperitoneal injection of a mixture of ketamine / xylazine and receive the indicated dose by intranasal inoculation of 0.1 mL divided between both nostrils using a pipette tip. Virus administration The virus material is stored at -75°C ± 10°C and is defrosted prior to administration. Once defrosted, the material is diluted in cold PBS and kept on ice until administration to the mice. The animals are anesthetized by intraperitoneal injection of a mixture of ketamine / xylazine and each animal receives approximately 50 µL of virus by intranasal inoculation using a pipette tip. Unused material is returned on ice to the lab for back titration along with the material that is kept on ice in the lab during inoculation of the animals. Laboratory analysis Laboratory analyses are performed in class II biological safety cabinets. Inoculum is returned to the lab and the actual dose of the virus administered is verified by titrating eight replicate samples on MDCK cells. Virus titres (TCID50 / mL) were determined by the method of Reed and Münch. Clinical monitoring General health observations are performed on each animal from the day of arrival until the end of the study at least once daily (during normal servicing procedures). Clinical signs are scored from day -1 until the end of the study on day 21 using a scoring system (0=no clinical signs; 1=rough coat; 2=rough coat, less reactive during handling; 3=rough coat, rolled up, laboured breathing, less reactive during handling; 4=rough coat, rolled up, laboured breathing, inactive in response to manipulation / handlings). Animals are inspected twice a day as long as they received a score of 3 and are euthanized when they received a score of 4 (humane end point). Each animal is weighed daily beginning one day prior to infection (day -1). Calibrated weighing scales are used. Terminal investigations At the end of the study, on day 21, mice are euthanized by cervical dislocation. Gross necropsy is not performed. Data analysis and statistical methods Repeated body weight and clinical score measurements in the challenge phase are summarized as a single outcome per animal using an Area Under the Curve (AUC) approach where missing values for animals that died before day 21 are imputed with a last-observation-carried-forward method. Body weight data will be expressed as are the change relative to the day 0 measurement. The AUC is then defined as the summation of the area above and below the day 0 measurement. Survival proportions at day 21, survival times, change in bodyweight (using the Area Under the Curve) and clinical scores (using the Area Under the Curve) are summarized by group. Survival dose response curves are analyzed using Probit regression. For each mAb, the median effective dose is estimated and the differences between parental antibodies and bispecific antibody tested for statistical significance. Statistical analysis is performed using R and statistical significance is set at α = 0.05. Example 3A: Intranasal administration of the bispecific in the treatment of influenza B. The objective of this study was to compare the prophylactic efficacy of a single dose of a Bispecific Antibody having a first antigen-binding domain (first arm) that binds to hemagglutinin, the antigen-binding domain having a VH with a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022, with that of a single dose of CR9114 (Parental Antibody 1) as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 administered intranasally (IN) against challenge with influenza B virus. Study Set-up The test item was a Bispecific Antibody as described above produced in HEK293 cells and formulated in PBS. The Bispecific Antibody was compared to CR9114 (Parental Antibody 1), also produced in HEK293 cells, and formulated in 20 mM Sodium acetate, 75mM NaCl, 5% Sucrose, pH 5.5. 120 adult female BALB / c at a weight of ~ 18.7 g (~ 6 weeks) on the day of arrival at the facility were allocated to treatment and vehicle control group. Antibodies were administered intranasally based on an average weight of the animals of 20 g in a volume of 100 ^l split between the nares with a pipette tip on D-1 to treatment groups or vehicle control group (n=10) with approximately 25 times the 50% lethal dose of mouse-adapted B / Malaysia / 2506 / 2004 influenza virus in a volume of 100 ^l split between the nares. A sample of the inoculum was taken and used to confirm the infectious titer by a TCID50 assay. assay. Animals were monitored daily until Day 21 for clinical signs of ill-health and bodyweights were recorded daily and percentage change in weight compared with pre-infection (Day - 1) weight. Animals were euthanized if their clinical score reached the humane endpoint.

