WO2012112489A2 - 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
WO2012112489A2
WO2012112489A2 PCT/US2012/024971 US2012024971W WO2012112489A2 WO 2012112489 A2 WO2012112489 A2 WO 2012112489A2 US 2012024971 W US2012024971 W US 2012024971W WO 2012112489 A2 WO2012112489 A2 WO 2012112489A2
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Prior art keywords
seq
tcn
amino acid
antibody
acid sequence
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English (en)
French (fr)
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WO2012112489A3 (en
Inventor
Andres G. Grandea
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 SG2013061122A priority Critical patent/SG192727A1/en
Priority to JP2013553646A priority patent/JP2014506580A/ja
Priority to NZ614215A priority patent/NZ614215B2/en
Priority to CA 2827301 priority patent/CA2827301A1/en
Priority to BR112013020743A priority patent/BR112013020743A2/pt
Priority to KR20137024393A priority patent/KR20140012098A/ko
Priority to MX2013009357A priority patent/MX2013009357A/es
Priority to CN201280018154.2A priority patent/CN103687619A/zh
Application filed by Theraclone Sciences Inc filed Critical Theraclone Sciences Inc
Priority to AU2012217867A priority patent/AU2012217867A1/en
Priority to EP12747475.7A priority patent/EP2675478A4/en
Publication of WO2012112489A2 publication Critical patent/WO2012112489A2/en
Publication of WO2012112489A3 publication Critical patent/WO2012112489A3/en
Priority to IL227947A priority patent/IL227947A0/en
Anticipated expiration legal-status Critical
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • 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
    • 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
    • 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
    • A61K2039/507—Comprising a combination of two or more separate 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
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • 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
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
  • 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 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 an isolated human antibody raised against an epitope of the Influenza hemagglutinin protein and an isolated human monoclonal antibody raised against an epitope of the Influenza M2 protein. Furthermore, these compositions are pharmaceutical' compositions that include a
  • 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) an isolated human antibody that specifically binds to an epitope of the hemagglutinin (HA) glycoprotein of an influenza virus; and (b) an isolated human monoclonal antibody that specifically binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus.
  • the isolated human monoclonal antibody that specifically binds an epitope of the M2e polypeptide is TCN-032 (8110), 21 B 15, TCN-031 (23K12), 3241_G23, 3244J10, 3243_J07, 3259J21, 3245_019,
  • the isolated human antibody that specifically binds an epitope of the HA glycoprotein is optionally TCN-522 (3212J12), TCN-521 (3280_D 18), TCN-523 (5248_A17), TCN-563 (5237_B21), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-529 (523 ⁇ 47_ ⁇ 01 ), TCN-530 (5248_H 10), TCN-531 (5091_H 13), TCN-532 (5262_H18), TCN-533 ' (5256 ⁇ A 17), TCN-534 (5249_B02), TCN-535 (5246_P19), TCN-536 (5095_N01), TCN-537 (3194_D21), TCN-538 (3206_O17), TCN-539 (5056_A08), TCN-540 (5060_F05), TCN-541 (5062_M1 1 ), TCN-542 (5079_A
  • the epitope of the HA glycoprotein is optionally GVTNKVNSIIDK (SEQ ID NO: 198), GVTNKVNSIINK (SEQ ID NO: 283), GVTNKENSIIDK (SEQ ID NO: 202), GVTN VNRIIDK (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 HA1 and HA2 subunit.
  • Exemplary epitopes of the HA glycoprotein include the HA1 subunit, HA2 subunit, or both the HA1 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
  • SLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1 ) or the amino acid at positions 2, 5, and 6 of SLLTEV (SEQ ID NO: 42).
  • 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 CDR1 : SEQ ID NOs: 247, 571 , 586, 597, 603, 609, 615, 627, 633, 637, 643, 649, 658, 664, 670, 303, 251 , 242, or 222; VH CDR2: SEQ ID NOs: 248, 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:
  • VL CDR2 SEQ ID NOs: 570, 575, 578, 581 , 584, 590, 595, 601 , 607, 613, 619, 622, 625, 631 , 653, 662, ' 668, 305, 223, or 231
  • VL CDR3 SEQ ID NOs: 289, 576, 579, 582, 585, 591 , 596, 602, 608, 6 ⁇ 4, 620, 623, 626, 632, 636, 642, 648, 654, 657, 663, 669, 308, 250, 227, or 280; and (b) an isolated anti-matrix 2 ectodomain (M2e) antibody, or antigen-binding fragment thereof, including a heavy chain variable (VH) domain and a light chain variable (V
  • VH CDR2 SEQ ID NOs: 74, 105, 180,
  • VL CDR1 SEQ ID NOs: 59, 92, 184, 192, 208, 192, 233, 241 , 265, or 273
  • VL CDR2 SEQ ID NOs: 61 , 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282
  • VL CDR3 SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291 , or 300.
  • VH CDR2 SEQ ID NOs: 1 10, 1 13, 183,
  • VH CDR3 SEQ ID NOs: 76, 107, 181 , 189, 197, 205, 213, 230, 238, 254, 262, 270, 286, or 295;
  • VL CDR1 SEQ ID NOs: 59, 92, 184, 192, 208, 192, 233, 241 , 265, or 273;
  • VL CDR2 SEQ ID NOs: 61 , 94, 185, 193, 209, 217, 226, 234, 258, 274, or 282; and
  • VL CDR3 SEQ ID NOs: 63, 96, 186, 194, 210, 218, 243, 259, 267, 275, 291 , or 300.
