WO2011019932A2 - Compositions and methods for the therapy and diagnosis of influenza - Google Patents

Compositions and methods for the therapy and diagnosis of influenza Download PDF

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Publication number
WO2011019932A2
WO2011019932A2 PCT/US2010/045346 US2010045346W WO2011019932A2 WO 2011019932 A2 WO2011019932 A2 WO 2011019932A2 US 2010045346 W US2010045346 W US 2010045346W WO 2011019932 A2 WO2011019932 A2 WO 2011019932A2
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seq
antibody
amino acid
acid sequence
nos
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French (fr)
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WO2011019932A3 (en
WO2011019932A9 (en
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Andres G. Grandea, Iii
Gordon King
Thomas C. Cox
Ole Olsen
Jennifer Mitcham
Matthew Moyle
Phil Hammond
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Theraclone Sciences Inc
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Theraclone Sciences Inc
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Priority to EP10808769A priority Critical patent/EP2464383A4/en
Priority to JP2012524878A priority patent/JP2013501807A/ja
Priority to AU2010282415A priority patent/AU2010282415A1/en
Priority to CA2771105A priority patent/CA2771105A1/en
Publication of WO2011019932A2 publication Critical patent/WO2011019932A2/en
Publication of WO2011019932A9 publication Critical patent/WO2011019932A9/en
Publication of WO2011019932A3 publication Critical patent/WO2011019932A3/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/11—Orthomyxoviridae, e.g. influenza virus

Definitions

  • the present invention relates generally to prevention, diagnosis, therapy and monitoring of influenza infection.
  • the invention is more specifically related to compositions containing a combination of human antibodies raised against either the influenza hemagglutinin or matrix 2 protein. Such compositions are useful in pharmaceutical compositions for the prevention and treatment of influenza, and for the diagnosis and monitoring of influenza infection.
  • Influenza virus infects 5-20% of the population and results in 30,000-50,000 deaths each year in the U.S. Disease caused by influenza A viral infections is typified by its cyclical nature. Antigenic drift and shift allow for different A strains to emerge every year. Added to that, the threat of highly pathogenic strains entering into the general population has stressed the need for novel therapies for flu infections.
  • the predominant fraction of neutralizing antibodies is directed to the polymorphic regions of the hemagglutinin and neuraminidase proteins.
  • M2 matrix 2
  • M2 protein is found in a homotetramer that forms an ion channel and is thought to aid in the uncoating of the virus upon entering the cell. After infection, M2 can be found in abundance at the cell surface. It is subsequently incorporated into the virion coat, where it only comprises about 2% of total coat protein.
  • M2 extracellular domain (M2e) is short, with the aminoterminal 2-24 amino acids displayed outside of the cell. Anti-M2 MAbs to date have been directed towards this linear sequence. Thus, they may not exhibit desired binding properties to cellularly expressed M2, including conformational determinants on native M2.
  • the invention provides diagnostic, prophylactic, and therapeutic compositions including a human antibody raised against the Influenza hemagglutinin protein and a human monoclonal antibody raised against the Influenza M2 protein. Moreover, the invention provides diagnostic, prophylactic, and therapeutic compositions including a human antibody raised against an epitope of the Influenza hemagglutinin protein and a human monoclonal antibody raised against an epitope of the Influenza M2 protein. Furthermore, these compositions are pharmaceutical compositions that include a pharmaceutical carrier. These compositions address a long-felt need in the art for pharmaceutical compositions that both strongly neutralizes Influenza virus infection and recognizes constant regions within proteins common to all Influenza strains.
  • the invention provides a composition including: (a) a human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) a human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
  • a human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus
  • M2e matrix 2 ectodomain
  • the human monoclonal antibody that specifically binds an epitope of the M2e polypeptide is TCN-032 (8110), 21 Bl 5, TCN-031 (23 K 12), 3241_G23, 3244J10, 3243J07, 3259J21, 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B1 1, or 3242_P05.
  • the human antibody that specifically binds an epitope of the HA glycoprotein is optionally SC06-141 , SC06-255, SC06-257, SC06-260, SC06-261 , SC06-262, SC06-268, SC06-272, SC06-296, SC06-301, SC06-307, SC06-310, SC06-314, SC06-323, SC06-325, SC06-327, SC06-328, SC06-329, SC06-331 , SC06-332, SC06-334, SC06-336, SC06-339, SC06-342, SC06-343, SC06-344, CR6141, CR6255, CR6257, CR6260, CR6261, CR6262, CR6268, CR6272, CR6296, CR6301 , CR6307, CR6310, CR6314, CR6323, CR6325, CR6327, CR6328, CR6329, CR6331 ,
  • the epitope of the HA glycoprotein is optionally GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK (SEQ ID NO: 201), GITNKVNSVIEK (SEQ ID NO: 281),
  • GITNKENSVIEK (SEQ ID NO: 257)
  • GITNKVNSIIDK (SEQ ID NO: 225)
  • the influenza hemaglutinin (HA) glycoprotein includes an HAl and HA2 subunit.
  • exemplary epitopes of the HA glycoprotein include the HAl subunit, HA2 subunit, or both the HAl and HA2 subunits.
  • the epitope of the M2e polypeptide is a discontinuous epitope.
  • the epitope of the M2e polypeptide includes the amino acid at positions 2, 5, and 6 of
  • MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1).
  • the invention further provides a composition including: (a) an isolated human anti- HA antibody, or an antigen-binding fragment thereof, including a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each contain three complementarity determining regions 1 to 3 (CDRl-3), and wherein each CDR includes the following amino acid sequences: VH CDRl : SEQ ID NOs: 566, 571 , 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251 , 242, or 222; VH CDR2: SEQ ID NOs: 567, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671 , 306, 249, 307, or 221 ; VH CDR3: SEQ ID NOs
  • the invention provides a composition including: (a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, including a heavy chain variable region (VH) domain and a light chain variable (VL) domain, wherein the VH domain and the VL domain each contain three complementarity determining regions 1 to 3 (CDR 1-3), and wherein each CDR includes the following amino acid sequences: VH CDRl : SEQ ID NOs: 566, 571 , 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251 , 242, or 222; VH CDR2: SEQ ID NOs: 567, 572, 587, 592, 598, 604, 610, 616, 628, 634, 638, 644, 650, 655, 659, 665, 671 , 306, 249, 307, or 221 ; VH CDR
  • the invention provides a composition including: (a) an isolated human anti-HA antibody, or an antigen-binding fragment thereof, including a heavy chain variable region (VH) domain, wherein the VH domain includes the following amino acid sequences: SEQ ID NOs 309, 313, 317, 321 , 325, 329, 333, 337, 341 , 345, 349, 353, 357, 361 , 365, 369, 373, 377, 381 , 385, 389, 393, 397, 401 ; 405, 409, 199, 417, 423, 429, 435, 441, 447, 453, 459, 465, 471 , 477, 483, 489, 495, 501 , 507, 513, 519, 525, 531 , 537, 543, 550, 556, or 562, and a light chain variable (VL) domain, wherein the VL domain includes the following amino acid sequences: SEQ ID NOs 310,
  • the invention provides a multivalent vaccine composition including any of the compositionsdescribed herein containing an isolated human anti-HA antibody, or an antigen-binding fragment thereof and an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof.
  • the multivalent vaccine includes antibodies that bind to the epitopes to which the antibodies of the invention bind.
  • Exemplary antibodies of the invention include, but are not limited to, TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259_J21, 32451O19, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B1 1 , 3242_P05, SC06-141 , SC06-255, SC06-257, SC06-260, SC06-261, SC06-262, SC06-268, SC06-272, SC06-296, SC06-301 , SC06-307, SC06-310, SC06-314, SC06-323, SC06-325, SC06-327, SC06-328, SC06-329, SC06-331 , SC06-332, SC06-334, SC06-336, SC06-339, SC06-342, SC
  • the multivalent vaccine may include one or more of the following epitopes: GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTNKVNRIIDK (SEQ ID NO: 201 ), GITNKVNSVIEK (SEQ ID NO: 281), GITNKENSVIEK (SEQ ID NO: 257),
  • GITNKVNSIIDK (SEQ ID NO: 225), KITSKVNMVDK (SEQ ID NO: 216),
  • MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1) provided in its native conformation.
  • the multivalent vaccine also includes a composition including: (a) a human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) a human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
  • a composition including: (a) a human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) a human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
  • HA hemagglutinin
  • M2e matrix 2 ectodomain
  • the invention provides a pharmaceutical composition including any one of the compositions described herein. Moreover, the pharmaceutical composition includes a pharmaceutical carrier.
  • the invention provides a method for stimulating an immune response in a subject, including administering to the subject the pharmaceutical composition described herein.
  • the pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus.
  • the invention also provides a method for the treatment of an influenza virus infection in a subject in need thereof, including administering to the subject the pharmaceutical composition described herein.
  • the subjection may have been exposed to an influenza virus.
  • the subject has not been diagnosed with an influenza infection.
  • the pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus.
  • the pharmaceutical composition is administered at a dose sufficient to promote viral clearance or eliminate influenza infected cells.
  • the invention further provides a method for the prevention of an influenza virus infection in a subject in need thereof, including administering to the subject a vaccine composition described herein, prior to exposure of the subject to an influenza virus.
  • the subject is at risk of contracting an influenza infection.
  • the pharmaceutical composition may administered prior to or after exposure of the subject to an Influenza virus.
  • the pharmaceutical composition is administered at a dose sufficient to promote viral clearance or eliminate influenza infected cells.
  • the treatment and prevention methods provided by the invention further include administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.
  • anti-viral drugs include, but are not limited to, a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor, or an M2 ion channel inhibitor.
  • the M2 ion channel inhibitor is amantadine or rimantadine.
  • the neuraminidase inhibitor is zanamivir or oseltamivir phosphate.
  • the antiviral drug may administered prior to or after exposure of the subject to an Influenza virus.
  • the treatment and prevention methods provided by the invention further include administering a second anti-Influenza A antibody.
  • the second antibody is optionally an antibody described herein.
  • the second antibody may administered prior to or after exposure of the subject to an Influenza virus.
  • the invention provides a method for determining the presence of an Influenza virus infection in a subject, including the steps of: (a) contacting a biological sample obtained from the subject with any one of the antibodies or pharmaceutical compositions described herein; (b) detecting an amount of the antibody that binds to the biological sample; and (c) comparing the amount of antibody that binds to the biological sample to a control value, and therefrom determining the presence of the Influenza virus in the subject.
  • the control value is determined by contacting a control sample obtained from the subject with any one of the antibodies or pharmaceutical compositions described herein and detecting an amount of the antibody that binds to the control sample.
  • the invention also provides a diagnostic kit including any one of the antibodies, compositions, or pharmaceutical compositions described herein.
  • the invention further provides a prophylactic kit including a vaccine composition described herein.
  • the vaccine is a multivalent vaccine.
  • multivalent vaccine describes a single vaccine that elicits an immune response either to more than one infectious agent, e.g. the influenza HA glycoprotein and the influenza M2e polypeptide, or to several different epitopes of a molecule, e.g. HA epitopes shown in SEQ ID NOs 198, 283,
  • multivalent vaccine is meant to describe the administration of a combination of human antibodies raised against more than one infectious agent, e.g. the influenza HA glycoprotein and the influenza M2e polypeptide.
  • Figure 1 shows the binding of three antibodies of the present invention and control hul4C2 antibody to 293-HEK cells transfected with an M2 expression construct or control vector, in the presence or absence of free M2 peptide.
  • Figures 2 A and. B are graphs showing human monoclonal antibody binding to influenza A/Puerto Rico/8/32.
  • Figure 3A is a chart showing amino acid sequences of extracellular domains of M2 variants.
  • Figures 3 B and C are bar charts showing binding of human monoclonal anti-influenza antibody binding to M2 variants shown in Figure 3A.
  • Figures 4 A and B are bar charts showing binding of human monoclonal anti- influenza antibody binding to M2 peptides subjected to alanine scanning mutagenesis.