[0002] Table 3A. Treatment schedule. * one animal was excluded as it died during inoculation of the test item on D-1. Test Admin. Dose Day of No. of mAb IgG group route (mg / kg) admin. Animals 1 IN 0.1 -1 10 2 IN 0.05 -1 10 Parental 3 IN 0.025 -1 10 Antibody 1 4 IN 0.012 -1 10 5 IN 0.012 -1 9* 6 IN 1.7 -1 10 7 IN 0.42 -1 10 8 Bispecific IN 0.10 -1 10 9 Antibody IN 0.026 -1 10 10 IN 0.007 -1 10 11 IN 0.002 -1 10 12 Vehicle control IN - -1 10 Data analysis and statistical methods Survival proportions at Day 21 and change in bodyweight (using the Area Under the Curve) were compared to the control group using Fisher’s exact test, and Welch's t-test, respectively. Survival proportions at Day 21 were used to estimate the survival dose response curve using Probit regression without assuming a parallel dose response curve for the two antibodies. The model was used to estimate the median effective dose and determine the ratio between the Bispecific Antibody and CR9114 (Parental Antibody 1). Group wise comparisons to the vehicle control group were adjusted for two comparisons according to Bonferroni followed by a stepwise approach for each treatment group (starting with the highest dose and conditionally testing the lower dose if the previous dose was statistically significant). Results The vehicle control group showed 0% survival with a median survival time of 7 days. It was observed that prophylactic intranasal treatment with ≥ 0.007 mg / kg of the Bispecific Antibody and ≥ 0.012 mg / kg of CR9114 (Parental Antibody 1) provided a statistically significant increase in survival compared to control group (See Figure 3A and Figure 4A). Regarding bodyweight loss, an intranasal dose of ≥ 0.007 mg / kg of the Bispecific Antibody and ≥ 0.006 mg / kg of CR9114 (Parental Antibody 1) provided a statistically significant reduction in bodyweight loss compared to the vehicle group (See Figure 3B and 4B). The intranasal median effective dose was comparable for the Bispecific Antibody and CR9114 (Parental Antibody 1), as depicted in Table 4, no significant difference in ED50 was observed (See Figure 3C and 4C), based on the ratio of the Bispecific Antibody over the Parental Antibody being 0.8 with a 95% confidence interval including 1 (0.40- 1.59). Table 4: Estimated ED50s (in mg / kg, rounded to three decimals). Treatment ED50 (mg / kg, 95% confidence interval (CI.)) Parental Antibody 1 0.008 (0.006 – 0.012) Bispecific Antibody 0.007 (0.004 – 0.012) The results of this study demonstrated that, in this Influenza B / Malaysia mouse model, the prophylactic intranasal administration of a Bispecific Antibody according to the invention provides significant increases in survival and a reduction in body weight loss at doses ≥ 0.007 mg / kg (as indicated in Table 3A compared with control group. Moreover, the median effective dose determined for the Bispecific Antibody was not significantly different to the ED50 for CR9114 (Parental Antibody 1). Example 4: Binding data via ELISA. The objective of this study was to assess the binding of the Bispecific Antibodies (comprising SEQ ID NO 001 to 006 and SEQ ID NO 017 to 022) compared to CR9114 (Parental Antibody 1) (Having SEQ ID NO 001 to 006) and 1G01 (Parental Antibody 2) (having SEQ ID NO 017 to 022) against different Hemagglutinin (HA) and Neuraminidase (NA) antigens and compare to the Parental Antibodies 1 and 2. Binding was tested in an enzyme-linked immunosorbent assay (ELISA). Briefly, either a HA or NA antigen was used to coat the surface of a well of an ELISA plate. The antibody was then added in decreasing concentration to the coated and pre-blocked well surface in duplicates. A detection antibody, labeled with horse radish peroxide (HRP), was then added that generates a colorimetric signal upon addition of the substrate. The readout was optical density and reflects binding. The antibody was assayed in duplicate against a number of HA and NA antigens, including but not limited to H1, H3, HA / B, N1, N2, N7 and NA / B. The Bispecific Antibodies were tested in comparison to the Parental Antibodies 1 and 2 in dilution curves, at a starting concentration of 100 nM. A negative isotype control antibody was used for all studies. Half maximal effective concentration (EC50) was calculated for each antibody on each antigen as an estimate of binding affinity, if more than one experimental run (with duplicates) was performed, the geomean is reported. Table 5 and Table 6 report binding of the Bispecific Antibody 1, 2 and 3 compared to the CR9114 (Parental Antibody 1) and 1G01 (Parental Antibody 2) against HA and NA antigens, respectively. Table 5: ELISA binding results reported as EC50 (nM) for different HA antigens from A1, A2 and B influenza strains. ND = sample was assayed but no EC50 was determined due to lack of binding. >100 indicates that while the 50% effective concentration was not reached for an accurate EC50 determination, EC50 is set to the highest tested concentration of >100 nM. (W(H(( Pis oDhc n a uSampleongs AK rAwkAeB in / / Ho / Hin / Ht / 3 / HID5n8 1g / 8 / 390 / 2373A / 1 / 2 1 02 / 20 91 6 1 019 8 )) 3)CR9114 0.0099 0.28 1.0 1.8 1G01 ND ND ND ND LLC0010 0.018 9.2 19.7 40.2 LLC0021 0.012 27.8 28.4 > 100 LLC0022 0.017 45.3 36.9 91.7 Isotype ND ND ND ND Table 6: ELISA binding results reported as EC50 (nM) for different HA antigens from A1, A2 and B influenza strains. ND = sample was assayed but no EC50 was determined due to lack of binding. >100 indicates that while the 50% effective concentration was not reached for an accurate EC50 determination, EC50 is set to the highest tested concentration of >100 nM. (CA( / HA(A(A(B(B / D / N / B CalN N N N / N / NifAonAar AetA / B oAlA or1g2w2he7ri osnKiVrVSampleiao n / 0n / r9 la b aa i d i / c2n n c o / 04g / 10ID / 2 / 2des / / 6 6 / 20 10 9 1 2 0) 19 / 2 019 68 / 00 7) ) 200 8 )3 ))CR9114 ND ND ND ND ND ND 1G01 0.019 0.014 0.027 0.49 ND 0.036 LLC0010 0.68 0.075 0.18 > 100 ND 1.2 LLC0021 0.11 0.022 0.044 48.8 ND 0.34 LLC0022 0.10 0.028 0.060 40.7 ND 0.42 Isotype ND ND ND ND ND ND The ELISA binding results demonstrated specific binding of the Parental Antibodies to the specific target antigen (i.e. CR9114 (Parental Antibody 1) showed binding to the HA antigens and 1G01 (Parental Antibody 2) showed binding to the NA antigens). Additionally, it was observed that all three Bispecific Antibodies bound to both HA and NA antigens for H1, H3 and HA / B (B / HA (Washington / 02 / 2019) was also tested but none of the tested compounds bound) as well as NA1, NA2, NA7 and NA / B. In general, the Bispecific Antibodies showed reduced affinity compared to CR9114 (Parental Antibody 1) for the HA antigens tested, except for H1N1. A similar trend was observed for the NA antigens tested, where the Bispecific Antibodies also showed reduced affinity compared to 1G01 (Parental Antibody 2). Overall, these data demonstrated that the Bispecific Antibody bound both antigens (HA and NA) across different strains. Example 5: Live virus neutralization assay (VNA) The objective of this study was to assess the ability of the Bispecific Antibodies comprised of the first antigen-binding domain binding hemagglutinin as listed in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 to neutralize live influenza viruses and compare to CR9114 (Parental Antibody 1) comprised of SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and 1G01 (Parental Antibody 2) comprised of SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022. Thus, compounds were tested for functional activity in a live virus microneutralization assay against Influenza H1N1 Michigan (A1), H3N2 Hong Kong (A2) and Influenza B (Victoria and Yamagata lineage). Briefly, dilution series of the antibodies and bispecific antibodies were pre-incubated with the corresponding virus and then added to MDCK cell line in quadruplicates. After incubation of 90 min, the inoculum was removed, cells were washed once with medium and replaced with compound dilution (without virus). After completion of the incubation period, the