  • composition including:, (a) an isolated human anti-HA
  • VH domain heavy chain variable region
  • 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, 314, 318, 322, 326, 330, 334, 338
  • 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), 21B 15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259J21, 3245_019, 3244_H04, 3136_G05, 3252_C13, 3255_J06, 3420J23, 3139_P23, 3248_Pi 8, 3253_P10, 3260_D 19, 3362_B 1 1, 3242_P05, TCN-522 (3212J12), TCN-521 (3280_D18), TCN-523 (5248_A 17), TCN-563 (5237_B21 ), TCN-526 (5084_C17), TCN-527 (5086_C06), TCN-528 (5087_P17), TCN-529 (5297_H01), TCN-530 (5248_H10), TCN-531 (5091_H13), TCN-532 (5262_H 18), TCN- 533 (5256_A
  • TCN-545 (5082_A19), TCN-545 (5082J15), TCN-546 (5089_L08), TCN-547 (5092_F1 1), TCN-548 (5092_P01 ), TCN-549 (5092_P04), TCN-550 (5096_F06), TCN-551 (5243_D01), TCN-552 (5249J23), TCN-553 (5261_C18), TCN-554 (5277_M05), TCN-555 (5246_L16), TCN-556 (5089_K12), TCN-557 (5081_A04), TCN 558 (5248_H10b), TCN-559 (5097_G08), TCN- 560 (5084_P10), TCN-504 (3251_K17), SC06-141 , SC06-255, SC06-257, SC06-260, SC06- 261 , SC06-262, SC06-268, SC06-272, SC06-296, SC06-301 , 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),
  • GITNKVNSVIE (SEQ ID NO: 281 ), GITNKENSVIEK (SEQ ID NO: 257),
  • GITNKVNSIIDK (SEQ ID NO: 225), KITSKVNNIVDK (SEQ ID NO: 216),
  • MSLLTEVETPTRNEWGCRCNDSSD (SEQ ID NO: 1 )
  • 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 o 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, 202, 201 , 281 , 257, 225, and 216.
  • the term 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 2e polypeptide.
  • Figure 1 shows the binding of three antibodies of the present invention and control hu l 4C2 antibody to 293-HEK cells transfected with an M2 expression construct or control vector, in the presence or absence of free M2 peptide.
  • Figures 2A 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 2 variants (SEQ ID NOS 1 -3, 679 &5-40, respectively, in order of appearance).
  • Figures 3B and C are bar charts showing binding of human monoclonal anti-influenza antibody binding to M2 variants shown in Figure 3A.
  • Figures 4A 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 8i 10 and 23K12 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 (SEQ ID NOS 680-704, respectively, in order of appearance).
  • Figure 6B is a chart showing binding activity of M2 antibodies to truncated M2 peptides (SEQ ID NOS 680, 705-724 & 19, respectively, in order of appearance).
  • 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 (SEQ ID NO: 19).
  • Figure 9 is a graph showing anti-M2 rH Ab 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 an ti-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 FMAT plate scanner.
  • 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 VN 1 203 M2 proteins. Plasmids encoding full length M2 cDNAs corresponding to influenza strains H3N2, HK483, and VN1203, as well as a mock plasmid control, were transiently transfected into 293 cells. The 14C2, 8 ⁇ 0, 23K12, and 21B 15 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 EvIGT database (EVIGT®, the International ImMunoGeneTics Information system® http://www.imgt.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.
  • Figure 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 ⁇ - TCN-032 Fab fragment.
  • the anti-M2e mAb bound to the cell surface was detected with goat'anti-huIgG 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.
  • Figure 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
  • 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.
  • A/Vietnam 1203/04 (H5N 1 ) are representative of 2 experiments.
  • 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 (H1N1) 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. T e results are representative of two separate experiments with two different normal human donors.
  • Figure 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 Koiig/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.
  • Q The deduced epitope for TCN-031 and TCN-032 occurs in a highly conserved region of M2e and is distinct from that found for ch l4C2. Results shown for ( ⁇ ) and (B) are representative of 3 experiments.
  • Figure 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
  • Figure 21 is a graph depicting anti-M2e mAbs TCN-031 and TCN-032 bind cells that have been infected with H 1N1 A California/4/09. MDCK cells were infected with Influenza A strain H1 N1 A/Memphis/ 14/96, H 1N 1 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 H5N 1 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 (M l and M2), polymerases (PA, PB and PB2) and non-structural proteins (NS l and NS2).
  • M l and M2 membrane proteins
  • PA polymerases
  • PB and PB2 polymerases
  • NS l 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 1 97 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 fi!
  • HA hemagglutinin
  • M2e matrix 2 ectodomain
  • influenza infections including H5N 1.
  • 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 B 15, TCN-031 (23K 12), 3241_G23, 3244 110, 3243J07, 3259J21 , 3245_019, 3244_H04, 3136_G05, 3252_C 13, 3255J06, 3420J23, 3139_P23, 3248JP18, 3253_P10, 3260_D19, 3362_B 1 1 , and
  • the monoclonal antibody is an antibody that binds to the same epitope as TCN-032 (8110), 21B 15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259_J21, 3245.019, 3244_H04, 3136_G05, 3252_C 13, 3255_J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_B 1 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.
  • 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, 11 ⁇ 46, 150, 154, 158, 162, 166, 170, 174, or 178.
  • the three heavy chain CDRs incliide 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, 951 14, X56360 and M951 17.
  • IgHV3 germline gene sequence are shown, e.g., in Accession numbers X92218, X70208, Z27504, M99679 and ABO 19437.
  • 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 Ig Vl V L germline gene sequence is shown, e.g.. Accession numbers X59315, X59312, X59318, J00248, and Y 14865.
  • the M2e antibodies include ' a VL 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 IgKV 1 germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgKV l 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 IgKV l 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 IgKV l germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by e the IgKVl germline gene sequence.
  • 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- linked to a therapeutic agent or a detectable label.
  • 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.
  • 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.
  • the 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 2e.
  • 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 characteristics: 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; and/or c) binds to influenza A virus (i.e., virons).