  • Figure 5 is a series of bar charts showing binding of MAbs 8ilO and 23Kl 2 to M2 protein representing influenza strain A/HK/483/1997 sequence that was stably expressed in the CHO cell line DG44.
  • Figure 6A is a chart showing cross reactivity binding of anti-M2 antibodies to variant M2 peptides.
  • Figure 6B is a chart showing binding activity of M2 antibodies to truncated M2 peptides.
  • Figure 7 is a graph showing survival of influenza infected mice treated with human anti-influenza monoclonal antibodies.
  • Figure 8 is an illustration showing the anti-M2 antibodies bind a highly conserved region in the N-Terminus of M2e.
  • Figure 9 is a graph showing anti-M2 rHMAb clones from crude supernatant bound to influenza on ELISA, whereas the control anti-M2e mAb 14C2 did not readily bind virus.
  • Figure 10 is a series of photographs showing anti-M2 rHMAbs bound to cells infected with influenza. MDCK cells were or were not infected with influencza A/PR/8/32 and Ab binding from crude supernatant was tested 24 hours later. Data were gathered from the
  • Figure 1 1 is a graph showing anti-M2 rHMAb clones from crude supernatant bound to cells transfected with the influenza subtypes H3N2, HK483, and VN1203 M2 proteins.
  • the 14C2, 8il O, 23Kl 2, and 21Bl 5 mABs were tested for binding to the transfectants, and were detected with an AF647-conjugated anti-human IgG secondary antibody. Shown are the mean fluorescence intensities of the specific mAB bound after FACS analysis.
  • Figures 12A-B are amino acid sequences of the variable regions of anti-M2e mAbs.
  • Framework regions 1 -4 (FR 1 -4) and complementarity determining regions 1 -3 (CDR 1 -3) for VH and Vk are shown.
  • FR, CDR, and gene names are defined using the nomenclature in the IMGT database (IMGT®, the International ImMunoGeneTics Information system® http://www.irngt.org).
  • Grey boxes denote identity with the germline sequence which is shown in light blue boxes, hyphens denote gaps, and white boxes are amino acid replacement mutations from the germline.
  • FIG. 13 is a graph depicting the results of a competition binding analysis of a panel of anti-M2e mAbs with TCN-032 Fab.
  • the indicated anti-M2e mAbs were used to bind to the stable CHO transfectant expressing M2 of A/Hong Kong/483/97 that had previously been treated with or without 10 ⁇ g/mL TCN-032 Fab fragment.
  • the anti-M2e mAb bound to the cell surface was detected with goat anti-hulgG FcAlexafluor488 FACS and analyzed by flow cytometry. The results are derived from one experiment.
  • Figure 14A is a graph depicting the ability of anti-M2e mAbs TCN-032 and TCN- 031 to bind virus particles and virus- infected cells but not M2e-derived synthetic peptide.
  • Purified influenza virus A/Puerto Rico/8/34
  • Figure 14B is a graph depicting the ability of anti-M2e mAbs TCN-032 and TCN- 031 to bind virus particles and virus-infected cells but not M2e-derived synthetic peptide.
  • 23mer synthetic peptide of M2 derived from A/Fort Worth/1/50 was coated at 1 ⁇ g/ml on ELISA wells and binding of mAbs TCN-031 , TCN-032, chl4C2, and 2N9 were evaluated as in panel a. Results shown are representative of 3 experiments.
  • Figure 14C is a graph depicting the ability of anti-M2e mAbs TCN-032 and TCN- 031 to bind virus particles and virus-infected cells but not M2e-derived synthetic peptide.
  • MDCK cells were infected with A/Puerto Rico/8/34 (PR8) and subsequently stained with mAbs TCN-031 , TCN-032, ch 14C2 and the HCMV mAb 5J 12. Binding of antibodies was detected using Alexafluor 647-conjugated goat anti-Human IgG H&L antibody and quantified by flow cytometry. Results shown are representative of 3 experiments.
  • FIG 14D is a series of photographs depicting HEK 293 cells stably transfected with the M2 ectodomain of A/Fort Worth /1/50 (D20) were stained with transient transfection supernatant containing mAbs TCN-031 , TCN-032, or the control chl4C2 and analyzed by FMAT for binding to M2 in the presence or absence of 5 ug/ml M2e peptide.
  • Mock transfected cells are 293 cells stably transfected with vector alone. Results shown are representative of one experiment.
  • FIGS 15A-D are graphs depicting the Therapeutic efficacy of anti-M2 mAbs TCN-031 and TCN-032 in mice.
  • FIG 16 is a series of graphs depicting the viral titers in lung, liver, and brain of mice treated with anti-M2e mAbs TCN-031 and TCN-032 after challenge with H5N1 A/Vietnam/ 1203/04.
  • Tissue viral titers were determined from 3 mice per group at 3 and 6 days post-infection in the lungs (as an indicator of local replication) and in liver and brain (as an indicator of the systemic spread which is characteristic of H5N1 infection).
  • FIG. 17 is a graph depicting the ability of TCN-031 and TCN-032 can potentiate cytolysis by NK cells.
  • MDCK cells were infected with A/Solomon Island/3/2006 (HlNl) virus, and were treated with mAbs TCN-031 , TCN-032, or the subclass-matched negative control mAb 2N9. The cells were then challenged with purified human NK cells, and the lactate dehydrogenase released as a result of cell lysis was measured through light absorbance. The results are representative of two separate experiments with two different normal human donors.
  • FIG 18 is a graph depicting complement-dependent cytolysis (CDC) of M2- expressing cells bound with anti-M2 mAb.
  • CDC complement-dependent cytolysis
  • Figures 19A-C are graphs depicting binding of anti-M2e mAbs TCN-031 and TCN- 032 to M2 mutants indicates the epitope is located in the highly conserved N-terminal of M2e. Mutants with alanine substituted at each position of the M2 ectodomain of A/Fort Worth /1/50 (D20)(A) or forty wild-type M2 mutants including
  • A/Vietnam/ 1203/04 (VN) and A/Hong Kong/483/97 (HK) (B) were transiently transfected into 293 cells.
  • the identity of each wild-type M2 mutant is listed in Table 6.
  • Transfected cells were stained with mAbs TCN-031 , TCN-032, or the control chl4C2 and analyzed by FACS for binding to M2 at 24 hours post-transfection.
  • mAbs TCN-031 and TCN-032 do not bind variants with amino acid substitutions at positions 1 , 4, or 5 of M2e.
  • FIG. 20 is a graph depicting mAbs TCN-031 and TCN-032 recognize the same region on M2e.
  • the CHO transfectant stably expressing M2 for A/Hong Kong/483/97 as stained with 10 ⁇ g/mL TCN-031 , TCN-032, or 2N9, followed by detection with Alexafluor647-labeled TCN-031 (TCN-031 AF647) or TCN-032(TCN-032AF647) and analysis by flow cytometry.
  • TCN-031 AF647 Alexafluor647-labeled TCN-031
  • TCN-032 TCN-032(TCN-032AF647)
  • Figure 21 is a graph depicting anti-M2e mAbs TCN-031 and TCN-032 bind cells that have been infected with HlNl A/California/4/09. MDCK cells were infected with Influenza A strain HlNl A/Memphis/ 14/96, HlNl A/California/4/09, or mock infected. Twenty four hours post-infection cells were stained with mAbs TCN-031, TCN-032, or the control chl4C2 and analyzed by FACS for binding to M2. Results shown are for one experiment.
  • Influenza viruses consist of three types, A, B and C. Influenza A viruses infect a wide variety of birds and mammals, including humans, horses, marine mammals, pigs, ferrets, and chickens. In animals most influenza A viruses cause mild localized infections of the respiratory and intestinal tract. However, highly pathogenic influenza A strains such as H5N1 exist that cause systemic infections in poultry in which mortality may reach 100%. Animals infected with influenza A often act as a reservoir for the influenza viruses and certain subtypes have been shown to cross the species barrier to humans.
  • Influenza A viruses can be classified into subtypes based on allelic variations in antigenic regions of two genes that encode surface glycoproteins, namely, hemagglutinin (HA) and neuraminidase (NA) which are required for viral attachment and cellular release.
  • Other major viral proteins include the nucleoprotein, the nucleocapsid structural protein, membrane proteins (Ml and M2), polymerases (PA, PB and PB2) and non-structural proteins (NSl and NS2).
  • Ml and M2 membrane proteins
  • PA polymerases
  • PB and PB2 polymerases
  • NSl and NS2 non-structural proteins
  • avian influenza A has been reported to cross the species barrier and infect humans as documented in Hong Kong in 1997 and 2003, leading to the death of several patients.
  • the avian influenza virus infects cells of the respiratory tract as well as the intestinal tract, liver, spleen, kidneys and other organs. Symptoms of avian influenza infection include fever, respiratory difficulties including shortness of breath and cough, lymphopenia, diarrhea and difficulties regulating blood sugar levels.
  • the group most at risk is healthy adults, which make up the bulk of the population.
  • compositions including human antibodies raised against two influenza proteins, hemagglutinin (HA) and matrix 2 ectodomain (M2e), and shows that these compositions can be used in medicine, in particular for diagnosis, prevention and treatment of influenza infections, including H5N1.
  • HA hemagglutinin
  • M2e matrix 2 ectodomain
  • the present invention provides fully human monoclonal antibodies specifically directed against M2e.
  • the antibody is isolated form a B-cell from a human donor.
  • Exemplary monoclonal antibodies include TCN-032 (8110), 21 B15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259J21, 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B1 1, and
  • the monoclonal antibody is an antibody that binds to the same epitope as TCN-032 (8110), 21 B15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259J21 , 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420J23, 3139 P23, 3248_P18, 3253_P10, 3260_D19, 3362 B1 1, and 3242_P05.
  • the antibodies respectively referred to herein are huM2e antibodies.
  • the huM2e antibody has one or more of the following characteristics: a) binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus; b) binds to influenza A infected cells; or c) binds to influenza A virus.
  • M2e matrix 2 ectodomain
  • the epitope that huM2e antibody binds to is a non-linear epitope of a M2 polypeptide.
  • the epitope includes the amino terminal region of the M2e polypeptide. More preferably the epitope wholly or partially includes the amino acid sequence SLLTEV (SEQ ID NO: 42).
  • the epitope includes the amino acid at position 2, 5 and 6 of the M2e polypeptide when numbered in accordance with SEQ ID NO: 1.
  • the amino acid at position 2 is a serine; at position 5 is a threonine; and at position 6 is a glutamic acid.
  • a huM2e antibody contains a heavy chain variable having the amino acid sequence of SEQ ID NOs: 44, 277, 276, 50, 236, 235, 1 16, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, or 176 and a light chain variable having the amino acid sequence of SEQ ID NOs: 46, 52, 1 18, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, or 178.
  • the three heavy chain CDRs include an amino acid sequence at least 90%, 92%, 95%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NOs: 72, 74, 76, 103, 105, 107, 179, 180, 181 , 187, 188, 189, 197, 203, 204, 205, 21 , 212, 213, 228, 229, 230, 237, 238, 252, 253, 254, 260, 261, 262, 268, 269, 270, 284, 285, 286, 293, 294, 295, and 301 (as determined by the Kabat method) or SEQ ID NOs: 109, 1 10, 76, 1 12, 1 13, 107, 182, 183, 181 , 190, 191 , 189, , 197, 206, 207, 205, 214, 215, 213, 232, 230, 239, 240, 238, 255, 256, 254, 263, 264, 262, 2
  • the heavy chain of a M2e antibody is derived from a germ line V (variable) gene such as, for example, the IgHV4 or the IgHV3 germline gene.
  • the M2e antibodies of the invention include a variable heavy chain (V H ) region encoded by a human IgHV4 or the IgHV3 germline gene sequence.
  • V H variable heavy chain
  • a IgHV4 germline gene sequence are shown, e.g., in Accession numbers L10088, M29812, M951 14, X56360 and M951 17.
  • IgHV3 germline gene sequence are shown, e.g., in Accession numbers X92218, X70208, Z27504, M99679 and AB019437.
  • the M2e antibodies of the invention include a V H region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgHV4 or the IgHV3 germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgHV4 or the IgHV3 germline gene sequence.