cells were formalin-fixed Triton X-100 permeabilized followed by incubation with a primary antibody directed against the viral nucleoprotein, followed by a secondary antibody peroxidase conjugate and TrueBlue substrate. This formed a blue precipitate on virus-positive cells. Colored precipitate signaling nucleocapsid presence was read out via an Immunospot analyzer and 50% inhibitory concentration (IC50), was reported via the Zielinska method. The compounds were tested for neutralizing activity in the range of 0.005 to 100 µg / ml. The IC50 values from the live virus neutralization assessment are depicted in Table 7. Table 7: Live virus neutralization assessment, IC50 in µg / ml is depicted for the Parental Antibodies and the Bispecific Antibodies. >100 indicates that while the 50% inhibition was not reached for an accurate IC50 determination, IC50 is set to >100 µg / ml. A / MA / HB / B Bic o r / FhAnigAi lg / H Ks / HbaBoriB Sample IDan8o n / e / Vda / Ya41Nn 3N / / 0 m5 / 1g / 6ic202 10 4 / / 2 20 / 1 1 0 05 96 0 08 6CR9114 0.09 0.76 >100 >100 1G01 0.23 0.01 >100 >100 LLC0010 0.05 0.01 >100 >100 LLC0021 0.03 0.01 >100 >100 LLC0022 0.02 0.01 >100 >100 The results of the live virus neutralization study demonstrate that the three Bispecific Antibodies neutralized both Influenza A1 and A2, but not Influenza B, since the Parental Antibodies are also unable to neutralize Influenza B, which was supported by literature and in the case of B / Brisbane also confirmed by a lack of binding in the ELISA assay. The Bispecific Antibodies maintain the potency of the most effective Parental Antibody: For H1N1, CR9114 (Parental Antibody 1) was more potent and the IC50 of the Bispecific Antibody was closer to the IC50 of CR9114 (Parental Antibody 1), and even showed slightly lower IC50 values compared to this more potent Parental Antibody. For H3N2, the Bispecific Antibodies retained the potency of 1G01 (Parental Antibody 2) and did not lose any potency due to monovalency and lower potency of CR9114 (Parental Antibody 1). Overall, these neutralization data indicate that the Bispecific Antibodies are at least as potent as one of the corresponding Parental Antibodies, indicating that they can leverage the most potent Fab arm and possibly crosslink two adjacent spikes on the virion (inter- spike). In addition, these data suggest that the reduced binding observed in the ELISA assay when comparing the Bispecific Antibodies to the corresponding Parental Antibody to the single antigen does not translate to reduced neutralization potency in this VNA assay. Example 6: ELLA and NA star functional assessment The objective of this study was to assess the ability of the Bispecific Antibodies comprised of the first antigen-binding domain binding hemagglutinin as listed in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 to inhibit enzymatic NA activity, compared to CR9114 (Parental Antibody 1) as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and 1G01 (Parental Antibody 2) comprised of SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022. The mechanism of action of anti-NA antibodies like the 1G01 (Parental Antibody 2) relies on blocking the cleavage of sialic acid from the cell surface, therefore inhibiting release of budding virions from the infected cell. Thus, anti-NA antibodies do not prevent initial infection but the propagation of infection via budding of new virions. Conversely, the mechanism of action of anti-HA antibodies such as CR9114 (Parental Antibody 1) includes the prevention of HA binding to the cell-surface sialic acid of host cells and therefore blocking the virus invasion of the host cell by endocytosis. There are two widely used assays to measure NA-dependent inhibition of viral egress: Enzyme-Linked Lectin Assay (ELLA) and NA-star (commercial kit for Influenza Neuraminidase Inhibitor Resistance Detection). ELLA uses immobilized fetuin as a substrate, detecting steric hindrance and active-site binding of HA and NA while NA-Star uses a small soluble chemiluminescent substrate and explicitly distinguishes antibodies that directly inhibit the enzymatic activity of NA by binding close to the enzymatic site and not steric hindrance. Briefly, for both assays, compounds were serially diluted 3-fold, for a range between 0.005 - 100 μg / ml. Equal volumes of the diluted antibody were mixed with the appropriate virus (quadruplicate) For ELLA, mixture was added to fetuin-coated plates. Plates were incubated for 16- 18 h and then washed and incubated with a lectin (PNA-HRPO), followed by addition of substrate. Absorbance was measured at 490 nm using the SpectraMax M3 plate reader. For NA-Star, mixture was added to white plates with equal volume of NA-XTD assay buffer (NA-XTD™ Influenza Neuraminidase Assay Kit; Catalog Number-4457535). Plates were incubated, substrate added and incubated, followed by the addition of the accelerator. Plates were read under Lum96 conditions with integral time of 550 ms using a SpectraMax Paradigm Multimode plate reader. For the ELLA assay, IC50 values (μg / ml) were estimates based on a four-parameter logistic curve fit (without anchoring the plateaus on the control samples), with the IC50 as the X value of inflexion point of the curve fit, IC50 values were expressed as concentrations. For the NA star assay, a four-parameter logistic curve fit was applied, with plateaus anchored on cell and virus control. Area under the curve (AUC) was calculated as the area between the upper plateau and the curves (connected points using the lg(Conc) as X value). The resulting AUC values were expressed as fold differences compared to the AUC values determined for 1G01 (Parental Antibody 2). The tested virus strains included H1N1 Puerto Rico / 08 / 1934, H3N2 Cambodia / E0826360 / 2020, B / Malaysia / 2506 / 04 (Victoria Lineage) and B / Phuket / 3073 / 2013 (Yamagata Lineage) in both assays. Table 8: IC50 of ELLA assay (μg / ml). N / D = not determined due to lack of inhibition. CaPmubMPer ot d a huoAiaAla kR / H / / HyBetB Sample IDic E so / 01N08 3 iNa / / 2 V / 30 / Ya826 5ic 73 m / 1 13206 6 / 29 0 / 0 034 / 2 4 10 320CR9114 0.07 1.1 N / D N / D 1G01 2.89 1.4 0.49 N / D LLC0010 0.08 0.53 6.57 N / D LLC0021 0.12 0.88 3.08 N / D LLC0022 0.07 0.49 2.68 N / D isotype N / D N / D N / D N / D The ELLA assay results show that all tested mAbs inhibited the enzymatic activity, although with different potency depending on the strain (see Table 8). For H1N1, the 1G01 (Parental Antibody 2) which is an anti-NA mAb, showed less potency than CR9114 (Parental Antibody 1) that acts via steric hindrance and not via active site binding in this assay. The Bispecific Antibodies retained inhibiting activity at similar IC50 values than CR9114 (Parental Antibody 1), indicating that they can leverage the more potent Fab arm and reduced affinity reported via ELISA does not hamper neutralizing activity, likely because both arms of the Bispecific Antibodies can bind the pathogen via the respective epitope. For H3N2, all tested compounds showed similar inhibition, with slightly lower IC50 values for the Bispecific Antibodies compared to the Parental Antibodies. Data for B / Malaysia demonstrated that CR9114 (Parental Antibody 1) is not effective while the Parental mAb 2 and the three Bispecific Antibodies showed activity, albeit at higher concentrations due to the presence of one functional arm. For B / Phuket, none of the tested compounds were able to inhibit NA enzymatic activity at the tested concentrations, this is expected for 1G01 (Parental Antibody 2) based on literature. While ELISA data showed binding capacity for CR9114 (Parental Antibody 1) and the Bispecific Antibodies (albeit at lower levels), this did not translate to functionality in this assay, which has been indicated previously in literature against different Yamagata strains. Overall, the data show that the three Bispecific Antibodies retained functional activity based on the IC50 values that were closer to the most potent Parental Antibody for each strain.