  • M2 matrix 2
  • 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 [70] Table 1
  • 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), 21 B 15, TCN-031 (23K12), 3241_G23, 3244J 10, 3243_J07, 3259J21 , 3245_019, 3244_H04, 3136_G05, 3252_C 13, 3255_J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D 19, 3362_B 1 1 , and 3242_P05 antibodies described herein. J u
  • 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), AASGLQS (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 short amino acid sequence: (SEQ ID NO: 277)
  • TCN-032 (8110) VH long nucleotide sequence: (SEQ ID NO: 196)
  • 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 21 B 15 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 21 B 15 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 21B 15 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 21B 15 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 (23K 12) 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 (23K12) 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 (23K12) 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 (23K12) 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 (23K12) 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 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)
  • 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: RASQSIGAYVN (SEQ ID NO: 184), GASNLQS (SEQ ID NO: 185) and 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: RASQSIGAYVN (SEQ ID NO: 184), GASNLQS (SEQ ID NO: 185) and QQTYSTPIT (SEQ ID NO: 186).
  • the 3244_I10 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: 1 19, and 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 110 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 (SEQ ID NO: 193) and QQSYNTPLI (SEQ ID NO: 194).
  • 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
  • HDAKFSGSYYVAS (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). [128] 3243_J07 VH nucleotide sequence (SEQ ID NO: 123)
  • 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: 127, and a light chain variable region (SEQ ID NO: 130) encoded by the nucleic acid sequence shown in SEQ ID NO: 129.
  • 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 :ehain 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 PLG ILHYYAMDL (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 019) 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.
  • 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 019 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 019 antibody have the following sequences per Chothia definition: GLSVSS (SEQ ID NO: 214), VFYSETRTY (SEQ ID NO: 215) and
  • VQRLSYGMDV (SEQ ED NO: 213).
  • the light chain CDRs of the 019 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 ), VFYSETRTYYADSVKG (SEQ ID NO: 212) and VQRLSYGMDV (SEQ ID NO: 21 ).
  • the light chain CDRs of the H04 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GASSLQS (SEQ ID NO: 226) and QQTYSIPL (SEQ ID NO: 218).
  • 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 (SEQ ID NO: 226) and QQTYSIPL (SEQ ID NO: 218).
  • 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, and a light chain variable region (SEQ ID NO: 142) encoded by the nucleic acid sequence shown in SEQ ID NO: 141.
  • SEQ ID NO: 140 heavy chain variable region
  • SEQ ID NO: 142 light chain variable region
  • 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 Chothia definition: GGSISS (SEQ ID NO: 206), YVYNRGSTK (SEQ ID NO: 232) and 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, and a light chain variable region (SEQ ID NO: 146) encoded by the nucleic acid sequence shown in SEQ ID NO: 145.
  • the heavy chain CDRs of the CI 3 antibody have the following sequences per Kabat definition: SDYWS (SEQ ID NO: 187), YIYNRGSTKYTPSLKS (SEQ ID NO: 237) and HVGGHTYGIDY (SEQ ID NO: 238).
  • the light chain CDRs of the C I 3 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241 ), AASSLQS (SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
  • the heavy chain CDRs of the C 13 antibody have the following sequences per Chothia definition: GASISS (SEQ ID NO: 239), YIYNRGSTK (SEQ ID NO: 240) and
  • HVGGHTYGIDY SEQ ID NO: 2378.
  • the light chain CDRs of the C I 3 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241 ), AASSLQS (SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
  • 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: 238).
  • the light chain CDRs of the J06 antibody have the following sequences per Kabat definition: RASQSISNYLN (SEQ ID NO: 241 ), AASSLQS (SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
  • 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
  • HVGGHTYGIDY SEQ ID NO: 2378.
  • the light chain CDRs of the J06 antibody have the following sequences per Chothia definition: RASQSISNYLN (SEQ ID NO: 241 ), AASSLQS (SEQ ID NO: 234) and QQSYNTPIT (SEQ ID NO: 243).
  • LVTVSS [178] 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: 151 , and a light chain variable region (SEQ ID NO: 154) encoded by the nucleic acid sequence shown in SEQ ID NO: 153.
  • the heavy chain CDRs of the 3410_I23 antibody have the following sequences per Kabat definition: SYSWS (SEQ ID NO: 252), YLYYSGSTKYNPSLKS (SEQ ID NO: 253) and TGSESTTGYGMDV (SEQ ID NO: 254).
  • the light chain CDRs of the 3410J23 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), AASSLHS (SEQ ID NO: 258) and QQSYSPPIT (SEQ ID NO: 259).
  • the heavy chain CDRs of the 3410_I23 antibody have the following sequences per Chothia definition: GDSISS (SEQ ID NO: 255), YLYYSGSTK (SEQ ID NO: 256) and 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, and a light chain variable region (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 Chothia definition: GGSISN (SEQ ID NO: 263), YVYNSGNTK (SEQ ID NO: 264) and 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).
  • 3139_P23 VH nucleotide sequence SEQ ID NO: 155)
  • the 3248_P18 antibody (also referred to herein as PI 8) includes a heavy chain variable region (SEQ ID NO: 160) encoded by the nucleic acid sequence shown below in SEQ ID NO: 159, and a light chain variable region (SEQ ID NO: 162) 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 Kabat definition: AYHWS (SEQ ID NO: 268), HIFDSGSTYYNPSLKS (SEQ ID NO: 269) and PLGSRYYYGMDV (SEQ ID NO: 270).
  • the light chain CDRs of the 3248_P18 antibody have the following sequences per Kabat definition: RASQSISRYLN (SEQ ID NO: 273), GASTLQN (SEQ ID NO: 274) and QQSYSVPA (SEQ ID NO: 275).
  • the heavy chain CDRs of the 3248_P18 antibody have the following sequences per Chothia definition: GGSISA (SEQ ID NO: 271), HIFDSGSTY (SEQ ID NO: 272) and 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
  • GASTLQN SEQ ID NO: 274
  • QQSYSVPA SEQ ID NO: 275.
  • the 3253_P10 antibody (also referred to herein as P10) 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 Kabat definition: SDYWS (SEQ ID NO: 187),.FFYNGGSTKYNPSLKS (SEQ ID NO: 188) and HDAKFSGSYYVAS (SEQ ID NO: 189).