  • the V H region of the M2e antibody is at least 80% homologous to the amino acid sequence of the V H region encoded by the IgHV4 or the IgHV3 V H germline gene sequence.
  • the amino acid sequence of V H region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgHV4 or the
  • IgHV3 germline gene sequence and more preferably, at least 98%, 99% homologous to the sequence encoded by the IgHV4 or the IgHV3 germline gene sequence.
  • the M2e antibodies of the invention also include a variable light chain (VL) region encoded by a human IgKVl germline gene sequence.
  • VL variable light chain
  • a human IgKVl V L germline gene sequence is shown, e.g., Accession numbers X59315, X59312, X59318, J00248, and
  • the M2e antibodies include a V L region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgKVl germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the
  • IgKVl germline gene sequence and more preferably, at least 98%, 99% homologous to the
  • the V L region of the M2e antibody is at least 80% homologous to the amino acid sequence of the V L region encoded the IgKVl germline gene sequence.
  • the amino acid sequence of V L region of the M2e antibody is at least
  • the invention provides a composition including an huM2e antibody according to the invention.
  • the composition further includes an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.
  • the anti-viral drug is for example a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel inhibitor.
  • the M2 ion channel inhibitor is for example amantadine or rimantadine.
  • the neuraminidase inhibitor for example zanamivir, or oseltamivir phosphate.
  • the composition further includes a second anti-influenza A antibody.
  • huM2e antibodies according to the invention are operably-
  • the invention provides methods for stimulating an immune response, treating, preventing or alleviating a symptom of an influenza viral infection by administering an huM2e antibody to a subject
  • the subject is further administered with a second agent such as, but not limited to, an influenza virus antibody, an anti-viral drug such as a neuraminidase inhibitor, a
  • HA inhibitor a sialic acid inhibitor or an M2 ion channel inhibitor, a viral entry inhibitor or a viral attachment inhibitor.
  • M2 ion channel inhibitor is, for example, amantadine or rimantadine.
  • the neuraminidase inhibitor is, for example, zanamivir or oseltamivir phosphate.
  • the subject is suffering from or is predisposed to developing an influenza virus infection, such as, for example, an autoimmune disease or an inflammatory disorder.
  • the invention provides methods of administering the huM2e antibody of the invention to a subject prior to, and/or after exposure to an influenza virus.
  • the huM2e antibody of the invention is used to treat or prevent
  • the huM2e antibody is administered at a dose sufficient to promote viral clearance or eliminate influenza A infected cells.
  • Also included in the invention is a method for determining the presence of an influenza virus infection in a patient, by contacting a biological sample obtained from the patient with a humM2e antibody; detecting an amount of the antibody that binds to the biological sample; and comparing the amount of antibody that binds to the biological sample to a control value.
  • the invention further provides a diagnostic kit comprising a huM2e antibody.
  • the present invention provides fully human monoclonal antibodies specific against the extracellular domain of the matrix 2 (M2) polypeptide.
  • the antibodies are respectively referred to herein as huM2e antibodies.
  • M2 is a 96 amino acid transmembrane protein present as a homotetramer on the surface of influenza virus and virally infected cells.
  • M2 contains a 23 amino acid ectodomain (M2e) that is highly conserved across influenza A strains. Few amino acid changes have occurred since the 1918 pandemic strain thus M2e is an attractive target for influenza therapies.
  • monoclonal antibodies specific to the M2 ectodomain (M2e) were derived upon immunizations with a peptide corresponding to the linear sequence of M2e.
  • the present invention provides a novel process whereby full-length M2 is expressed in cell lines, which allows for the identification of human antibodies that bound this cell- expressed M2e.
  • the huM2e antibodies have been shown to bind conformational determinants on the M2-transfected cells, as well as native M2, either on influenza infected cells, or on the virus itself.
  • the huM2e antibodies did not bind the linear M2e peptide, but they do bind several natural M2 variants, also expressed upon cDNA transfection into cell lines.
  • this invention has allowed for the identification and production of human monoclonal antibodies that exhibit novel specificity for a very broad range of influenza A virus strains. These antibodies may be used diagnostically to identify influenza A infection and therapeutically to treat influenza A infection.
  • the huM2e antibodies of the invention have one or more of the following
  • the huM2e antibody binds a) to an epitope in the extracellular domain of the matrix 2 (M2) polypeptide of an influenza virus; b) binds to influenza A infected cells;
  • influenza A virus i.e., virons.
  • the huM2e antibodies of the invention eliminate influenza infected cells through immune effector mechanisms, such as ADCC, and promote direct viral clearance by binding to influenza virons.
  • the huM2e antibodies of the invention bind to the amino-terminal region of the M2e polypeptide.
  • the huM2e antibodies of the invention bind to the amino-terminal region of the M2e polypeptide wherein the N-terminal methionine residue is absent.
  • Exemplary M2e sequences include those sequences listed on Table 1 below
  • the huM2e antibodies of the invention bind to a M2e that wholly or partially includes the amino acid residues from position 2 to position 7 of M2e when numbered in accordance with SEQ ID NO: 1.
  • the huM2e antibodies of the invention bind wholly or partially to the amino acid sequence SLLTEVET (SEQ ID NO: 41)
  • the huM2e antibodies of the invention bind wholly or partially to the amino acid sequence SLLTEV (SEQ ID NO: 42)
  • the huM2e antibodies of the invention bind to non-linear epitope of the M2e protein.
  • the huM2e antibodies bind to an epitope comprising position 2, 5, and 6 of the M2e polypeptide when numbered in accordance to SEQ ID NO: 1 where the amino acid at a) position 2 is a serine;b) position 5 is a threonine; and c) position 6 is a glutamic acid.
  • Exemplary huM2e monoclonal antibodies that bind to this epitope are the TCN-032 (8110), 21B15, TCN-031 (23K12), 3241_G23, 3244 110, 3243J07, 3259J21 , 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255_J06, 3420J23, 3139 P23, 3248_P18, 3253_P10, 3260_D19, 3362_B1 1 , and 3242 P05 antibodies described herein.
  • the TCN-032 (8110) antibody includes a heavy chain variable region (SEQ ID NO: 44) encoded by the nucleic acid sequence shown below in SEQ ID NO: 43, a short heavy chain variable region (SEQ ID NO: 277) encoded by the nucleic acid sequence shown below in SEQ ID NO: 278, a long heavy chain variable region (SEQ ID NO: 276) encoded by the nucleic acid sequence shown below in SEQ ID NO: 196, and a light chain variable region (SEQ ID NO: 46) encoded by the nucleic acid sequence shown in SEQ ID NO: 45.
  • the heavy chain CDRs of the TCN-032 (8110) antibody have the following sequences per Kabat definition: NYYWS (SEQ ID NO: 72), FIYYGGNTKYNPSLKS (SEQ ID NO: 74) and ASCSGGYCILD (SEQ ID NO: 76).
  • the light chain CDRs of the TCN-032 (8110) antibody have the following sequences per Kabat definition: RASQNIYKYLN (SEQ ID NO: 59), AA SGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
  • the heavy chain CDRs of the TCN-032 (8110) antibody have the following sequences per Chothia definition: GSSISN (SEQ ID NO: 109), FIYYGGNTK (SEQ ID NO: 1 10) and ASCSGGYCILD (SEQ ID NO: 76).
  • the light chain CDRs of the TCN-032 (8110) antibody have the following sequences per Chothia definition: RASQNIYKYLN (SEQ ID NO: 59), AASGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
  • TCN-032 (8110) VH nucleotide sequence: (SEQ ID NO: 43)
  • TCN-032 (8110) VH amino acid sequence: (SEQ ID NO: 44)
  • TCN-032 (8110) VH short nucleotide sequence: (SEQ ID NO: 278)
  • TCN-032 (8110) VH long nucleotide sequence: (SEQ ID NO: 196)
  • TCN-032 (8110) VH long amino acid sequence: (SEQ ID NO: 276)
  • TCN-032 (8110) VL nucleotide sequence: (SEQ ID NO: 45)
  • TCN-032 (8110) VL amino acid sequence: (SEQ ID NO: 46)
  • the 21 B 15 antibody includes a heavy chain variable region (SEQ ID NO: 44) encoded by the nucleic acid sequence shown below in SEQ ID NO: 47, a short heavy chain variable region (SEQ ID NO: 277) encoded by the nucleic acid sequence shown below in SEQ ID NO: 278, a long heavy chain variable region (SEQ ID NO: 276) encoded by the nucleic acid sequence shown below in SEQ ID NO: 196, and a light chain variable region (SEQ ID NO: 46) encoded by the nucleic acid sequence shown in SEQ ID NO: 48.
  • the heavy chain CDRs of the 2 IBl 5 antibody have the following sequences per Kabat definition: NYYWS (SEQ ID NO: 72), FIYYGGNTKYNPSLKS (SEQ ID NO: 74) and ASCSGGYCILD (SEQ ID NO: 76).
  • the light chain CDRs of the 21Bl 5 antibody have the following sequences per Kabat definition: RASQNIYKYLN (SEQ ID NO: 59),
  • AASGLQS (SEQ ID NO: 61 ) and QQSYSPPLT (SEQ ID NO: 63).
  • the heavy chain CDRs of the 21 Bl 5 antibody have the following sequences per Chothia definition: GSSISN (SEQ ID NO: 109), FIYYGGNTK (SEQ ID NO: 1 10) and ASCSGGYCILD (SEQ ID NO: 76).
  • the light chain CDRs of the 21 Bl 5 antibody have the following sequences per Chothia definition: RASQNIYKYLN (SEQ ID NO: 59), AASGLQS (SEQ ID NO: 61) and QQSYSPPLT (SEQ ID NO: 63).
  • the TCN-031 (23Kl 2) antibody includes a heavy chain variable region (SEQ ID NO: 50) encoded by the nucleic acid sequence shown below in SEQ ID NO: 49, a short heavy chain variable region (SEQ ID NO: 236) encoded by the nucleic acid sequence shown below in SEQ ID NO: 244, a long heavy chain variable region (SEQ ID NO: 195) encoded by the nucleic acid sequence shown below in SEQ ID NO: 235, and a light chain variable region (SEQ ID NO: 52) encoded by the nucleic acid sequence shown in SEQ ID NO: 51.
  • the heavy chain CDRs of the TCN-031 (23Kl 2) antibody have the following sequences per Kabat definition: SNYMS (SEQ ID NO: 103), VIYSGGSTYYADSVK (SEQ ID NO: 105) and CLSRMRGYGLDV (SEQ ID NO: 107).
  • the light chain CDRs of the TCN-031 (23Kl 2) antibody have the following sequences per Kabat definition:
  • RTSQSISSYLN (SEQ ID NO: 92), AASSLQSGVPSRF (SEQ ID NO: 94) and QQSYSMPA (SEQ ID NO: 96).
  • the heavy chain CDRs of the TCN-031 (23Kl 2) antibody have the following sequences per Chothia definition: GFTVSSN (SEQ ID NO: 1 12), VIYSGGSTY (SEQ ID NO: 1 13) and CLSRMRGYGLDV (SEQ ID NO: 107).
  • the light chain CDRs of the TCN- 031 (23Kl 2) antibody have the following sequences per Chothia definition: RTSQSISSYLN (SEQ ID NO: 92), AASSLQSGVPSRF (SEQ ID NO: 94) and QQSYSMPA (SEQ ID NO: 96).
  • TCN-031 (23K12) VH nucleotide sequence: (SEQ ID NO: 49)
  • TCN-031 (23K12) VH amino acid sequence: (SEQ ID NO: 50)
  • TCN-031 (23K12) VH short nucleotide sequence: (SEQ ID NO: 244)
  • TCN-031 (23K12) VH short amino acid sequence: (SEQ ID NO: 236)
  • TCN-031 (23K12) VH long nucleotide sequence: (SEQ ID NO: 195)
  • TCN-031 (23K12) VH long amino acid sequence: (SEQ ID NO: 235)
  • TCN-031 (23K12) VL nucleotide sequence: (SEQ ID NO: 51)
  • TCN-031 (23K12) VL amino acid sequence: (SEQ ID NO: 52)
  • the 3241 G23 antibody (also referred to herein as G23) includes a heavy chain variable region (SEQ ID NO: 1 16) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 1 15 and a light chain variable region (SEQ ID NO: 1 18) encoded by the nucleic acid sequence shown in SEQ ID NO: 1 17.