[0003] Table 9: Fold difference of samples compared to 1G01 (Parental Antibody 2) which is an anti- NA antibody, calculated using AUC of NA star assay (lgConc*OD) for samples that have passed criteria of AUC(x)≥4*AUC(isotype) N / D = not determined due to lack of inhibition or not passing criteria. CaPmubMPe o hrt d aoAiR aAla uk / H / / ysBetB Sample IDi Eco / 0Hia / V / 3 / Y01N823N / 2i07 am816 5 c 3 / 1 320 / 6 6 29 / 03 04 / 02 4 13020CR9114 N / D N / D N / D N / D LLC0010 0.81 0.50 0.51 N / D LLC0021 0.97 0.74 0.68 N / D LLC0022 0.90 0.76 0.66 N / D The NA star assay corroborates that the three Bispecific Antibodies bound the active site of NA at comparable (H1N1) or slightly lower potency than 1G01 (Parental Antibody 2) (H3N2, Bs) and hence inhibited the enzymatic activity of NA resulting in lack of sialic acid cleavage (see Table 9). All three Bispecific Antibodies showed similar potency compared to each other. The observed AUC values for CR9114 (Parental Antibody 1) in this assay were low and comparable to the isotype control, indicating that only assay background-level inhibition was measured. For B / Phuket, none of the tested compounds were able to effectively inhibit NA enzymatic activity at the tested concentrations. These results confirmed recently published data on 1G01 (Parental Antibody 2) which showed no NA binding for B / Phuket strain. Example 7: Evaluation of HA escape mutants The objective of this study was to assess the ability of the Bispecific Antibodies comprised of the first antigen-binding domain binding hemagglutinin as listed in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 to bind and neutralize HA antigens with specific mutations described in the literature that cause CR9114 (Parental Antibody 1) comprised of SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 to (partially) lose the capability to bind and / or neutralize the escape viral mutant. Due to the ability of the Bispecific Antibody to leverage two arms, one NA- and one HA-binding, in case of an escape mutant of one Parental Antibody, the other Fab arm against the second antigen would allow for coverage of the pathogen and binding. A recent publication demonstrated that the replacement of a certain amino acid (i.e. Isoleucine 45) in the subunit 2 of the HA structure by other specific amino acid can result in an escape variant for CR9114 (Parental Antibody 1), meaning that the mutated HA antigen is no longer bound and neutralized by CR9114 (Parental Antibody 1). More specifically, three mutations with three different amino acid substitutions, showed reduced or abolished binding and functionality when compared to the wildtype HA in the literature. However, these mutations only occurred after >10 passages in an in vitro setting under selective pressure of CR9114 (Parental Antibody 1). They are unlikely to occur in naturally circulating influenza strains, only I45T had a chance of <10% and has not been observed yet in naturally circulating strains. These three mutations showed substitutions in the HA subunit 2 at the position 45 where the Isoleucine (I45) was replaced by Phenylalanine (I45F), Methionine (I45M) or Threonine (I45T). The first mutation described in the stem region I45F, resulted in abolishment of binding and neutralization. The second and third mutations, I45M and I45T replace the Isoleucine with a Methionine or Threonine respectively, resulting in a reduction of binding and neutralization capacity to different extend, with I45M having the mildest effect of all three mutations compared to wildtype HA. To confirm these findings of reduced or abolished HA binding, SPR binding kinetics were assessed for the Parental and the Bispecific Antibodies. Further, to investigate if the Bispecific Antibody is able to neutralize the escape virus with the mutated HA and hence show functionality via one functional arm i.e.1G01 (Parental Antibody 2), despite one Fab arm having lost affinity, Reporter Virus Particles (RVPs) expressing HA mutated versions and NA were generated and Pseudovirion neutralization assays (PNA) were performed. Binding kinetics via SPR For SPR binding kinetic assessment, the HA wildtype or HA mutant antigen were produced by a well-established protein vendor and cDNA was generated of the HA sequence of H3N2 Hong Kong / 1 / 1968 with the mutations. cDNA was inserted into baculovirus vector and cells were infected, cell culture supernatant was harvested, purified and quality controlled via SDS-PAGE. Antibodies were captured on a protein A chip and the antigens were flowed over: Antigens were injected, diluted in 1xHBS-EP+ pH 7.4 buffer, in five consecutive concentrations starting at 12,5 nM in 2-fold serial dilution up to 200 nM for the WT protein and at 100 nM in 2-fold serial dilution up to 1600 nM for the mutant proteins, during 1 min at 30 µl / min with an off-rate of 5 min. Antibody samples were captured at 50 nM in the active flow cell for 30 sec min at 20 µl / min. The association (on-rate) and dissociation (off-rate) of the antibody to the capture protein resulted in changes of the refractive index of the bound mass that was detected and monitored over time. The binding affinity, represented as KD, was calculated from the ratio of the dissociation constant (kd) by the association constant (ka). Table 10: Binding kinetics data (SPR). KD values (nM) for HA H3N2 Hong Kong wildtype, I45F, I45M and I45T mutation are shown for CR9114 (Parental Antibody 1), Bispecific Antibody 1 and a positive control. Antigen KD Sample ID HA H3N2 Hong Kong / 1 / 1968 (nM) Wildtype 100 I45F N / D CR9114 I45T 731 I45M 128 Wildtype 1455 I45F N / D LLC0010 I45T 1105 I45M 206 Wildtype 35 I45F 111 positive control I45T 62 I45M 27 The SPR data (Table 10) corroborated previously published data and showed that all antibodies can bind well to H3N2 Hong Kong wildtype HA protein, however the affinity of the Bispecific Antibody is reduced due to monovalency and diminished avidity. Both CR9114 (Parental Antibody 1) and the Bispecific Antibody, which contains the Fab of CR9114 (Parental Antibody 1), cannot bind the I45F HA, and reduced affinity is observed for the I45M and I45T mutations, being less remarkable for I45M, which confirms the same trend on potency binding as described in literature. The positive control antibody can bind to the wildtype and mutated HAs, albeit with increased KD values for the I45F mutation, indicating that the mutation also alters binding for the control, which was also observed in literature. Neutralization assessment via PNA To confirm that the Bispecific Antibody which is composed of two arms with different mechanism of action can rescue the escape mutant on the HA antigen, neutralization assessment via PNA was performed. For this purpose, RVPs were produced and the specific mutation I45F was included in the HA sequence of H3N2 Hong Kong / 1 / 1968, and both the wildtype HA H3N2 Hong Kong and