  • the li'ght chain CDRs of the 3253_P10 antibody have the following sequences per Kabat definition: RASQSISTYLN (SEQ ID NO: 192), GATDLQS (SEQ ID NO: 282) and QQSYNTPLI (SEQ ID NO: 194).
  • the heavy chain CDRs of the 3253_P10 antibody have the following sequences per ⁇ Chothia definition: GGSITS (SEQ ID NO: 190), FFYNGGSTK (SEQ ID NO: 191 ) and HDA FSGSYYVAS (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 D 19) 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 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 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'lD NO: 291).
  • the 3362_B 1 1 antibody (also referred to herein as B l 1 ) includes a heavy chain variable region (SEQ ID NO: 172) encoded by the nucleic acid sequence shown below in SEQ ID NO: 171 , and a light chain variable region (SEQ ID NO: 174) encoded by the nucleic acid sequence shown in SEQ ID NO: 173.
  • SEQ ID NO: 172 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 B 1 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 B l 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 B l 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 B l 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.
  • 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 VQKS YYGMDV (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 VQKS YYGMDV (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, 144, 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), 21B 15, TCN-031 (23K12), 3241_G23, 3244J10, 3243J07, 3259J21 , 3245_019, 3244_H04, 3136_G05, 3252_C13, 3255_J06, 3420J23, 3139_P23, 3248_P18, 3253_P10, 3260_D19, 3362_ ⁇ ⁇ , 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 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
  • An IgHV4 germline gene sequence is shown, e.g., in Accession numbers LI 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 ABO 19437.
  • 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 IgHV.4 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 Ig V l germline gene sequence.
  • V L variable light chain
  • a human IgKV l V L germline gene sequence is shown, e.g. , Accession numbers X59315, X59312, X59318, J00248, and Y 14865.
  • the M2e antibodies include a V L region that is encoded by a nucleic acid sequence that is at least 80% homologous to the IgKV l germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the IgKV l germline gene sequence, and more preferably, at least 98%, 99% homologous to the IgKV l germline gene sequence.
  • the VL region of the M2e antibody is at least 80% homologous to the amino acid sequence of the V L region encoded.the IgKV l 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 IgKV l germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by e the IgKV l germline gene sequence.
  • the HA antibodies of the invention may also be capable of specifically binding to one or more fragments of influenza virus H5N 1 , such as the surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which are required for viral attachment and cellular release, or membrane proteins (M l and M2).
  • the HA antibodies of the invention are capable of specifically binding to the HA molecule of H5N 1 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 (NS 1 and NS2).
  • the nucleotide and/or amino acid sequence of proteins of various H5N 1 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 H5N 1 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 infec.tion.
  • M2 inhibitors e.g., amantidine, rimantadine
  • neuraminidase inhibitors e.g., zanamivir, oseltamivir
  • HA antibodies can bind to their binding partners, i.e. influenza virus H5N 1 or fragments thereof, with an affinity constant (Kd-value) that is lower than 0.2 l0 "4 M, l .Ox l O "5 M, l .Ox lO "6 M, l .Ox l O "7 , preferably lower than l .Ox l O "8 M, more preferably lower than l .O l O “9 M, more preferably lower than 1.0x 10 10 M, even more preferably lower than 1.0x 10 " " M, and in particular lower than l .Ox l O "12 M.
  • Kd-value affinity constant
  • the affinity constants can vary for antibody isotypes.
  • affinity binding for an IgM isotype refers to a binding affinity of at least about 1.0x l O "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 H5N 1 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 H5N 1 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. H5N 1. 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
  • HA antibodies can be divided info 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.
  • human when applied to HA antibodies, refers to molecules that are either directly derived from a human or based upon a human sequence.
  • an HA antibody when applied to HA antibodies, refers to molecules that are either directly derived from a human or based upon a human sequence.
  • 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 PGR methods, or synthetically made matching the template exactly or with minor modifications.
  • Semi-synthetic molecules bas ⁇ ' d 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 VH 1 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 VH 1 or VH3 germline gene sequence.
  • the nucleic acid sequence is at least 90%, 95%, 96%, 97% homologous to the VH 1 or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the VH 1 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 VH 1 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 VH 1 or VH3 germline gene sequence, and more preferably, at least 98%, 99% homologous to the sequence encoded by the VH 1 or VH3 germline gene sequence.
  • the VH 1 germline gene is VH 1 ( 1 -2), VH 1 ( 1- 18), VH1 (3-23), or VH1 ( 1 -69).
  • the VH3 germline gene is VH3 (3-21 )
  • the HA antibodies of the invention also include a variable light chain (VL) region encoded by a human germline gene sequence selected from the group consisting of VKI, V II, VKIII, VKIV, VL l , VL2, and VL3 (see, Ton linson 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 VL 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, VL l , 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, VL l , 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 VL l germline gene is VLl (V l - 13), VLl (V l - 16), VLl (Vl - 17), or. VLl (V l - 19).
  • the VL2 germline gene is VL2 (V l -3) or VL2 (V l -4).
  • the VL3 germline gene is VL3 (V2- 14).
  • HA antibodies contain two, three, four, five or all six CDR regions as disclosed herein. Preferably, 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 VH 1 (1 -18) and the VL locus is H IV (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 (HCDR1 , SEQ ID NO: 247), WISAYNGNTNYAQKFQG (HCDR2, SEQ ID NO: 248) and SRSLDV (HCDR3, SEQ ID NO: 568).
  • the light chain CDRs of the SC06- 141 antibody have the following CDR sequences: KSSQSVLYSSNNKNYLA (LCDR1 , SEQ ID NO: 569), WASTRES (LCDR2, SEQ ID NO: 570) and QQYYSTPLT (LCDR3, SEQ ID NO: 289).