  • the heavy chain CDRs of the G23 antibody have the following sequences per Kabat definition: GGGYSWN (SEQ ID NO: 179), FMFHSGSPRYNPTLKS (SEQ ID NO: 180) and VGQMDKYYAMDV (SEQ ID NO: 181).
  • the light chain CDRs of the G23 antibody have the following sequences per Kabat definition: RASQSIGA YVN (SEQ ID NO: 184),
  • GASNLQS SEQ ID NO: 185
  • QQTYSTPIT SEQ ID NO: 186
  • the heavy chain CDRs of the G23 antibody have the following sequences per Chothia definition: GGPVSGGG (SEQ ID NO: 182), FMFHSGSPR (SEQ ID NO: 183) and
  • VGQMDKYYAMDV (SEQ ID NO: 181).
  • the light chain CDRs of the G23 antibody have the following sequences per Chothia definition: RASQSIGA YVN (SEQ ID NO: 184),
  • the 3244 110 antibody (also referred to herein as 110) includes a heavy chain variable region (SEQ ID NO: 120) encoded by the nucleic acid sequence shown below in SEQ ID NO: 120) encoded by the nucleic acid sequence shown below in SEQ ID NO: 120
  • SEQ ID NO: 1 19 a light chain variable region (SEQ ID NO: 122) encoded by the nucleic acid sequence shown in SEQ ID NO: 121.
  • the heavy chain CDRs of the U O antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and
  • HDAKFSGSYYVAS (SEQ ID NO: 189).
  • the light chain CDRs of the 110 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS
  • the heavy chain CDRs of the 110 antibody have the following sequences per Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGGSTK (SEQ ID NO: 191) and HDAKFSGSYYVA (SEQ ID NO: 189).
  • the light chain CDRs of the 110 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS (SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
  • the 3243 J07 antibody (also referred to herein as J07) includes a heavy chain variable region (SEQ ID NO: 124) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 123 and a light chain variable region (SEQ ID NO: 126) encoded by the nucleic acid sequence shown in SEQ ID NO: 125.
  • the heavy chain CDRs of the J07 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and
  • HDVKFSGSYYVAS (SEQ ID NO: 197).
  • the light chain CDRs of the J07 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS (SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
  • the heavy chain CDRs of the J07 antibody have the following sequences per Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGGSTK (SEQ ID NO: 191) and
  • HDVKFSGSYYVAS (SEQ ID NO: 197).
  • the light chain CDRs of the J07 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GATNLQS (SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
  • the 3259_J21 antibody (also referred to herein as J21) includes a heavy chain variable region (SEQ ID NO: 128) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 130 a light chain variable region encoded by the nucleic acid sequence shown in SEQ ID NO: 129.
  • the amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the J21 antibody have the following sequences per Kabat definition: SYNWI (SEQ ID NO: 203), HIYDYGRTFYNSSLQS (SEQ ID NO: 204) and PLGILHYYAMDL (SEQ ID NO: 205).
  • the light chain CDRs of the J21 antibody have the following sequences per Kabat definition: RASQSIDKFLN (SEQ ID NO: 208), GASNLHS (SEQ ID NO: 209) and QQSFSVPA (SEQ ID NO: 210).
  • the heavy chain CDRs of the J21 antibody have the following sequences per Chothia definition: GGSISS (SEQ ID NO: 206), HIYDYGRTF (SEQ ID NO: 207) and
  • PLGILHYYAMDL (SEQ ID NO: 205).
  • the light chain CDRs of the J21 antibody have the following sequences per Chothia definition: RASQSIDKFLN (SEQ ID NO: 208),
  • GASNLHS SEQ ID NO: 209
  • QQSFSVPA SEQ ID NO: 210
  • the 3245 019 antibody (also referred to herein as O19) includes a heavy chain variable region (SEQ ID NO: 132) encoded by the nucleic acid sequence shown below in SEQ ID NO: 131 , and a light chain variable region (SEQ ID NO: 134) encoded by the nucleic acid sequence shown in SEQ ID NO: 133.
  • SEQ ID NO: 132 The amino acids encompassing the CDRs as defined by Chothia et al., 1989 are underlined and those defined by Kabat et al., 1991 are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the 019 antibody have the following sequences per Kabat definition: STYMN (SEQ ID NO: 21 1), VFYSETRTYYADSVKG (SEQ ID NO: 212) and VQRLSYGMDV (SEQ ID NO: 213).
  • the light chain CDRs of the Ol 9 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GASTLQS (SEQ ID NO: 217) and QQTYSIPL (SEQ ID NO: 218).
  • the heavy chain CDRs of the O19 antibody have the following sequences per Chothia definition: GLSVSS (SEQ ID NO: 214), VFYSETRTY (SEQ ID NO: 215) and
  • VQRLSYGMDV (SEQ ID NO: 213).
  • the light chain CDRs of the Ol 9 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GASTLQS (SEQ ID NO: 217) and QQTYSIPL (SEQ ID NO: 218).
  • the 3244_H04 antibody (also referred to herein as H04) includes a heavy chain variable region (SEQ ID NO: 136) encoded by the nucleic acid sequence shown below in SEQ ID NO: 135, and a light chain variable region (SEQ ID NO: 138) encoded by the nucleic acid sequence shown in SEQ ID NO: 137.
  • the heavy chain CDRs of the H04 antibody have the following sequences per Kabat definition: STYMN (SEQ ID NO: 21 1), VFYSETRTYY ADSVKG (SEQ ID NO: 212) and
  • VQRLSYGMDV (SEQ ID NO: 213).
  • the light chain CDRs of the H04 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GASSLQS
  • the heavy chain CDRs of the H04 antibody have the following sequences per Chothia definition: GLSVSS (SEQ ID NO: 214), VFYSETRTY (SEQ ID NO: 215) and
  • VQRLSYGMDV (SEQ ID NO: 213).
  • the light chain CDRs of the H04 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GASSLQS
  • the 3136 G05 antibody (also referred to herein as G05) includes a heavy chain variable region (SEQ ID NO: 140) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 139 SEQ ID NO: 142
  • SEQ ID NO: 142 a light chain variable region encoded by the nucleic acid sequence shown in SEQ ID NO: 141.
  • the heavy chain CDRs of the G05 antibody have the following sequences per Kabat definition: SDFWS (SEQ ID NO: 228), YVYNRGSTKYSPSLKS (SEQ ID NO: 229) and
  • NGRSSTSWGIDV (SEQ ID NO: 230).
  • the light chain CDRs of the 3136_G05 antibody have the following sequences per Kabat definition: RASQSISTYLH (SEQ ID NO: 233),
  • AASSLQS (SEQ ID NO: 234) and QQSYSPPLT (SEQ ID NO: 63).
  • the heavy chain CDRs of the 3136 G05 antibody have the following sequences per
  • NGRSSTSWGIDV (SEQ ID NO: 230).
  • the light chain CDRs of the 3136_G05 antibody have the following sequences per Chothia definition: RASQSISTYLH (SEQ ID NO: 233),
  • AASSLQS (SEQ ID NO: 234) and QQSYSPPLT (SEQ ID NO: 63).
  • the 3252_C13 antibody (also referred to herein as C13) includes a heavy chain variable region (SEQ ID NO: 144) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 143 SEQ ID NO: 143
  • SEQ ID NO: 146 encoded by the nucleic acid sequence shown in SEQ ID NO: 145.
  • the heavy chain CDRs of the C13 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), YIYNRGSTKYTPSLKS (SEQ ID NO: 237) and
  • the light chain CDRs of the C13 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
  • the heavy chain CDRs of the Cl 3 antibody have the following sequences per Chothia definition: GASISS (SEQ ID NO: 239), YIYNRGSTK (SEQ ID NO: 240) and
  • the light chain CDRs of the Cl 3 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
  • the 3259 J06 antibody (also referred to herein as J06) includes a heavy chain variable region (SEQ ID NO: 148) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 147 and a light chain variable region (SEQ ID NO: 150) encoded by the nucleic acid sequence shown in SEQ ID NO: 149.
  • the heavy chain CDRs of the J06 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), YIYNRGSTKYTPSLKS (SEQ ID NO: 237) and
  • HVGGHTYGIDY SEQ ID NO: 2348.
  • the light chain CDRs of the J06 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
  • the heavy chain CDRs of the J06 antibody have the following sequences per Chothia definition: GASISS (SEQ ID NO: 239), YIYNRGSTK (SEQ ID NO: 240) and
  • the light chain CDRs of the J06 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241), AASSLQS
  • LVTVSS [179] 3255_J06 VL nucleotide sequence (SEQ ID NO: 149)
  • the 3410_I23 antibody (also referred to herein as 123) includes a heavy chain variable region (SEQ ID NO: 152) encoded by the nucleic acid sequence shown below in SEQ ID NO: 152)
  • SEQ ID NO: 151 a light chain variable region encoded by the nucleic acid sequence shown in SEQ ID NO: 153.
  • the heavy chain CDRs of the 3410 123 antibody have the following sequences per
  • the heavy chain CDRs of the 3410 123 antibody have the following sequences per
  • TGSESTTGYGMDV (SEQ ID NO: 254).
  • the light chain CDRs of the 3410J23 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192),
  • AASSLHS (SEQ ID NO: 258) and QQSYSPPIT (SEQ ID NO: 259).
  • the 3139 P23 antibody (also referred to herein as P23) includes a heavy chain variable region (SEQ ID NO: 156) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 155 SEQ ID NO: 155
  • SEQ ID NO: 158 encoded by the nucleic acid sequence shown in SEQ ID NO: 157.
  • the heavy chain CDRs of the P23 antibody have the following sequences per Kabat definition: NSFWG (SEQ ID NO: 260), YVYNSGNTKYNPSLKS (SEQ ID NO: 261) and
  • HDDASHGYSIS (SEQ ID NO: 262).
  • the light chain CDRs of the 3139_P23 antibody have the following sequences per Kabat definition: RASQTISTYLN (SEQ ID NO: 265),
  • AASGLQS (SEQ ID NO: 61) and QQSYNTPLT (SEQ ID NO: 267).
  • the heavy chain CDRs of the 3139_P23 antibody have the following sequences per
  • HDDASHGYSIS (SEQ ID NO: 262).
  • the light chain CDRs of the 3139_P23 antibody have the following sequences per Chothia definition: RASQTISTYLN (SEQ ID NO: 265),
  • AASGLQS (SEQ ID NO: 61) and QQSYNTPLT (SEQ ID NO: 267).
  • the 3248 P18 antibody (also referred to herein as Pl 8) includes a heavy chain variable region (SEQ ID NO: 160) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 159 SEQ ID NO: 159
  • SEQ ID NO: 162 a light chain variable region encoded by the nucleic acid sequence shown in SEQ ID NO: 161.
  • the heavy chain CDRs of the 3248_P18 antibody have the following sequences per
  • the heavy chain CDRs of the 3248 P18 antibody have the following sequences per
  • PLGSRYYYGMDV (SEQ ID NO: 270).
  • the light chain CDRs of the 3248_P18 antibody have the following sequences per Chothia definition: RASQSISRYLN (SEQ ID NO: 273),
  • the 3253 P10 antibody (also referred to herein as PlO) includes a heavy chain variable region (SEQ ID NO: 164) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 163 and a light chain variable region (SEQ ID NO: 166) encoded by the nucleic acid sequence shown in SEQ ID NO: 165.
  • the heavy chain CDRs of the 3253 P10 antibody have the following sequences per
  • the light chain CDRs of the 3253_P10 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 187), FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and HDAKFSGSYYVAS (SEQ ID NO: 189).
  • the light chain CDRs of the 3253_P10 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO:
  • the heavy chain CDRs of the 3253_P10 antibody have the following sequences per
  • GGSITS SEQ ID NO: 190
  • FFYNGGSTK SEQ ID NO: 191
  • HDAKFSGSYYVAS (SEQ ID NO: 189).