the I45F mutation sequence was cloned into a high-expression vector. Similarly, the same procedure was followed for the WT NA sequence of the same strain. Afterwards, RVP producing cell lines were transfected with both NA and HA vectors, either expressing the mutant or wildtype HA, and RVPs were harvested, filtered, frozen and quality controlled according to the guidelines of the manufacturer. Neutralization assessment was performed using the wildtype and I45F mutant HA and NA expressing RVPs in 384-well assay plates against controls and compounds. Both Parental Antibodies 1 (HA-binding) and 2 (NA-binding) were tested, as well as the Bispecific Antibody 1 and a positive and negative control antibody. Antibodies were tested at a 3-fold dilution starting at a concentration of 900 μg / ml for a total of 11 titration points and one null antibody control point. A neutralization curve was calculated by normalizing all data to the quadruplicate average of the null-antibody control condition, and a four-parameter logistic regression fit of the normalized data against the log (antibody concentration) was performed in GraphPad Prism and IC50s were determined. Table 11 shows the IC50 values for the neutralization assessment of the CR9114 (Parental Antibody 1) and 2 and the Bispecific Antibodies for the wildtype RVP and the I45F HA2 RVP. Table 11: Pseudovirion neutralization assessment. IC50 (ng / ul) are shown for CR9114 and 1G01 (Parental Antibodies 1 and 2) and the Bispecific Antibodies for the RVPs containing the wildtype or the I45F HA mutation. N / D = not determined Sample ID HA H3N2 Hong Kong / 1 / 1968 IC50 (ng / ul) Wildtype 0.27 CR9114 I45F N / D Wildtype 0.04 1G01 I45F 0.07 Wildtype 0.22 LLC0010 I45F 1.04 Wildtype 0.18 LLC0021 I45F 0.56 Wildtype 0.69 LLC0022 I45F 0.91 The neutralization data demonstrated that the RVP expressing the wildtype HA antigen were neutralized by both Parental Antibodies and the Bispecific Antibodies. On the contrary, it was observed that CR9114 (Parental Antibody 1) lost neutralization capacity against the RVP expressing the HA with the I45F mutation and the wildtype NA. However, the results demonstrated that the three Bispecific Antibodies, as well as 1G01 (Parental Antibody 2) (NA-binder) maintain neutralization activity against the mutant I45F. These data confirmed that while CR9114 (Parental Antibody 1) loses activity against the I45F HA escape mutant, the Bispecific Antibody can rescue the activity via its NA-binding Fab arm, albeit slightly higher IC50s are required. Example 8: SPR binning To confirm that the Bispecific Antibody as listed in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 , can bind both antigens, HA and NA, simultaneously, a binning experiment was conducted using SPR compared to CR9114 (Parental Antibody 1) comprised of SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and 1G01 (Parental Antibody 2) as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022. Antibodies were captured on protein A chip and the antigens were flowed over the captured antibodies sequentially. Injection of HA antigen followed by NA antigen was tested as well as the reverse order (NA followed by HA). HA antigen was injected at 100 nM and HA antigen at 400 nM, on both flow cells (active and reference) diluted in 1xHBS- EP+ pH 7.4, during 2 min at 30 µl / min with an off-rate of 30 sec after each injection. Antibody samples were captured at 50 nM in the active flow cell for 30 sec min at 20 µl / min. A negative isotype control antibody was taken along the experiment. Response Units (RU) were extracted from a report point at the end of each association phase using Biacore Insight Evaluation Software. Experiment run in duplicate and RU levels average for the two cycles is presented. Table 12: Response Units (RU) for binning experiment are shown for the Parental Antibodies 1 and 2 and the Bispecific Antibodies for the RVPs. Antigen sequence injection Sample ID Buffer + Buffer HA5 + NA2 NA2 + HA5 CR9114 < 5 < 5 572 < 5 < 5 566 1G01 < 5 < 5 6 196 197 < 5 LLC0010 < 5 < 5 206 79 88 198 LLC0021 < 5 < 5 183 128 134 164 Isotype < 5 < 5 < 5 < 5 < 5 < 5 The binning data (Table 12) showed that both Parental Antibodies could only bind their respective antigen counterpart while the Bispecific Antibodies can bind simultaneously both antigens regardless of which is bound primarily. These data demonstrated that the Bispecific Antibodies have two functional arms from the Parental Antibodies and can bind simultaneously to both antigens as also supported separately by previously shown neutralization and binding data. Example 9: Intranasal administration of the combination of Parental Antibody 1 and 2 in the treatment of influenza A1. The objective of this study was to compare the prophylactic efficacy of a single dose of CR9114 (Parental Antibody 1) as described in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a dose of 1G01 (Parental Antibody 2) as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 , was compared to a combination of both Parental Antibodies as described above, in a 1:1 ratio, administered intranasally (IN) against challenge with influenza H1N1 (A1) virus. Study Set-up CR9114 (Parental Antibody 1) was produced in CHO cells and formulated in 20 mM Sodium Acetate 75 mM Sodium Chloride pH 5.5. 1G01 (Parental Antibody 2) was produced in HEK293 cells and also formulated in 20mM Sodium acetate, 75mM NaCl, 5% Sucrose, pH 5.5. These Antibodies were combined in a 1:1 ratio and compared to CR9114 (Parental Antibody 1) and 1G01 (Parental Antibody 2) for efficacy in the H1N1 mouse model. On Day -1, 122 adult female BALB / c at a weight of ~ 20 g (6-8 weeks) on the day of arrival at the facility were weighed and randomly assigned to experimental groups that produced similar group mean bodyweight values. Antibodies were administered intranasally in a volume of 35 ^l split between the nares with a pipette tip on Day -1 to treatment groups (n=8) or vehicle control group (n=10) according to Table 13. On Day 0, animals were challenged intranasally with a dose of ~ 50 TCID50 of A / Puerto Rico / 8 / 1934 (H1N1) (PR8) in a volume of 35 ^l split between the nares. A sample of the inoculum was taken and used to confirm the infectious titer by a TCID50 assay. Animals were monitored daily until Day 21 for clinical signs of ill-health and bodyweights were recorded daily and percentage change in weight compared with pre-infection (Day 0) weight. Animals were terminated if their bodyweight loss, clinical score, or combination of both, exceeded humane endpoints. Table 13: Treatment schedule D D oTAseoseotD N Temdsm(PPala oma (maDy . otAi re re o of fgb n g / n g n sa AroI . kt / ktednugGro g) al g a (m m imp ute m ) lmA Ag / in albb kg . s1 2 )1ParIN 0.06 - 0.06 -1 8 en2talIN 0.02 - 0.02 -1 8 A 3ntibIN 0.007 - 0.007 -1 8 od4y1IN 0.002 - 0.002 -1 8 5PIN - 5.0 5.0 -1 8 a6 renIN - 1.67 1.67 -1 8 ta7 lA n