  • GGTGSGTGGSTDVVMTQSPDSLAVSLGERATINC SSQSVLYSSNN NYLAWYQQKPGQPP LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPLTFGGGTKVDIK
  • 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 VH 1 ( 1 -69) and the VL locus is VL 1 (V I - 16).
  • the amino acids encompassing the CDRs are jiighlighted in bold in the sequences below.
  • the heavy chain CDRs of the SC06-255 antibody have the following CDR sequences: SYAIS (HCDR1 , SEQ ID NO: 571), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRET DV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 255 antibody .have the following CDR sequences: SGSTFNIGSNAVD (LCDR 1 , SEQ ID NO: 574), SNNQRPS (LCDR2, SEQ ID NO: 575) and AAWDDILNVPV (LCDR3, SEQ ID NO: 576).
  • the SC06-257 HA-specific single-chain Fv antibody includes a heavy chain variable region (SEQ ID NO: 3 17) and a light chain variable region (SEQ ID NO: 3 18) 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 VH 1 ( 1 -69) and the VL locus is VL2 (V I -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 (HCDR 1 , SEQ ID NO: 571 ), GIIPIFGTTKYAPKFQG (HCDR2, SEQ ID NO: 572) and HMGYQVRET DV (HCDR3, SEQ ID NO: 573).
  • the light chain CDRs of the SC06- 257 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDR 1 , SEQ ID NO: 577), EVSNRPS (LCDR2, SEQ ID NO: 578) and SSYTSSSTY (LCDR3, SEQ ID NO: 579).
  • 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 VH1 (1 -69) and the VL locus is VL1 (V I- 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 (HCDR 1 , SEQ ID NO: 571 ), GIIPIFGTT YAPKFQG (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 (LCDR1 , SEQ ID NO: 580), KNTQRPS (LCDR2, SEQ ID NO: 581) and VAWDDSVDGYV (LCDR3, SEQ ID NO: 582).
  • 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 VH1 (1 -69) and the VL locus is VL1 (V l - 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 (HCDR 1 , SEQ ID NO: 571 ), GIIPIFGTT YAP FQG (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 (LCDR 1 , SEQ ID NO: 583), DNNKRPS (LCDR2, SEQ ID NO: 584) and ATWDRRPTAYVV (LCDR3, SEQ ID NO: 585).
  • 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: 33.1 and the amino acid sequence shown in SEQ ID NO: 332.
  • the VH-locus is VH 1 ( 1 -69) and the VL locus is V I (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), GISPLFGTTNYAQKFQG (HCDR2, SEQ ID NO: 587) and GPKYYSEYMDV (HCDR3, SEQ ID NO: 588).
  • TheMight chain CDRs of the SC06-262 antibody have the following CDR sequences: RASQGISSYLA (LCDR 1 , SEQ ID NO: 589), DASTLRS (LCDR2, SEQ ID NO: 590) and QRYNSAPPI (LCDR3, SEQ ID NO: 591).
  • 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 VH 1 (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 (HCDR l , SEQ ID NO: 571 ), GIMGMFGTTNYAQKFQG (HCDR2, SEQ ID NO: 592) and SSGYYPEYFQD (HCDR3, SEQ ID ⁇ : 593).
  • the light chain CDRs of the SC06- 268 antibody have the following CDR sequences: SGHKLGD YVS (LCDR1 , SEQ ID NO: 594), QDNRRPS (LCDR2, SEQ ID NO: 595) and QAWDSSTA (LCDR3, SEQ ID NO: 596).
  • 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 VH 1 ( 1 -69) and the VL locus is VL2 (V I -3).
  • the heavy chain CDRs of the SC06-272 antibody have the following CDR sequences: SYAIT (HCDR1, SEQ ID NO: 597), GIIGMFGSTNYAQNFQG (HCDR2, SEQ ID NO: 598) and STGYYPAYLHH (HCDR3, SEQ ID NO:'599).
  • the light chain CDRs of the SC06-272 antibody have the following CDR sequences: TGTSSDVGGYNYVS (LCDR1, SEQ ID NO: 577), DVS RPS (LCDR2, SEQ ID NO: 601 ) and SSYTSSSTHV (LCDR3, SEQ ID NO: 602).
  • 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 VH 1 ( 1 -2) and the VL locus is V III (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 (HCDR 1 , SEQ ID NO: 603), WINPNSGGTNYAQKFQG (HCDR2, SEQ YD NO: 604) and EG WGPQ A AFDI (HCDR3, SEQ ID NO; 605).
  • the light chain CDRs of the SC06-296 antibody have the following CDR sequences: RASQSVSSSYLA (LCDR 1 , SEQ ID NO: 646), 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 Fly. 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 VH1 (3-23) and the VL locus is V II (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: IYA S (HCDR 1 , SEQ ID NO: 609), AISSSGDSTYYADSVKG (HCDR2, SEQ ID NO: 610) and AYGYTFDP (HCDR3, SEQ ID NO: 611 ).
  • the light chain CDRs of the SC06-301 antibody have the following CDR sequences: RSSQSLLHSNGYNYLD (LCDR1 , 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 variablVregipn (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), SISSSSSYIYYVDSVKG (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 (LCDR1 , 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 VH 1 (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 (HCDR 1 , SEQ ID NO: 571 ), GIIPIFGTTKYAPKFQG (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 (LCDR 1 , 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 Fy 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 VH 1 ( 1 -69) and the VL locus is VL1 (V I - 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 (HCDR 1 , 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 (LCDR 1 , 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 VH1 (1-69) and the VL locus is V III (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 (HCDR1 , SEQ ID NO: 627), DIIGMFGSTNYAQNFQG (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 (LCDR 1 , SEQ ID NO: 646), 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 VH 1 ( 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 SC06-325 antibody have the following CDR sequences: FYSMS (HCDR 1 , SEQ ID NO: 633), GIIPMFGTTNYAQKFQG (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 (LCDR 1 , 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 VH 1 ( 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), GIIAIFGTANYAQKFQG (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: 622) and QVWDSSSDHVV (SEQ ID NO: 642). [354] 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 VH1 ( 1-69) and the VL locus is V III (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 (HCDR 1 , 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 (LCDR1 , SEQ ID NO: 646), GASSRAT (LCDR2, SEQ ID NQ: 631 ) and QQYGSSLT (LCDR3, SEQ ID NO: 648).