  • the light chain CDRs of the 3253_P10 antibody have the following sequences per Chothia definition: RASQSISTYLN (SEQ ID NO: 192), GATDLQS (SEQ ID NO: 282) and QQSYNTPLI (SEQ ID NO: 194).
  • the 3260 D19 antibody (also referred to herein as D19) includes a heavy chain variable region (SEQ ID NO: 168) encoded by the nucleic acid sequence shown below in SEQ ID NO: 167, and a light chain variable region (SEQ ID NO: 170) encoded by the nucleic acid sequence shown in SEQ ID NO: 169.
  • the heavy chain CDRs of the 3260 D19 antibody have the following sequences per Kabat definition: DNYIN (SEQ ID NO: 284), VFYSADRTSYADSVKG (SEQ ID NO: 285) and VQKSYYGMDV (SEQ ID NO: 286).
  • the light chain CDRs of the 3260_D19 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291).
  • the heavy chain CDRs of the 3260_D19 antibody have the following sequences per Chothia definition: GFSVSD (SEQ ID NO: 287), VFYSADRTS (SEQ ID NO: 288) and VQKSYYGMDV (SEQ ID NO: 286).
  • the light chain CDRs of the 3260_D19 antibody have the following sequences per Chothia definition: RASQSISRYLN (SEQ ID NO: 273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291 ).
  • the 3362_B1 1 antibody (also referred to herein as Bl 1) includes a heavy chain variable region (SEQ ID NO: 172) encoded by the nucleic acid sequence shown below in
  • SEQ ID NO: 171 SEQ ID NO: 171
  • SEQ ID NO: 174 a light chain variable region encoded by the nucleic acid sequence shown in SEQ ID NO: 173.
  • the heavy chain CDRs of the Bl 1 antibody have the following sequences per Kabat definition: SGAYYWT (SEQ ID NO: 293), YIYYSGNTYYNPSLKS (SEQ ID NO: 294) and
  • AASTSVLGYGMDV (SEQ ID NO: 295).
  • the light chain CDRs of the Bl 1 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273),
  • AASSLQS (SEQ ID NO: 234) and QQSYSTPLT (SEQ ID NO: 300).
  • the heavy chain CDRs of the Bl 1 antibody have the following sequences per Chothia definition: GDSITSGA (SEQ ID NO: 296), YIYYSGNTY (SEQ ID NO: 297) and
  • AASTSVLGYGMDV (SEQ ID NO: 295).
  • the light chain CDRs of the Bl 1 antibody have the following sequences per Chothia definition: RASQSISRYLN (SEQ ID NO: 273), AASSLQS (SEQ ID NO: 234) and QQSYSTPLT (SEQ ID NO: 300).
  • the 3242_P05 antibody (also referred to herein as P05) includes a heavy chain variable region (SEQ ID NO: 176) encoded by the nucleic acid sequence shown below in SEQ ID NO: 175, and a light chain variable region (SEQ ID NO: 178) encoded by the nucleic acid sequence shown in SEQ ID NO: 177.
  • SEQ ID NO: 176 encoded by the nucleic acid sequence shown below in SEQ ID NO: 175
  • SEQ ID NO: 178 encoded by the nucleic acid sequence shown in SEQ ID NO: 177.
  • the heavy chain CDRs of the 3242 P05 antibody have the following sequences per Kabat definition: VSDNYIN (SEQ ID NO: 301), VFYSADRTSYADSVKG (SEQ ID NO: 285) and VQKSYYGMDV (SEQ ID NO: 286).
  • the light chain CDRs of the 3242_P05 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291).
  • the heavy chain CDRs of the 3242 P05 antibody have the following sequences per Chothia definition: SGFSV (SEQ ID NO: 304), VFYSADRTS (SEQ ID NO: 288) and VQKSYYGMDV (SEQ ID NO: 286).
  • the light chain CDRs of the 3242_P05 antibody have the following sequences per Chothia definition:
  • the light chain CDRs of the 3242 P05 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273), GASSLQS (SEQ ID NO: 226) and QQTFSIPL (SEQ ID NO: 291).
  • HuM2e antibodies of the invention also include antibodies that include a heavy chain variable amino acid sequence that is at least 90%, 92%, 95%, 97% 98%, 99% or more identical the amino acid sequence of SEQ ID NO: 44, 277, 276, 50, 236, 235, 1 16, 120, 124, 128, 132, 136, 140, 14.4, 148, 152, 156, 160, 164, 168, 172, or 176.
  • a light chain variable amino acid that is at least 90%, 92%, 95%, 97% 98%, 99% or more identical the amino acid sequence of SEQ ID NO: 46, 52, 1 18, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178.
  • the monoclonal antibody is an antibody that binds to the same epitope as TCN-032 (8110), 21 Bl 5, TCN-031 (23Kl 2), 3241_G23, 3244_I10, 3243J07, 3259_J21 , 3245_O19, 3244_H04, 3136_G05, 3252_C13, 3255J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B1 1, or 3242 P05.
  • the heavy chain of a M2e antibody is derived from a germ line V (variable) gene such as, for example, the IgHV4 or the IgHV3 germ line gene.
  • the M2e antibodies of the invention include a variable heavy chain (V H ) region encoded by a human IgHV4 or the IgHV3 germline gene sequence.
  • V H variable heavy chain
  • An IgHV4 germline gene sequence is shown, e.g., in Accession numbers Ll 0088, M29812, M951 14, X56360 and M951 17.
  • An IgHV3 germline gene sequence is shown, e.g., in Accession numbers X92218, X70208, Z27504, M99679 and AB019437.
  • the M2e antibodies of the invention include a V H region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgHV4 or the IgHV3 germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgHV4 or the IgHV3 germline gene sequence.
  • the V H region of the M2e antibody is at least 80% homologous to the amino acid sequence of the V H region encoded by the IgHV4 or the IgHV3 V H germline gene sequence.
  • the amino acid sequence of V H region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgHV4 or the IgHV3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by the IgHV4 or the IgHV3 germline gene sequence.
  • the M2e antibodies of the invention also include a variable light chain (V L ) region encoded by a human IgKVl germline gene sequence.
  • V L variable light chain
  • a human IgKVl V L germline gene sequence is shown, e.g., Accession numbers X59315, X59312, X59318, J00248, and Y14865.
  • the M2e antibodies include a V L region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgKVl germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgKVl germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgKVl germline gene sequence.
  • the V L region of the M2e antibody is at least 80% homologous to the amino acid sequence of the V L region encoded the IgKVl germline gene sequence.
  • the amino acid sequence of V L region of the M2e antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the IgKVl germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by e the IgKVl germline gene sequence.
  • the HA antibodies of the invention may also be capable of specifically binding to one or more fragments of influenza virus H5N1, such as the surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which are required for viral attachment and cellular release, or membrane proteins (Ml and M2).
  • H5N1 hemagglutinin
  • NA neuraminidase
  • the HA antibodies of the invention are capable of specifically binding to the HA molecule of H5N1
  • strains They may be capable of specifically binding to the HAl and/or HA2 subunit of the HA molecule. They may be capable of specifically binding to linear or structural and/or conformational epitopes on the HAl and/or HA2 subunit of the HA molecule.
  • the HA molecule may be purified from viruses or recombinantly produced and optionally isolated before use. Alternatively, HA may be expressed on the surface of cells.
  • the HA antibodies may also be capable of specifically binding to proteins not present on the surface of H5N1 including the nucleoprotein, the nucleocapsid structural protein, polymerases (PA, PB and PB2), and non-structural proteins (NSl and NS2).
  • the nucleotide and/or amino acid sequence of proteins of various H5N1 strains can be found in the GenBank-database, NCBI Influenza Virus Sequence Database, Influenza Sequence Database (ISD), EMBL-database and/or other databases. It is well within the reach of the skilled person to find such sequences in the respective databases.
  • the HA antibodies of the invention are capable of specifically binding to a fragment of the above-mentioned proteins and/or polypeptides, wherein the fragment at least includes an antigenic determinant recognized by the HA antibodies of the invention.
  • An "antigenic determinant” as used herein is a moiety that is capable of binding to an HA antibody of the invention with sufficiently high affinity to form a detectable antigen-antibody complex.
  • the terms “antigenic determinant” and “epitope” are equivalents.
  • the HA antibodies of the invention may or may not be capable of specifically binding to the extracellular part of HA (also called herein soluble HA (sHA)).
  • the HA antibodies of the invention can be intact immunoglobulin molecules such as polyclonal or monoclonal antibodies or the HA antibodies can be antigen-binding fragments including, but not limited to, Fab, F(ab'), F(ab')2, Fv, dAb, Fd, complementarity determining region (CDR) fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, triabodies, tetrabodies, and (poly)peptides that contain at least a fragment of an immunoglobulin that is sufficient to confer specific antigen binding to influenza virus H5N1 strains or a fragment thereof.
  • the HA antibodies are human monoclonal antibodies.
  • HA antibodies can be used in non-isolated or isolated form. Furthermore, the HA antibodies can be used alone or in a mixture including at least one HA antibody (or variant or fragment thereof). Thus, HA antibodies can be used in combination, e.g., as a pharmaceutical composition comprising two or more antibodies of the invention, variants or fragments thereof. For example, antibodies having different, but complementary activities can be combined in a single therapy to achieve a desired prophylactic, therapeutic or diagnostic effect, but alternatively, antibodies having identical activities can also be
  • the mixture further includes at least one other therapeutic agent.
  • the therapeutic agent such as, e.g., M2 inhibitors (e.g., amantidine, rimantadine) and/or neuraminidase inhibitors (e.g., zanamivir, oseltamivir) is useful in the prophylaxis and/or treatment of an influenza virus H5N1 infection.
  • M2 inhibitors e.g., amantidine, rimantadine
  • neuraminidase inhibitors e.g., zanamivir, oseltamivir
  • HA antibodies can bind to their binding partners, i.e. influenza virus H5N1 or fragments thereof, with an affinity constant (Kd-value) that is lower than 0.2x10 "4 M, 1.OxI O '5 M, 1.0x10 6 M, 1.OxIO '7 M, preferably lower than 1.0x10 8 M, more preferably lower than 1.0x10 " M, more preferably lower than 1.0x10 "l0 M, even more preferably lower than 1.0x10 " " M, and in particular lower than 1.OxIO '12 M.
  • the affinity constants can vary for antibody isotypes.
  • affinity binding for an IgM isotype refers to a binding affinity of at least about 1.OxIO "7 M.
  • Affinity constants can for instance be measured using surface plasmon resonance, for example using the BIACORE system (Pharmacia Biosensor AB, Uppsala, Sweden).
  • HA antibodies may bind to influenza virus H5N1 or a fragment thereof in soluble form such as for instance in a sample or in suspension or may bind to influenza virus H5N1 or a fragment thereof bound or attached to a carrier or substrate, e.g., microtiter plates, membranes and beads, etc.
  • Carriers or substrates may be made of glass, plastic (e.g., polystyrene), polysaccharides, nylon, nitrocellulose, or Teflon, etc.
  • the surface of such supports may be solid or porous and of any convenient shape.
  • the HA antibodies may bind to influenza virus H5N1 in purified/isolated or non purified/non-isolated form.
  • HA antibodies exhibit neutralizing activity.
  • Neutralizing activity can for instance be measured as described in International Patent Application PCT/EP2007/059356 (Publication No. WO 2008/028946, the contents of which are incorporated herein in their entirety).
  • the invention relates to an isolated human HA antibody that recognizes and binds to an epitope in the HA2 subunit of the influenza haemagglutinin protein (HA), characterized in that said HA antibody has neutralizing activity against an influenza virus, for instance, including HA of the H5 subtype.
  • influenza strains that contain such a HA of the H5 subtype and that are important strains in view of pandemic threats are H5N1 , H5N2, H5N8, and H5N9.
  • Particularly preferred are HA antibodies that at least neutralize the H5N1 influenza strain.