IN - 0.56 0.56 -1 8 ti8bodIN - 0.19 0.19 -1 8 y 92IN - 0.06 0.06 -1 8 10ParIN 0.089 0.089 0.19 -1 8 en 11t :1a 1lCoIN 0.030 0.030 0.06 -1 8 A 12nmtibbIN 0.010 0.010 0.02 -1 8 oidna13yt1ionIN 0.003 0.003 0.007 -1 8 an od f14 2 IN 0.001 0.001 0.002 -1 8co V15nterhicIN - - - -1 10 ol leData analysis and statistical methods Survival proportions at Day 21 and change in bodyweight (using the Area Under the Curve) were compared to the control group using Fisher’s exact test, and Welch's t-test , respectively. Survival proportions at Day 21 were used to estimate the survival dose response curve using Probit regression. The model was used to estimate the median effective dose and determine the ratio between CR9114 (Parental Antibody 1) and the combination of CR9114 (Parental Antibody 1) and 1G01 (Parental Antibody 2). Comparisons to the control group were adjusted according to Bonferroni for 3 comparisons followed by a stepwise approach for each antibody (starting with the highest dose and conditionally testing a lower dose if the previous dose was statistically significant). Results The vehicle control group showed 0% survival with a median survival time of 6 days. Prophylactic intranasal treatment with ≥ 0.020 mg / kg of CR9114 (Parental Antibody 1) and the combination and ≥ 0.062 mg / kg of 1G01 (Parental Antibody 2) provided a statistically significant increase in survival compared to control group (See Figure 5A, 6A and Figure 7A). Regarding bodyweight loss, an intranasal dose of ≥ 0.007 mg / kg of CR9114 (Parental Antibody 1) and ≥ 0.062 mg / kg of the 1G01 (Parental Antibody 2) and ≥ 0.020 mg / kg of the combination provided a statistically significant reduction in bodyweight loss compared to the vehicle group (See Figure 5B, 6B and Figure 7B) The intranasal median effective dose was comparable for the combination compared to CR9114 (Parental Antibody 1), as depicted in Table 14, no significant difference in ED50 was determined (See Figure 5C and 7C). Table 14: Estimated ED50 (in mg / kg, rounded to three decimals). ED50 was not assessed for 1G01 (Parental Antibody 2) due to a lack of response curve. Treatment ED50 (mg / kg, 95% confidence interval (CI.)) Parental Antibody 1 0.012 Combination 0.008 Conclusion In this Influenza H1N1 PR8 mouse model, the prophylactic intranasal administration of a combination CR9114 (Parental Antibody 1) and 1G01 (Parental Antibody 2) (as indicated in Table 13) at doses ≥ 0.020 mg / kg provides significant increases in survival and a reduction in body weight loss compared with control group. Moreover, median effective doses of the combination were not significantly different to CR9114 (Parental Antibody 1), while comparison to 1G01 (Parental Antibody 2) was not possible because all tested doses lead to full survival and a follow-up study would be needed. Example 10: Binding via MSD To assess relative binding affinity to trimeric Influenza HA antigens in a multiplexed approach, with high specificity and low sample input requirement, the Bispecific Antibodies as listed in SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and a second antigen-binding domain (second arm) that binds to neuraminidase, VH having a HCDR 1 having the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 were tested compared to CR9114 (Parental Antibody 1) comprised of SEQ ID NO: 001, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 003, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 006 and 1G01 (Parental Antibody 2) as described in SEQ ID NO: 017, a HCDR 2 having the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 having the amino acid sequence as described in SEQ ID NO: 019, and a VL having a LCDR 1 having the amino acid sequence as described in SEQ ID NO: 020, a LCDR 2 having the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 having the amino acid sequence as described in SEQ ID NO: 022 using a Meso Scale Discovery (MSD) binding assay, which uses electrochemiluminescent labels conjugated to detection antibodies. Briefly, viral antigens were separately printed onto a spot in each well of the plate, test antibodies bind the antigens and detected via an anti-human IgG Sulfo-Tag detection antibody. Upon addition of read buffer containing substrate, and running a current through the plate electrodes, an electro- (current) chemi- (buffer substrate) luminescent (light) cascade was initiated which resulted in light emission. The intensity of emitted light was measured per spot with a readout of electrochemiluminescent units (eCLU). The Parental and Bispecific Antibodies were assayed in duplicates against Influenza HA antigens, including A / Michigan / H1, A / Hong Kong / H3, A / Shanghai / H7, B / Brisbane / HA and B / Phuket / HA (V V-Plex MSD COVID-19 IgG Panel (Meso-Scale Discovery cat# K153994-2). An isotype control antibody was also included as a negative control. The samples were tested in a dilution range from 0.03 - 555 ng / ml, with 3-fold dilution steps. Light emission from the MSD sulfo-tag antibody was quantified with MSD Discovery workbench. Calibration curves were used to calculate antibody concentrations by fitting eCLUs from the calibrators using a four-parameter logistic curve with model asymptotes constrained to the lower limit of detection (LLOQ) and the upper limit of detection (ULOQ). The concentration (nM) corresponding to the midpoint of the dynamic range (that is, the range between the lower and upper limit of quantification, LLOQ and ULOQ) was reported as an estimation of binding affinity. Table 15: Binding data via MSD. Antibody concentrations (in ng / ml) corresponding to the midpoint of the dynamic range (LLOQ+ULOQ) / 2 against different HA proteins from Influenza A and B strains. When half dynamic range was not reached, it is set >555 ng / ml as the highest tested concentration. BLD = below limit of detection. Influenza A Influenza B A A A B / / H / / B sampleMio SB / c n hPar hIDhgiigKngsb uaha keno / na ne t / H g i / H / H H / HA A 1 3 7 CR9114 1.72 12.01 0.37 5.71 10.31 1G01 BLD BLD BLD BLD BLD LLC0010 3.41 157.26 6.19 100.49 164.86 LLC0021 6.18 >555 6.86 528.96 >555 LLC0022 5.80 344.15 6.81 185.46 304.05 isotype BLD BLD BLD BLD BLD The MSD binding data show that only CR9114 (Parental Antibody 1) and the Bispecific Antibodies 1, 2 and 3 (LLC0010, LLC0021 and LLC0022) can bind HA antigens from Influenza A and B strains.1G01 (Parental Antibody 2) which targets the NA structure and the isotype control cannot bind HA. Except for H1N1, the Bispecific Antibodies show reduced affinity compared to Parental Antibody 1 (CR9114), possibly because of the monovalency of the Fab arms compared to the bivalency of the Parental Antibody. MSD and ELISA data show the same trend across the shared antigens Hong Kong and B / Phuket, highlighting that the three Bispecific Antibodies show comparable binding capacity which is reduced compared to the Parental Antibody 1 (CR9114).