  • SC06-328 nucleotide sequence SEQ ID NO: 375
  • 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: 3,7$ and the amino acid sequence shown in SEQ ID NO: 380.
  • the VH-locus is VH1 (1-69) and the VL locus is V III (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), GIFALFGTTDYAQKFQG (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 (LCDR1 , 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 SC06-33 1 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 VH 1 ( 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 (HCDR 1 , SEQ ID NO: 571), GIIGMFGTANYAQKFQG (HCDR2, SEQ ID NO: 655) and GNYYYESSLDY (HCDR3, SEQ ID ⁇ : ⁇ 3 ⁇ 456)
  • the light chain CDRs of the SC06-33 1 antibody have the following CDR sequences: GGNNIGSKSVH (LCDR l , 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-specific 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 VH1 (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 (HCDR l , SEQ ID NO: 658), GIIAVFGTTKYAHKFQG (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 (LCDR1 , 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 VH 1 (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 (HCDR 1 , SEQ ID NO: 664), GILGVFGSPSYAQKFQG (HCDR2, SEQ ID NO: 665) and GPTYYYSY DV (HCDR3, SEQ ID NO: 666).
  • the light chain CDRs of the SC06-334 antibody have the following CDR sequences: GGNNIGRNSVH (LCDR l , SEQ ID NO: 667), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWHSSSDHYV (LCDR3, SEQ ID NO: 669).
  • the SC06-336 HA-specific 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 VH 1 ( 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 (HCDR 1 , SEQ ID NO: 670), GIFGMFGTANYAQKFQG (HCDR2, SEQ ID NO: 671 ) and SSGYYPQYFQD (HCDR3, SEQ ID NO: 672)
  • SYAIS HCDR 1 , SEQ ID NO: 670
  • GIFGMFGTANYAQKFQG HCDR2, SEQ ID NO: 671
  • SSGYYPQYFQD HCDR3, SEQ ID NO: 672
  • the SC06-339 HA-specific 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 VH1 (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 (HCDR1 , SEQ ID NO: 303), GIIAIFHTPKYAQKFQG (HCDR2, SEQ ID NO: 306) and GSTYDFSSGLDY (HCDR3, SEQ ID NO: 725).
  • the light chain CDRs of the SC06-339 antibody have the following CDR sequences: GGNNIGSKSVH (LCDRl , SEQ ID NO: 621), DDSDRPS (LCDR2, SEQ ID NO: 622) and QVWDSSSDHVV (LCDR3, SEQ ID NO: 642).
  • SC06-339 nucleotide sequence SEQ ID NO: 399)
  • the SC06-342 HA-specific single-chain Fy-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 VH l ( 1 -69) and the VL locus is V IV (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 (HCDR l , SEQ ID NO: 251 ), GVIPIFRTANYAQNFQG (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: SSQSILNSSNNKNYLA (LCDR 1 , SEQ ID NO: 245), WASTRES (LCDR2, SEQ ID NO: 570) 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 VH1 (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 (HCDR1 , SEQ ID NO: 242), GISPMFGTTTYAQKFQG (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).
  • SC06-343 nucleotide sequence SEQ ID NO: 407
  • 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 ID NO: 41 1 and the amino acid sequence shown in SEQ ID NO: 4 1 2.
  • the VH-locus is VH 1 ( 1 -69) and the VL locus is VL 1 (V l - 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 (HCDR 1 , SEQ ID NO: 222), GIIAIFGTPKYAQ FQG (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 (LCDR1 , SEQ ID NO: 219), GNSNRPS (LCDR2, SEQ ID NO: 231 ) and GTWDSSLSAYV (LCDR3, SEQ ID NO: 280).
  • SC06-344 nucleotide sequence SEQ ID NO: 411)
  • the CR6141 HA-specific IgG antibody includes a f 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: 16.
  • 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 ID NO: 418 and the heavy chain amino acid sequence shown in SEQ ID NO: 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 ID NO: 430 and the heavy chain amino acid sequence shown in SEQ ID NO: 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.
  • cagtctgtgt tgacgcagcc gccctcagtgtgcggccc caggacagaa ggtcaccatc 60 tcctgctctg gaagcagctc caacattggg aatgattatg tatcctggta ccagcagctc 120 ccaggaacag cccccaaact cctcatttat gacaataata agcgaccctc agggattcct 180 gaccgattct ctggctccaa gtctggcacg tcagccac'c ' c tgggcatcac cggactccag 240 actggggacg aggccaacta ttactgcgca acatgggatc gccgcccgac tgttatgtt 300 gtcttc
  • 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-specific IgG antibody includes a heavy chain variable region (SEQ ID NO: 453) encoded by the heavy chain nucleotide sequence shown in SEQ ID NO: 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 ID NO: 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 ID NO: 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.