  • HA antibodies do not depend on an epitope in the HAl subunit of the HA protein for binding to said HA protein.
  • human HA antibody describes an intact immunoglobulin including monoclonal antibodies, such as chimeric, humanized or human monoclonal antibodies, or to an antigen-binding and/or variable domain comprising fragment of an immunoglobulin that competes with the intact immunoglobulin for specific binding to the binding partner of the immunoglobulin, e.g. H5N1. Regardless of structure, the antigen binding fragment binds with the same antigen that is recognized by the intact immunoglobulin.
  • An antigen-binding fragment can comprise a peptide or polypeptide comprising an amino acid sequence of at least 2, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or 250 contiguous amino acid residues of the amino acid sequence of the HA antibody.
  • HA antibody includes all immunoglobulin classes and subclasses known in the art. Depending on the amino acid sequence of the constant domain of their heavy chains, HA antibodies can be divided into the five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • Antigen-binding fragments include, inter alia, Fab, F(ab'), F(ab')2, Fv, dAb, Fd, complementarity determining region (CDR) fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, single-chain phage antibodies, diabodies, triabodies, tetrabodies, (poly)peptides 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 methods of production are well known in the art and are described, for example, in Antibodies: A Laboratory Manual, Edited by: E. Harlow and D, Lane (1988), Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, which is incorporated herein by reference.
  • An HA antibody or antigen-binding fragment thereof may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or they may be different.
  • CDR complementarity determining regions
  • the CDR regions of HA antibodies 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, e.g., by solubilization in SDS.
  • Epitopes of HA antibodies may also consist of posttranslational modifications of proteins.
  • the term "functional variant”, as used herein, refers to an HA antibody that includes a nucleotide and/or amino acid sequence that is altered by one or more nucleotides and/or amino acids compared to the nucleotide and/or amino acid sequences of the parental HA antibody and that is still capable of competing for binding to the binding partner, e.g. H5N1 , with the parental HA antibody.
  • the modifications in the amino acid and/or nucleotide sequence of the parental HA antibody do not significantly affect or alter the binding characteristics of the HA antibody encoded by the nucleotide sequence or containing the amino acid sequence, i.e. the antibody is still able to recognize and bind its target.
  • the functional variant may have conservative sequence modifications including nucleotide and amino acid substitutions, additions and deletions. These modifications can be introduced by standard techniques known in the art, such as site-directed mutagenesis and random PCR- mediated mutagenesis, and may include natural as well as non-natural nucleotides and amino acids.
  • Conservative amino acid substitutions include the ones in which the amino acid residue is replaced with an amino acid residue having similar structural or chemical properties. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan).
  • basic side chains e.g.
  • a HA antibody functional variant may have non-conservative amino acid substitutions, e.g., replacement of an amino acid with an amino acid residue having different structural or chemical properties. Similar minor variations may also include amino acid deletions or insertions, or both. Guidance in determining which amino acid residues may be substituted, inserted, or deleted without abolishing immunological activity may be found using computer programs well known in the art.
  • a mutation in a nucleotide sequence can be a single alteration made at a locus (a point mutation), such as transition or transversion mutations, or alternatively, multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleotide sequence.
  • the mutations may be performed by any suitable method known in the art.
  • HA antibodies when applied to HA antibodies, refers to molecules that are either directly derived from a human or based upon a human sequence.
  • HA antibody When an HA antibody is derived from or based on a human sequence and subsequently modified,
  • human when applied to HA antibodies is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences or based on variable or constant regions occurring in a human or human lymphocyte and modified in some form.
  • the human HA antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences, contain substitutions and/or deletions (e.g., mutations introduced by for instance random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • nucleic acid sequence may be exactly copied from a template, or with minor mutations, such as by error-prone PCR methods, or synthetically made matching the template exactly or with minor modifications.
  • Semi-synthetic molecules based on human sequences are also considered to be human as used herein.
  • the heavy chain of an HA antibody is derived from a germ line V (variable) gene such as, for example, the VHl or VH3 germline gene ⁇ see, Tomlinson IM, Williams SC, Ignatovitch O, Corbett SJ, Winter G. V-BASE Sequence Directory. Cambridge, United Kingdom: MRC Centre for Protein Engineering (1997)).
  • the HA antibodies of the invention include a V H region that is encoded by a nucleic acid sequence that is at least 80% homologous to the VHl or VH3 germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the VHl or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the VHl or VH3 germline gene sequence.
  • the V H region of the HA antibody is at least 80% homologous to the amino acid sequence of the V H region encoded by the VHl or VH3 V H germline gene sequence.
  • the amino acid sequence of V H region of the HA antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the VHl or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by the VHl or VH3 germline gene sequence.
  • VHl germline gene is VHl (1-2), VHl (1-18), VHl (3-23), or VHl (1 -69).
  • VH3 germline gene is VH3 (3-21 )
  • the HA antibodies of the invention also include a variable light chain (V L ) region encoded by a human germline gene sequence selected from the group consisting of VKI, VKII, VKIII, VKIV, VLl , VL2, and VL3 ⁇ see, Tomlinson IM, Williams SC, Ignatovitch O, Corbett SJ, Winter G. V-BASE Sequence Directory. Cambridge, United Kingdom: MRC Centre for Protein Engineering (1997)).
  • the HA antibodies include a V L region that is encoded by a nucleic acid sequence that is at least 80% homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl , VL2, or VL3.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl , VL2, or VL3, and more preferably, at least 98%, 99% homologous to the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl , VL2, or VL3.
  • the V L region of the HA antibody is at least 80% homologous to the amino acid sequence of the V L region encoded the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl, VL2, or VL3.
  • the amino acid sequence of V L region of the HA antibody is at least 90%, 95%, 96%, 97% homologous to the amino acid sequence encoded by the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl, VL2, or VL3, and more preferably, at least 98%, 99% homologous to the sequence encoded by the germline gene sequence of VKI, VKII, VKIII, VKIV, VLl , VL2, or VL3.
  • the VKI germline gene is VKI (A20), the VKII germline gene is VKII (A3), the VKIII germline gene is VKIII (A27), and the VKIV germline gene is VKIV (B3).
  • the VLl germline gene is VLl (V l-13), VLl (Vl-16), VLl (Vl -17), or. VLl (Vl-19).
  • the VL2 germline gene is VL2 (Vl -3) or VL2 (Vl-4).
  • the VL3 germline gene is VL3 (V2-14).
  • HA antibodies contain two, three, four, five or all six CDR regions as disclosed herein.
  • HA antibodies contain at least two of the CDRs disclosed herein.
  • the SC06-141 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 309) and a light chain variable region (SEQ ID NO: 310) encoded by the nucleic acid sequence shown in SEQ ID NO: 31 1 and the amino acid sequence shown in SEQ ID NO: 312.
  • the VH-locus is VHl (1-18) and the VL locus is HKIV (B3).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-141 antibody have the following CDR sequences: GYYVY (HCDRl , SEQ ID NO: 566), WISAYNGNTNY AQKFQG (HCDR2, SEQ ID NO: 567) and SRSLDV (HCDR3, SEQ ID NO: 568).
  • the light chain CDRs of the SC06-141 antibody have the following CDR sequences: KSSQSVLYSSNNKNYLA (LCDRl , SEQ ID NO: 569), WASTRES (LCDR2, SEQ ID NO: 570) and QQYYSTPLT (LCDR3, SEQ ID NO: 200).
  • SC06-141 nucleotide sequence SEQ IDNO: 311)
  • the SC06-255 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 313) and a light chain variable region (SEQ ID NO: 314) encoded by the nucleic acid sequence shown in SEQ ID NO: 315 and the amino acid sequence shown in SEQ ID NO: 316.
  • the VH-locus is VHl (1-69) and the VL locus is VLl (Vl-16).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-255 antibody have the following CDR sequences: SYAIS (HCDRl, SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 255 antibody have the following CDR sequences: SGSTFNIGSNAVD (LCDRl , SEQ ID NO: 574), SNNQRPS (LCDR2, SEQ ID NO: 575) and AAWDDILNVPV (LCDR3, SEQ ID NO: 576).
  • SC06-255 nucleotide sequence SEQ ID NO: 315)
  • the SC06-257 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 317) and a light chain variable region (SEQ ID NO: 318) encoded by the nucleic acid sequence shown in SEQ ID NO: 319 and the amino acid sequence shown in SEQ ID NO: 320.
  • the VH-locus is VHl (1-69) and the VL locus is VL2 (V 1-4).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-257 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIIPIFGTTKY APKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 257 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDRl , SEQ ID NO: 577), EVSNRPS (LCDR2, SEQ ID NO: 578) and SSYTSSSTY (LCDR3, SEQ ID NO: 579).
  • SC06-257 nucleotide sequence SEQ ID NO: 319)
  • the SC06-260 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 321) and a light chain variable region (SEQ ID NO: 322) encoded by the nucleic acid sequence shown in SEQ ID NO: 323 and the amino acid sequence shown in SEQ ID NO: 324.
  • the VH-locus is VHl (1-69) and the VL locus is VLl (V l-17).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-260 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 260antibody have the following CDR sequences: SGSRSNVGDNSVY (LCDRl , SEQ ID NO: 580), KNTQRPS (LCDR2, SEQ ID NO: 581) and VA WDDSVDGYV (LCDR3, SEQ ID NO: 582).
  • SC06-260 nucleotide sequence SEQ ID NO: 323)
  • the SC06-261 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 325) and a light chain variable region (SEQ ID NO: 326) encoded by the nucleic acid sequence shown in SEQ ID NO: 327 and the amino acid sequence shown in SEQ ID NO: 328.
  • the VH-locus is VHl (1-69) and the VL locus is VLl (Vl-19).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-261 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 261 antibody have the following CDR sequences: SGSSSNIGNDYVS (LCDRl , SEQ ID NO: 583), DNNKRPS (LCDR2, SEQ ID NO: 584) and ATWDRRPTA YVV (LCDR3, SEQ ID NO: 585).
  • SC06-261 nucleotide sequence SEQ ID NO: 327)
  • the SC06-262 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 329) and a light chain variable region (SEQ ID NO: 330) encoded by the nucleic acid sequence shown in SEQ ID NO: 331 and the amino acid sequence shown in SEQ ID NO: 332.
  • the VH-locus is VHl (1-69) and the VL locus is VKI (A20).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-262 antibody have the following CDR sequences: GSAIS (HCDRl, SEQ ID NO: 586), GISPLFGTTNY AQKFQG (HCDR2, SEQ ID NO: 587) and GPKYYSEYMDV (HCDR3, SEQ ID NO: 588).
  • the light chain CDRs of the SC06-262 antibody have the following CDR sequences: RASQGISSYLA (LCDRl, SEQ ID NO: 589), DASTLRS (LCDR2, SEQ ID NO: 590) and QRYNSAPPI (LCDR3, SEQ ID NO: 591).
  • SC06-262 nucleotide sequence SEQ ID NO: 331)
  • the SC06-268 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 333) and a light chain variable region (SEQ ID NO: 334) encoded by the nucleic acid sequence shown in SEQ ID NO: 335 and the amino acid sequence shown in SEQ ID NO: 336.
  • the VH-locus is VHl (1-69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-268 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIMGMFGTTNYAQKFQG (HCDR2, SEQ ID NO: 592) and SSGYYPEYFQD (HCDR3, SEQ ID NO: 593).
  • the light chain CDRs of the SC06- 268 antibody have the following CDR sequences: SGHKLGDKYVS (LCDRl, SEQ ID NO: 594), QDNRRPS (LCDR2, SEQ ID NO: 595) and QAWDSSTA (LCDR3, SEQ ID NO: 596).
  • SC06-268 nucleotide sequence SEQ ID NO: 335)
  • the SC06-272 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 337) and a light chain variable region (SEQ ID NO: 338) encoded by the nucleic acid sequence shown in SEQ ID NO: 339 and the amino acid sequence shown in SEQ ID NO: 340.
  • the VH-locus is VHl (1-69) and the VL locus is VL2 (Vl-3).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-272 antibody have the following CDR sequences: SYAIT (HCDRl , SEQ ID NO: 597), GIIGMFGSTNYAQNFQG (HCDR2, SEQ ID NO: 598) and STGYYPA YLHH (HCDR3, SEQ ID NO: 599).