Claims

CLAIMS 1. A bispecific antibody or antigen-binding fragment thereof, that is capable of binding to influenza A virus subtype A2 hemagglutinin and neuraminidase.

2. A bispecific antibody or antigen-binding fragment thereof according to Claim 1, wherein the bispecific antibody or antigen-binding fragment is capable of binding to influenza A virus subtype A1 hemagglutinin and neuraminidase.

3. A bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 or 2, wherein the bispecific antibody or antigen-binding fragment is capable of binding to the distinct phylogenetic lineages of influenza virus B hemagglutinin and neuraminidase.

4. A bispecific antibody or antigen-binding fragment thereof according to Claim 3, wherein the antibody is capable of binding to influenza B virus hemagglutinin and neuraminidase in both Yamagata and Victoria lineages.

5. A bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 to 4, wherein the bispecific antibody or antigen-binding fragment comprises: (a) a first antigen-binding domain that binds to hemagglutinin, wherein the first antigen-binding domain comprises: a VH domain as described in SEQ ID NO: 007 comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 001, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 002, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 003, and a VL domain as described in SEQ ID NO: 008 comprising a LCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 004, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 005, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 006; and (b) a second antigen-binding domain that binds to neuraminidase, wherein the second antigen-binding domain comprises: a VH domain as described in SEQ ID NO: 023 comprising a HCDR 1 comprising the amino acid sequence as described in SEQ ID NO: 017, a HCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 018, and a HCDR 3 comprising the amino acid sequence as described in SEQ ID NO: 019, and a VL domain as described in SEQ ID NO: 024 comprising a LCDR 1 comprising the amino acidsequence as described in SEQ ID NO: 020, a LCDR 2 comprising the amino acid sequence as described in SEQ ID NO: 021, and a LCDR 3 comprising the amino acid sequence as described in SEQ ID NO:

022.