  • 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 CR63 14 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.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11773176B2 (en) 2020-01-24 2023-10-03 Aprilbio Co., Ltd. Multispecific antibodies, compositions comprising the same, and vectors and uses thereof

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102089324B (zh) * 2007-11-12 2014-04-16 特罗科隆科学有限公司 用于对流行性感冒进行治疗以及诊断的组合物以及方法
US20110033476A1 (en) * 2007-11-12 2011-02-10 Theraclone Sciences Inc. Compositions and methods for the therapy and diagnosis of influenza
AU2012229188A1 (en) * 2011-03-15 2013-09-26 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
PL3489261T3 (pl) 2012-08-24 2021-08-16 The Regents Of The University Of California Przeciwciała i szczepionki do stosowania w leczeniu nowotworów z ekspresją ROR1 i w hamowaniu przerzutu
JP2016519688A (ja) * 2013-04-22 2016-07-07 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
JPWO2015068781A1 (ja) * 2013-11-06 2017-03-09 国立大学法人大阪大学 インフルエンザウイルスａ型のグループ１に対して広域な中和活性を有する抗体
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
US9890206B2 (en) * 2015-08-20 2018-02-13 Medigen Biotechnology Corporation H1N1 flu virus neutralizing antibodies
CA3029003A1 (en) 2016-06-27 2018-01-04 The Regents Of The University Of California Cancer treatment combinations
WO2018170273A1 (en) 2017-03-15 2018-09-20 University Of Washington De novo designed hemagglutinin binding proteins
CA3079486A1 (en) 2017-10-18 2019-04-25 Xiamen University Mutant of hemagglutinin protein of h3n2 subtype influenza virus and use thereof
EP3816290A4 (en) * 2018-06-26 2022-03-30 Kyowa Kirin Co., Ltd. Antibody binding to cell adhesion molecule 3
WO2021201677A1 (en) 2020-04-01 2021-10-07 Kiadis Pharma Intellectual Property B.V. Compositions and methods targeting influenza
US20240018218A1 (en) * 2020-09-08 2024-01-18 Novelgen Co., Ltd. Antiviral composition against influenza a virus
TWI767434B (zh) * 2020-12-01 2022-06-11 國立成功大學 蛋白質微陣列、其檢測方法、其用途及含有該蛋白質微陣列之試劑盒

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3896111A (en) 1973-02-20 1975-07-22 Research Corp Ansa macrolides
US4151042A (en) 1977-03-31 1979-04-24 Takeda Chemical Industries, Ltd. Method for producing maytansinol and its derivatives
US4137230A (en) 1977-11-14 1979-01-30 Takeda Chemical Industries, Ltd. Method for the production of maytansinoids
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
US4265814A (en) 1978-03-24 1981-05-05 Takeda Chemical Industries Matansinol 3-n-hexadecanoate
JPS5562090A (en) 1978-10-27 1980-05-10 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
US4256746A (en) 1978-11-14 1981-03-17 Takeda Chemical Industries Dechloromaytansinoids, their pharmaceutical compositions and method of use
JPS55164687A (en) 1979-06-11 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS5566585A (en) 1978-11-14 1980-05-20 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS55102583A (en) 1979-01-31 1980-08-05 Takeda Chem Ind Ltd 20-acyloxy-20-demethylmaytansinoid compound
JPS55162791A (en) 1979-06-05 1980-12-18 Takeda Chem Ind Ltd Antibiotic c-15003pnd and its preparation
JPS55164685A (en) 1979-06-08 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
JPS55164686A (en) 1979-06-11 1980-12-22 Takeda Chem Ind Ltd Novel maytansinoid compound and its preparation
US4309428A (en) 1979-07-30 1982-01-05 Takeda Chemical Industries, Ltd. Maytansinoids
JPS5645483A (en) 1979-09-19 1981-04-25 Takeda Chem Ind Ltd C-15003phm and its preparation
JPS5645485A (en) 1979-09-21 1981-04-25 Takeda Chem Ind Ltd Production of c-15003pnd
EP0028683A1 (en) 1979-09-21 1981-05-20 Takeda Chemical Industries, Ltd. Antibiotic C-15003 PHO and production thereof
WO1981001145A1 (en) 1979-10-18 1981-04-30 Univ Illinois Hydrolytic enzyme-activatible pro-drugs
US4371553A (en) 1980-08-01 1983-02-01 James River-Dixie/Northern, Inc. Package including product support insert
US4450254A (en) 1980-11-03 1984-05-22 Standard Oil Company Impact improvement of high nitrile resins
US4554101A (en) 1981-01-09 1985-11-19 New York Blood Center, Inc. Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity
US4313946A (en) 1981-01-27 1982-02-02 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids from Trewia nudiflora
US4315929A (en) 1981-01-27 1982-02-16 The United States Of America As Represented By The Secretary Of Agriculture Method of controlling the European corn borer with trewiasine
JPS57192389A (en) 1981-05-20 1982-11-26 Takeda Chem Ind Ltd Novel maytansinoid
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
NZ201705A (en) 1981-08-31 1986-03-14 Genentech Inc Recombinant dna method for production of hepatitis b surface antigen in yeast
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
DD266710A3 (de) 1983-06-06 1989-04-12 Ve Forschungszentrum Biotechnologie Verfahren zur biotechnischen Herstellung van alkalischer Phosphatase
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4879231A (en) 1984-10-30 1989-11-07 Phillips Petroleum Company Transformation of yeasts of the genus pichia
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4676980A (en) 1985-09-23 1987-06-30 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Target specific cross-linked heteroantibodies
GB8610600D0 (en) 1986-04-30 1986-06-04 Novo Industri As Transformation of trichoderma
US5567610A (en) 1986-09-04 1996-10-22 Bioinvent International Ab Method of producing human monoclonal antibodies and kit therefor
IL85035A0 (en) 1987-01-08 1988-06-30 Int Genetic Eng Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same
GB8705477D0 (en) 1987-03-09 1987-04-15 Carlton Med Prod Drug delivery systems
US4975278A (en) 1988-02-26 1990-12-04 Bristol-Myers Company Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5053394A (en) 1988-09-21 1991-10-01 American Cyanamid Company Targeted forms of methyltrithio antitumor agents