  • the light chain CDRs of the SC06-272 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDRl , SEQ ID NO: 600), DVSKRPS (LCDR2, SEQ ID NO: 601 ) and SSYTSSSTHV (LCDR3, SEQ ID NO: 602).
  • SC06-272 nucleotide sequence SEQ ID NO: 339)
  • the SC06-296 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 341) and a light chain variable region (SEQ ID NO: 342) encoded by the nucleic acid sequence shown in SEQ ID NO: 343 and the amino acid sequence shown in SEQ ID NO: 344.
  • the VH-locus is VHl (1-2) and the VL locus is VKJII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-296 antibody have the following CDR sequences: SYYMH (HCDRl , SEQ ID NO: 603), WINPNSGGTNYAQKFQG (HCDR2, SEQ ID NO: 604) and EGKWGPQAAFDI (HCDR3, SEQ ID NO: 605).
  • the light chain CDRs of the SC06-296 antibody have the following CDR sequences: RASQSVSSSYLA (LCDRl, SEQ ID NO: 606), DASSRAT (LCDR2, SEQ ID NO: 607) and QQYGSSLW (LCDR3, SEQ ID NO: 608).
  • SC06-296 nucleotide sequence SEQ ID NO: 343
  • the SC06-301 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 345) and a light chain variable region (SEQ ID NO: 346) encoded by the nucleic acid sequence shown in SEQ ID NO: 347 and the amino acid sequence shown in SEQ ID NO: 348.
  • the VH-locus is VHl (3-23) and the VL locus is VKII (A3).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-301 antibody have the following CDR sequences: IYAMS (HCDRl, SEQ ID NO: 609), AISSSGDSTYYADSVKG (HCDR2, SEQ ID NO: 610) and AYGYTFDP (HCDR3, SEQ ID NO: 61 1).
  • the light chain CDRs of the SC06-301 antibody have the following CDR sequences: RSSQSLLHSNGYNYLD (LCDRl , SEQ ID NO: 612), LGSNRAS (LCDR2, SEQ ID NO: 613) and MQALQTPL (LCDR3, SEQ ID NO: 614).
  • SC06-301 nucleotide sequence SEQ ID NO: 347)
  • the SC06-307 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 349) and a light chain variable region (SEQ ID NO: 350) encoded by the nucleic acid sequence shown in SEQ ID NO: 351 and the amino acid sequence shown in SEQ ID NO: 352.
  • the VH-locus is VH3 (3-21) and the VL locus is VKIII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-307 antibody have the following CDR sequences: SYSMN (HCDRl , SEQ ID NO: 615), SISSSSSYTYYVDSVKG (HCDR2, SEQ ID NO: 616) and GGGSYGAYEGFDY (HCDR3, SEQ ID NO: 617).
  • the light chain CDRs of the SC06- 307 antibody have the following CDR sequences: RASQRVSSYLA (LCDRl , SEQ ID NO: 618), GASTRAA (LCDR2, SEQ ID NO: 619) and QQYGRTPLT (LCDR3, SEQ ID NO: 620).
  • SC06-307 nucleotide sequence SEQ ID NO: 351)
  • the SC06-310 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 353) and a light chain variable region (SEQ ID NO: 354) encoded by the nucleic acid sequence shown in SEQ ID NO: 355 and the amino acid sequence shown in SEQ ID NO: 356.
  • the VH-locus is VHl (1 -69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-310 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIIPIFGTTKYAPKPQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 310 antibody have the following CDR sequences: GGNNIGSKSVH (LCDRl , SEQ ID NO: 621 ), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWDSSSDHAV (LCDR3, SEQ ID NO: 623).
  • SC06-310 nucleotide sequence SEQ ID NO: 355)
  • the SC06-314 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 357) and a light chain variable region (SEQ ID NO: 358) encoded by the nucleic acid sequence shown in SEQ ID NO: 359 and the amino acid sequence shown in SEQ ID NO: 360.
  • the VH-locus is VHl (1-69) and the VL locus is VLl (Vl-17).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-314 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571 ), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRETMDV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 314 antibody have the following CDR sequences: SGSSSNIGSNYVY (LCDRl, SEQ ID NO: 624), RDGQRPS (LCDR2, SEQ ID NO: 625) and ATWDDNLSGPV (LCDR3, SEQ ID NO: 626).
  • SC06-314 nucleotide sequence SEQ ID NO: 359)
  • the SC06-323 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 361) and a light chain variable region (SEQ ID NO: 362) encoded by the nucleic acid sequence shown in SEQ ID NO: 363 and the amino acid sequence shown in SEQ ID NO: 364.
  • the VH-locus is VHl (1-69) and the VL locus is VKIII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-323 antibody have the following CDR sequences: SYGIS (HCDRl , SEQ ID NO: 627), DIIGMTGSTNYAQNFQG (HCDR2, SEQ ID NO: 628) and SSGYYPAYLPH (HCDR3, SEQ ID NO: 629).
  • the light chain CDRs of the SC06- 323 antibody have the following CDR sequences: RASQSVSSSYLA (LCDRl , SEQ ID NO: 630), GASSRAT (LCDR2, SEQ ID NO: 631 ) and QQYGSSPRT (LCDR3, SEQ ID NO: 632).
  • SC06-323 nucleotide sequence SEQ ID NO: 363)
  • the SC06-325 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 365) and a light chain variable region (SEQ ID NO: 366) encoded by the nucleic acid sequence shown in SEQ ID NO: 367 and the amino acid sequence shown in SEQ ID NO: 368.
  • the VH-locus is VHl (1-69) and the VL locus is VL2 (Vl-4).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-325 antibody have the following CDR sequences: FYSMS (HCDRl , SEQ ID NO: 633), GIIPMFGTTNY AQKFQG (HCDR2, SEQ ID NO: 634) and GDKGIYYYYMDV (HCDR3, SEQ ID NO: 635).
  • the light chain CDRs of the SC06-325 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDRl , SEQ ID NO: 577), EVSNRPS (LCDR2, SEQ ID NO: 578) and SSYTSSSTLV (LCDR3, SEQ ID NO: 636).
  • SC06-325 nucleotide sequence SEQ ID NO: 367)
  • the SC06-327 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 369) and a light chain variable region (SEQ ID NO: 370) encoded by the nucleic acid sequence shown in SEQ ID NO: 371 and the amino acid sequence shown in SEQ ID NO: 372.
  • the VH-locus is VHl (1-69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-327 antibody have the following CDR sequences: THAIS (SEQ ID NO: 637), GIIAIFGTANY AQKFQG (SEQ ID NO: 638) and
  • the light chain CDRs of the SC06-327 antibody have the following CDR sequences: GGNNIGSKGVH (SEQ ID NO: 640), DDSDRPS (SEQ ID NO: 641) and QV WDSSSDHVV (SEQ ID NO: 642). [351] SC06-327 nucleotide sequence (SEQ ID NO: 371)
  • the SC06-328 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 373) and a light chain variable region (SEQ ID NO: 374) encoded by the nucleic acid sequence shown in SEQ ID NO: 375 and the amino acid sequence shown in SEQ ID NO: 376.
  • the VH-locus is VHl (1 -69) and the VL locus is VKIII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-328 antibody have the following CDR sequences: GYAIS (HCDRl , SEQ ID NO: 643), GIIPIFGTTNYAQKFQG (HCDR2, SEQ ID NO: 644) and VKDGYCTLTSCPVGWYFDL (HCDR3, SEQ ID NO: 645).
  • the light chain CDRs of the SC06-328 antibody have the following CDR sequences: RASQSVSSSYLA (LCDRl , SEQ ID NO: 646), GASSRAT (LCDR2, SEQ ID NO: 647) and QQYGSSLT (LCDR3, SEQ ID NO: 648).
  • the SC06-329 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 377) and a light chain variable region (SEQ ID NO: 378) encoded by the nucleic acid sequence shown in SEQ ID NO: 379 and the amino acid sequence shown in SEQ ID NO: 380.
  • the VH-locus is VHl (1-69) and the VL locus is VKIII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-329 antibody have the following CDR sequences: SNSIS (HCDRl , SEQ ID NO: 649), GIFALFGTTD Y AQKFQG (HCDR2, SEQ ID NO: 650) and GSGYTTRNYFDY (HCDR3, SEQ ID NO: 651).
  • the light chain CDRs of the SC06- 329 antibody have the following CDR sequences: RASQSVSSNYLG (LCDRl , SEQ ID NO: 652), GASSRAS (LCDR2, SEQ ID NO: 653) and QQYGSSPLT (LCDR3, SEQ ID NO: 654).
  • SC06-329 nucleotide sequence SEQ ID NO: 379)
  • the SC06-331 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 381) and a light chain variable region (SEQ ID NO: 382) encoded by the nucleic acid sequence shown in SEQ ID NO: 383 and the amino acid sequence shown in SEQ ID NO: 384.
  • the VH-locus is VHl (1-69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-331 antibody have the following CDR sequences: SYAIS (HCDRl , SEQ ID NO: 571), GIIGMFGT ANY AQKFQG (HCDR2, SEQ ID NO: 655) and GNYYYESSLDY (HCDR3, SEQ ID NO: 656).
  • the light chain CDRs of the SC06-331 antibody have the following CDR sequences: GGNNIGSKSVH (LCDRl , SEQ ID NO: 621), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWDSSSDH (LCDR3, SEQ ID NO: 657).
  • SC06-331 nucleotide sequence SEQ ID NO: 383)
  • the SC06-332 HA-speciflc single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 385) and a light chain variable region (SEQ ID NO: 386) encoded by the nucleic acid sequence shown in SEQ ID NO: 387 and the amino acid sequence shown in SEQ ID NO: 388.
  • the VH-locus is VHl (1-69) and the VL locus is VKI (A20).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-332 antibody have the following CDR sequences: NFAIN (HCDRl , SEQ ID NO: 658), GIIAVFGTTKY AHKFQG (HCDR2, SEQ ID NO: 659) and GPHYYSSYMDV (HCDR3, SEQ ID NO: 660).
  • the light chain CDRs of the SC06-332 antibody have the following CDR sequences: RASQGISTYLA (LCDRl , SEQ ID NO: 661), AASTLQS (LCDR2, SEQ ID NO: 662) and QKYNSAPS (LCDR3, SEQ ID NO: 663).
  • SC06-332 nucleotide sequence SEQ ID NO: 387)
  • the SC06-334 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 389) and a light chain variable region (SEQ ID NO: 390) encoded by the nucleic acid sequence shown in SEQ ID NO: 391 and the amino acid sequence shown in SEQ ID NO: 392.
  • the VH-locus is VHl (1-69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-334 antibody have the following CDR sequences: SNAVS (HCDRl, SEQ ID NO: 664), GILG VFGSPSY AQKFQG (HCDR2, SEQ ID NO: 665) and GPTYYYSYMDV (HCDR3, SEQ ID NO: 666).
  • the light chain CDRs of the SC06-334 antibody have the following CDR sequences: GGNNIGRNSVH (LCDRl , SEQ ID NO: 667), DDSDRPS (LCDR2, SEQ ID NO: 668) and QVWHSSSDHYV (LCDR3, SEQ ID NO: 669).
  • SC06-334 nucleotide sequence SEQ ID NO: 391)
  • the SC06-336 HA-specif ⁇ c single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 393) and a light chain variable region (SEQ ID NO: 394) encoded by the nucleic acid sequence shown in SEQ ID NO: 395 and the amino acid sequence shown in SEQ ID NO: 396.
  • the VH-locus is VHl (1-69) and the VL locus is VKIII (A27).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-336 antibody have the following CDR sequences: SYAIS (HCDRl, SEQ ID NO: 670), GIFGMFGT ANY AQKFQG (HCDR2, SEQ ID NO: 671) and SSGYYPQYFQD (HCDR3, SEQ ID NO: 672).