6. A bispecific antibody or antigen-binding fragment thereof according to any preceding Claims, wherein the bispecific antibody or the antigen-binding fragment thereof comprises: (i) a first polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 001, or the amino acid sequence having at least 1, or 2 amino acids different from SEQ ID NO: 001, (ii) a second polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 002, or the amino acid sequence having at least 1, 2, 3, 4, or 5 amino acids different from SEQ ID NO: 002, (iii) a third polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 003, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 003, (iv) a fourth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 004, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 004, (v) a fifth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 005, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 005, (vi) a sixth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 006, or the amino acid sequence having at least 1, 2, or 3 amino acids different from SEQ ID NO: 006, (vii) a seventh polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 017, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 017, (viii) an eighth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 018, or the amino acid sequence having at least 1, 2, 3, 4 or 5 amino acids different from SEQ ID NO: 018, (ix) a ninth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 019, or the amino acid sequence having at least 1, 2, 3, 4, 5, or 6 amino acids different from SEQ ID NO: 019,(x) a tenth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 020, or the amino acid sequence having at least 1, 2 or 3 amino acids different from SEQ ID NO: 020, (xi) an eleventh polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 021, or the amino acid sequence having at least 1 or 2 amino acids different from SEQ ID NO: 021, and (xii) a twelfth polypeptide chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 022, or the amino acid sequence having at least 1, 2 or 3 amino acids different from SEQ ID NO:

022.

7. A bispecific antibody or antigen-binding fragment thereof according to any preceding Claims, wherein the bispecific antibody comprises (a) a first Fab fragment capable of specifically binding to hemagglutinin, (b) a second Fab fragment capable of specifically binding to neuraminidase, and (c) an Fc domain composed of a first and a second subunit capable of stable association.

8. A bispecific antibody or an antigen-binding fragment thereof according to any one of Claims 1 to 7, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein the constant domains CL and CH1 from the second arm are replaced by each other.

9. A bispecific antibody or an antigen-binding fragment thereof according to any of Claims 1 to 7, comprising:(a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein the constant domains CL and CH1 from the first arm are replaced by each other.

10. A bispecific antibody or an antigen-binding fragment thereof according to any one of Claims 1 to 5, comprising: (a.) a first arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to hemagglutinin of an influenza A virus, preferably influenza A virus subtypes A1 and / or A2, and (b.) a second arm which comprises a light chain comprising VL-CL domains and a heavy chain comprising VH-CH1-CH2-CH3 domains of the bispecific antibody or the antigen-binding fragment thereof, capable of binding to neuraminidase of an influenza A virus, preferably influenza A virus subtype A1 and / or A2, wherein domains VL-CL and VH-CH1 from the second arm are replaced by each other.

11. A bispecific antibody or antigen-binding fragment thereof according to any preceding Claims, wherein any one of the antigen-binding domains is chimeric, fully human or humanized.

12. A bispecific antibody or antigen-binding fragment thereof according to any preceding Claims, wherein any one of the antigen-binding domains comprises a Fab fragment, a Fab(ab')2 fragment, a scFv-Fc fragment, or a scFv fragment.

13. A bispecific antibody or antigen-binding fragment thereof according to any preceding Claims, wherein the bispecific antibody is bivalent, trivalent, tetravalent, hexavalent or multivalent.

14. A nucleic acid molecule comprising a nucleic acid sequence encoding a bispecific antibody or antigen-binding fragment thereof according to any preceding Claims.

15. A bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 to 13, and / or a nucleic acid molecule according to Claim 14, for use as a medicament.

16. A bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 to 13, and / or a nucleic acid molecule according to Claim 14, for use as a medicament for prophylactic and / or therapeutic treatment of influenza caused by at least one of influenza virus subtypes A1 and A2 and type B.

17. A vector, comprising one or more nucleic acids of Claim 14, wherein the vector is suitable for the recombinant production of the bispecific antibody of any one of claims 1 to 13.

18. A host cell, comprising one or more recombinant vectors or expression vectors of Claim 17.

19. An immunoconjugate, comprising the bispecific antibody or antigen-binding fragment of any one of Claims 1 to 13.

20. A pharmaceutical composition, comprising any combination of a bispecific antibody of any one of Claims 1 to 13, the nucleic acid of Claim 14, the vector of Claim 17, or the immunoconjugate of Claim 19, and optionally comprising a pharmaceutically acceptable excipient.

21. A bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 to 13, the nucleic acid of Claim 14, the vector of Claim 17, or the immunoconjugate of Claim 19, for use as a medicament for prophylactic and / ortherapeutic treatment caused by at least one of influenza virus subtypes A1 and A2 and influenza type B.

22. A method for treating or preventing influenza disease in a subject, comprising administering to the subject an effective amount of the bispecific antibody or antigen- binding fragment of any one of Claims 1 to 13, the nucleic acid of Claim 14, the vector of Claim 17, or the immunoconjugate of Claim 19, or the pharmaceutical composition of Claim 20.

23. Use of the bispecific antibody or antigen-binding fragment of any one of Claims 1 to 13, the nucleic acid of Claim 14, the vector of Claim 17, or the immunoconjugate of Claim 19, or the pharmaceutical composition of Claim 20 in the manufacture of a medicament for treating influenza disease in a subject.

24. A Method or Use according to Claims 22 or 23, wherein the antibody is administered intranasally and / or by oral inhalation.

25. A Kit comprising a bispecific antibody or antigen-binding fragment thereof according to any one of Claims 1 to 13, or a nucleic acid according to Claim 14, or the pharmaceutical composition of Claim 20 wherein said pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

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