US5606040A (en) 1987-10-30 1997-02-25 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
US5175384A (en) 1988-12-05 1992-12-29 Genpharm International Transgenic mice depleted in mature t-cells and methods for making transgenic mice
FR2646437B1 (fr) 1989-04-28 1991-08-30 Transgene Sa Nouvelles sequences d'adn, leur application en tant que sequence codant pour un peptide signal pour la secretion de proteines matures par des levures recombinantes, cassettes d'expression, levures transformees et procede de preparation de proteines correspondant
EP0402226A1 (en) 1989-06-06 1990-12-12 Institut National De La Recherche Agronomique Transformation vectors for yeast yarrowia
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
ATE144793T1 (de) 1989-06-29 1996-11-15 Medarex Inc Bispezifische reagenzien für die aids-therapie
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
CA2026147C (en) 1989-10-25 2006-02-07 Ravi J. Chari Cytotoxic agents comprising maytansinoids and their therapeutic use
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5229275A (en) 1990-04-26 1993-07-20 Akzo N.V. In-vitro method for producing antigen-specific human monoclonal antibodies
WO1992002551A1 (en) 1990-08-02 1992-02-20 B.R. Centre Limited Methods for the production of proteins with a desired function
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
KR100272077B1 (ko) 1990-08-29 2000-11-15 젠팜인터내셔날,인코포레이티드 이종 항체를 생산할 수 있는 전이유전자를 가진 인간이외의 동물
US5571894A (en) 1991-02-05 1996-11-05 Ciba-Geigy Corporation Recombinant antibodies specific for a growth factor receptor
WO1992020373A1 (en) 1991-05-14 1992-11-26 Repligen Corporation Heteroconjugate antibodies for treatment of hiv infection
EP0590058B1 (en) 1991-06-14 2003-11-26 Genentech, Inc. HUMANIZED Heregulin ANTIBODy
WO1993006217A1 (en) 1991-09-19 1993-04-01 Genentech, Inc. EXPRESSION IN E. COLI OF ANTIBODY FRAGMENTS HAVING AT LEAST A CYSTEINE PRESENT AS A FREE THIOL, USE FOR THE PRODUCTION OF BIFUNCTIONAL F(ab')2 ANTIBODIES
FI941572L (fi) 1991-10-07 1994-05-27 Oncologix Inc Anti-erbB-2-monoklonaalisten vasta-aineiden yhdistelmä ja käyttömenetelmä
WO1993008829A1 (en) 1991-11-04 1993-05-13 The Regents Of The University Of California Compositions that mediate killing of hiv-infected cells
AU3178993A (en) 1991-11-25 1993-06-28 Enzon, Inc. Multivalent antigen-binding proteins
ATE419355T1 (de) 1992-02-06 2009-01-15 Novartis Vaccines & Diagnostic Marker für krebs und biosynthetisches bindeprotein dafür
ZA932522B (en) 1992-04-10 1993-12-20 Res Dev Foundation Immunotoxins directed against c-erbB-2(HER/neu) related surface antigens
ATE149570T1 (de) 1992-08-17 1997-03-15 Genentech Inc Bispezifische immunoadhesine
ES2091684T3 (es) 1992-11-13 1996-11-01 Idec Pharma Corp Aplicacion terapeutica de anticuerpos quimericos y radiomarcados contra el antigeno de diferenciacion restringida de los linfocitos b humanos para el tratamiento del linfoma de las celulas b.
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US6214388B1 (en) 1994-11-09 2001-04-10 The Regents Of The University Of California Immunoliposomes that optimize internalization into target cells
EP1241264A1 (en) 1994-12-02 2002-09-18 Chiron Corporation Monoclonal antibodies to colon cancer antigen
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US5641870A (en) 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
US5739277A (en) 1995-04-14 1998-04-14 Genentech Inc. Altered polypeptides with increased half-life
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US5837234A (en) 1995-06-07 1998-11-17 Cytotherapeutics, Inc. Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
DE19544393A1 (de) 1995-11-15 1997-05-22 Hoechst Schering Agrevo Gmbh Synergistische herbizide Mischungen
US5922845A (en) 1996-07-11 1999-07-13 Medarex, Inc. Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies
US6824780B1 (en) 1999-10-29 2004-11-30 Genentech, Inc. Anti-tumor antibody compositions and methods of use
JP4773947B2 (ja) 2003-01-09 2011-09-14 マクロジェニクス，インコーポレーテッド 細菌細胞及び哺乳動物細胞における抗体発現のための二重発現ベクター系
MY170607A (en) 2006-09-07 2019-08-20 Crucell Holland Bv Human binding molecules capable of neutralizing influenza virus h5n1 and uses thereof
CN102089324B (zh) * 2007-11-12 2014-04-16 特罗科隆科学有限公司 用于对流行性感冒进行治疗以及诊断的组合物以及方法
US20110033476A1 (en) 2007-11-12 2011-02-10 Theraclone Sciences Inc. Compositions and methods for the therapy and diagnosis of influenza
RU2010127156A (ru) * 2007-12-06 2012-01-20 Дана-Фарбер Кэнсер Инститьют, Инк. (Us) Антитела против вируса гриппа и их применение
CA2736799A1 (en) 2008-08-25 2010-03-11 Burnham Institute For Medical Research Conserved hemagglutinin epitope, antibodies to the epitope, and methods of use
AU2009324251A1 (en) * 2008-12-04 2010-06-10 Elatos Gmbh Fully human influenza M2 specific antibodies
EP2432803A2 (en) * 2009-05-20 2012-03-28 Theraclone Sciences, Inc. Compositions and methods for the therapy and diagnosis of influenza
EP2464383A4 (en) * 2009-08-14 2013-02-13 Theraclone Sciences Inc COMPOSITIONS AND METHODS FOR THE TREATMENT AND DIAGNOSIS OF FLU
AU2011289275A1 (en) * 2010-08-12 2013-02-21 Theraclone Sciences, Inc. Anti-hemagglutinin antibody compositions and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP2675478A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11773176B2 (en) 2020-01-24 2023-10-03 Aprilbio Co., Ltd. Multispecific antibodies, compositions comprising the same, and vectors and uses thereof

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US8916160B2 (en) 2014-12-23
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US20150104459A1 (en) 2015-04-16
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EP2675478A4 (en) 2015-06-10
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CA2827301A1 (en) 2012-08-23
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