  • the light chain CDRs of the SC06- 336 antibody have the following CDR sequences: RASQSVSSSYLA (LCDRl , SEQ ID NO: 302), GASSRAT (LCDR2, SEQ ID NO: 305) and QQYGSSSLT (LCDR3, SEQ ID NO: 308).
  • SC06-336 nucleotide sequence SEQ ID NO: 395)
  • the SC06-339 HA-specif ⁇ c single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 397) and a light chain variable region (SEQ ID NO: 398) encoded by the nucleic acid sequence shown in SEQ ID NO: 399 and the amino acid sequence shown in SEQ ID NO: 400.
  • the VH-locus is VHl (1-69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-339 antibody have the following CDR sequences: SYAIS (HCDRl, SEQ ID NO: 303), GIIAIFHTPKY AQKFQG (HCDR2, SEQ ID NO: 306) and GSTYDFSSGLDY (HCDR3, SEQ ID NO: 398).
  • the light chain CDRs of the SC06-339 antibody have the following CDR sequences: GGNNIGSKSVH (LCDRl , SEQ ID NO: 289), DDSDRPS (LCDR2, SEQ ID NO: 248) and QVWDSSSDHVV (LCDR3, SEQ ID NO: 247).
  • SC06-339 nucleotide sequence SEQ ID NO: 399)
  • the SC06-342 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 401) and a light chain variable region (SEQ ID NO: 402) encoded by the nucleic acid sequence shown in SEQ ID NO: 403 and the amino acid sequence shown in SEQ ID NO: 404.
  • the VH-locus is VHl (1 -69) and the VL locus is VKIV (B3).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-342 antibody have the following CDR sequences: SYAIS (HCDRl, SEQ ID NO: 251 ), GVIPIFRTANY AQNFQG (HCDR2, SEQ ID NO: 249) and LNYHDSGTYYNAPRGWFDP (HCDR3, SEQ ID NO: 246).
  • the light chain CDRs of the SC06-342 antibody have the following CDR sequences: KSSQSILNSSNNKNYLA (LCDRl, SEQ ID NO: 245), WASTRES (LCDR2, SEQ ID NO: 299) and QQYYSSPPT (LCDR3, SEQ ID NO: 250).
  • SC06-342 nucleotide sequence SEQ ID NO: 403
  • the SC06-343 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 405) and a light chain variable region (SEQ ID NO: 406) encoded by the nucleic acid sequence shown in SEQ ID NO: 407 and the amino acid sequence shown in SEQ ID NO: 408.
  • the VH-locus is VHl (1 -69) and the VL locus is VL3 (V2-14).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-343 antibody have the following CDR sequences: YYAMS (HCDRl , SEQ ID NO: 242), GISPMFGTTT ⁇ AQKFQG (HCDR2, SEQ ID NO: 307) and SSNYYDSVYDY (HCDR3, SEQ ID NO: 290).
  • the light chain CDRs of the SC06-343 antibody have the following CDR sequences: GGHNIGSNSVH (LCDRl , SEQ ID NO: 224), DNSDRPS (LCDR2, SEQ ID NO: 223) and QVWGSSSDH (LCDR3, SEQ ID NO: 227).
  • the SC06-344 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 409) and a light chain variable region (SEQ ID NO: 410) encoded by the nucleic acid sequence shown in SEQ ED NO: 411 and the amino acid sequence shown in SEQ ID NO: 412.
  • the VH-locus is VHl (1-69) and the VL locus is VLl (Vl-13).
  • the amino acids encompassing the CDRs are highlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-344 antibody have the following CDR sequences: NYAMS (HCDRl , SEQ ID NO: 222), GIIAIFGTPKY AQKPQG (HCDR2, SEQ ID NO: 221) and IPHYNFGSGSYFDY (HCDR3, SEQ ID NO: 220).
  • the light chain CDRs of the SC06-344 antibody have the following CDR sequences: TGSSSNIGAGYDVH (LCDRl , SEQ ID NO: 219), GNSNRPS (LCDR2, SEQ ID NO: 231 ) and GTWDSSLSA YV (LCDR3, SEQ ID NO: 280).
  • SC06-344 nucleotide sequence SEQ ID NO: 411)
  • the CR6141 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 199) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 279 and the heavy chain amino acid sequence shown in SEQ ID NO: 413.
  • the CR6141 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 414) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 415 and the light chain amino acid sequence shown in SEQ ID NO: 416.
  • the CR6255 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 417) encoded by the heavy chain nucleotide sequence shown in SEQ IDNO: 418 and the heavy chain amino acid sequence shown in SEQ IDNO: 419.
  • the CR6255 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 420) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 421 and the light chain amino acid sequence shown in SEQ ID NO: 422.
  • the CR6257 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 423) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 424 and the heavy chain amino acid sequence shown in SEQ ID NO: 425.
  • the CR6257 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 426) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 427 and the light chain amino acid sequence shown in SEQ ID NO: 428.
  • the CR6260 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 429) encoded by the heavy chain nucleotide sequence shown in SEQ IDNO: 430 and the heavy chain amino acid sequence shown in SEQ IDNO: 431.
  • the CR6260 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 432) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 433 and the light chain amino acid sequence shown in SEQ ID NO: 434.
  • the CR6261 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 435) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 436 and the heavy chain amino acid sequence shown in SEQ ID NO: 437.
  • the CR6261 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 438) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 439 and the light chain amino acid sequence shown in SEQ ID NO: 440.
  • cagtctgcgt tgacgcagcc gccctcagtg tctgcggccc caggacagaa ggtcaccatc 60 tcctgctctg gaagcagctc caacattggg aatgattatg tatcctggta ccagcagctc 120 ccaggaacag cccccaaact cctcatttat gacaataata agcgaccctc agggattcct 180 gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240 actggggacg aggccaacca ttactgcgca acatgggatc gccgcccgac tgcttatgttt 300 gtcttcggc
  • the CR6262 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 441 ) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 442 and the heavy chain amino acid sequence shown in SEQ ID NO: 443.
  • the CR6262 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 444) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 445 and the light chain amino acid sequence shown in SEQ ID NO: 446.
  • the CR6268 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 447) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 448 and the heavy chain amino acid sequence shown in SEQ ID NO: 449.
  • the CR6268 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 450) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 451 and the light chain amino acid sequence shown in SEQ ID NO: 452.
  • the CR6272 HA-spe " cific IgG antibody includes a heavy chain variable region (SEQ ID NO: 453) encoded by the heavy chain nucleotide sequence shown in SEQ IDNO: 454 and the heavy chain amino acid sequence shown in SEQ ID NO: 455.
  • the CR6272 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 456) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 457 and the light chain amino acid sequence shown in SEQ ID NO: 458.
  • the CR696 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 459) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 460 and the heavy chain amino acid sequence shown in SEQ ID NO: 461.
  • the CR6296 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 462) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 463 and the light chain amino acid sequence shown in SEQ ID NO: 464.
  • the CR6301 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 465) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 466 and the heavy chain amino acid sequence shown in SEQ ID NO: 467.
  • the CR6301 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 468) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 469 and the light chain amino acid sequence shown in SEQ ID NO: 470.
  • the CR6307 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 471) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 472 and the heavy chain amino acid sequence shown in SEQ ID NO: 473.
  • the CR6307 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 474) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 475 and the light chain amino acid sequence shown in SEQ IDNO: 476.
  • the CR6310 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 477) encoded by the heavy chain nucleotide sequence shown in SEQ IDNO: 478 and the heavy chain amino acid sequence shown in SEQ ID NO: 479.
  • the CR6310 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 480) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 481 and the light chain amino acid sequence shown in SEQ ID NO: 482.
  • SEQ ID NO: 480 a light chain variable region encoded by the light chain nucleotide sequence shown in SEQ ID NO: 481 and the light chain amino acid sequence shown in SEQ ID NO: 482.
  • the CR6314 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 483) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 484 and the heavy chain amino acid sequence shown in SEQ ID NO: 485.
  • the CR6314 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 486) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 487 and the light chain amino acid sequence shown in SEQ ID NO: 488.
  • the CR6323 HA-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 489) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 490 and the heavy chain amino acid sequence shown in SEQ ID NO: 491.
  • the CR6323 HA-specific IgG antibody also includes a light chain variable region (SEQ ID NO: 492) encoded by the light chain nucleotide sequence shown in SEQ ID NO: 493 and the light chain amino acid sequence shown in SEQ ID NO: 494.

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JP2012524878A JP2013501807A (ja) 2009-08-14 2010-08-12 インフルエンザの治療および診断のための組成物および方法
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WO2012125614A1 (en) * 2011-03-15 2012-09-20 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
WO2012112489A3 (en) * 2011-02-14 2013-01-17 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
KR20150008164A (ko) * 2012-05-10 2015-01-21 비스테라, 인크. 신규 ha 결합 물질
US20160304586A1 (en) * 2013-12-05 2016-10-20 Crucell Holland B.V. Process for preparing influenza vaccines
US20180179265A1 (en) * 2015-04-27 2018-06-28 The Trustees Of The University Of Pennsylvania Engineered human anti-aav antibodies and uses thereof
TWI845955B (zh) * 2019-07-16 2024-06-21 美商基利科學股份有限公司 Hiv疫苗以及製造及使用方法
US12053517B2 (en) 2021-01-14 2024-08-06 Gilead Sciences, Inc. HIV vaccines and methods of using

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US20110033476A1 (en) * 2007-11-12 2011-02-10 Theraclone Sciences Inc. Compositions and methods for the therapy and diagnosis of influenza
EP2220116B1 (en) * 2007-11-12 2012-09-05 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
US20140363441A1 (en) * 2013-04-22 2014-12-11 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
TWI702229B (zh) 2014-12-19 2020-08-21 美商再生元醫藥公司 流行性感冒病毒血球凝集素之人類抗體
KR20210095781A (ko) 2020-01-24 2021-08-03 주식회사 에이프릴바이오 항원결합 단편 및 생리활성 이펙터 모이어티로 구성된 융합 컨스트럭트를 포함하는 다중결합항체 및 이를 포함하는 약학조성물
TWI867224B (zh) * 2020-06-08 2024-12-21 中央研究院 重組抗體或片段，以及其用途
WO2022132710A1 (en) * 2020-12-15 2022-06-23 Vanderbilt University Human hendra virus and nipah virus antibodies and methods of use therefor

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ES2520026T3 (es) * 2006-09-18 2014-11-11 The Board Of Trustees Of The University Of Arkansas Composiciones y métodos para potenciar respuestas inmunitarias
EP2220116B1 (en) * 2007-11-12 2012-09-05 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
JP5693460B2 (ja) * 2008-11-12 2015-04-01 セラクローン サイエンシーズ， インコーポレイテッド ヒトＭ２ｅペプチド免疫原
US8080244B2 (en) * 2008-11-21 2011-12-20 Los Alamos National Security, Llc Anti-influenza M2e antibody

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012112489A3 (en) * 2011-02-14 2013-01-17 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
WO2012125614A1 (en) * 2011-03-15 2012-09-20 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
JP2014509591A (ja) * 2011-03-15 2014-04-21 セラクローン サイエンシーズ， インコーポレイテッド インフルエンザの治療および診断のための組成物および方法
KR20150008164A (ko) * 2012-05-10 2015-01-21 비스테라, 인크. 신규 ha 결합 물질
KR102194936B1 (ko) 2012-05-10 2020-12-28 비스테라, 인크. 신규 ha 결합 물질
US20160304586A1 (en) * 2013-12-05 2016-10-20 Crucell Holland B.V. Process for preparing influenza vaccines
US20180179265A1 (en) * 2015-04-27 2018-06-28 The Trustees Of The University Of Pennsylvania Engineered human anti-aav antibodies and uses thereof
TWI845955B (zh) * 2019-07-16 2024-06-21 美商基利科學股份有限公司 Hiv疫苗以及製造及使用方法
US12053517B2 (en) 2021-01-14 2024-08-06 Gilead Sciences, Inc. HIV vaccines and methods of using

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US8974788B2 (en) 2015-03-10
CA2771105A1 (en) 2011-02-17
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US20110070235A1 (en) 2011-03-24
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JP2015120738A (ja) 2015-07-02

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