WO2010007533A2 - Human cytomegalovirus neutralizing antibodies and use thereof - Google Patents

Human cytomegalovirus neutralizing antibodies and use thereof Download PDF

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Publication number
WO2010007533A2
WO2010007533A2 PCT/IB2009/006641 IB2009006641W WO2010007533A2 WO 2010007533 A2 WO2010007533 A2 WO 2010007533A2 IB 2009006641 W IB2009006641 W IB 2009006641W WO 2010007533 A2 WO2010007533 A2 WO 2010007533A2
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seq
antibody
acid sequence
variable region
chain variable
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English (en)
French (fr)
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WO2010007533A3 (en
WO2010007533A9 (en
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Antonio Lanzavecchia
Annalisa Macagno
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Institute for Research in Biomedicine IRB
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Institute for Research in Biomedicine IRB
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Priority to EA201170205A priority Critical patent/EA031177B1/ru
Priority to US13/003,603 priority patent/US8603480B2/en
Priority to MX2013011720A priority patent/MX338067B/es
Priority to UAA201100565A priority patent/UA106354C2/ru
Priority to PL09745098T priority patent/PL2352759T3/pl
Priority to MX2013011719A priority patent/MX343250B/es
Priority to KR1020117001825A priority patent/KR101356350B1/ko
Priority to MX2011000543A priority patent/MX2011000543A/es
Priority to BRPI0916443A priority patent/BRPI0916443A2/pt
Priority to CN200980129827.XA priority patent/CN102203133B/zh
Priority to AU2009272284A priority patent/AU2009272284C1/en
Priority to DK09745098.5T priority patent/DK2352759T3/en
Priority to JP2011518030A priority patent/JP5422649B2/ja
Priority to ES09745098.5T priority patent/ES2654543T3/es
Priority to CR20160355A priority patent/CR20160355A/es
Priority to CA2730776A priority patent/CA2730776C/en
Priority to NZ591056A priority patent/NZ591056A/xx
Priority to EP09745098.5A priority patent/EP2352759B1/en
Priority to MX2013011716A priority patent/MX343490B/es
Application filed by Institute for Research in Biomedicine IRB filed Critical Institute for Research in Biomedicine IRB
Publication of WO2010007533A2 publication Critical patent/WO2010007533A2/en
Publication of WO2010007533A3 publication Critical patent/WO2010007533A3/en
Priority to TNP2010000621A priority patent/TN2010000621A1/fr
Priority to IL210356A priority patent/IL210356A/en
Anticipated expiration legal-status Critical
Priority to CU2011000009A priority patent/CU23953B1/es
Priority to MA33614A priority patent/MA32561B1/fr
Priority to US14/096,283 priority patent/US9221897B2/en
Priority to IL232861A priority patent/IL232861A/en
Priority to IL232862A priority patent/IL232862A/en
Priority to IL232865A priority patent/IL232865A/en
Priority to IL232864A priority patent/IL232864A/en
Priority to IL232863A priority patent/IL232863A/en
Priority to PH12015500782A priority patent/PH12015500782A1/en
Priority to IL238421A priority patent/IL238421A/en
Priority to US14/949,161 priority patent/US9365636B1/en
Priority to US15/154,178 priority patent/US9527902B2/en
Priority to US15/358,868 priority patent/US9796772B2/en
Priority to US15/358,845 priority patent/US9796771B2/en
Publication of WO2010007533A9 publication Critical patent/WO2010007533A9/en
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    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
    • C07K16/088—Varicella-zoster virus
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    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
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    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • A61P31/20—Antivirals for DNA viruses
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
    • C07K16/089—Cytomegalovirus
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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    • A01D—HARVESTING; MOWING
    • A01D2101/00—Lawn-mowers
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01D—HARVESTING; MOWING
    • A01D34/00—Mowers; Mowing apparatus of harvesters
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    • A01D34/412—Mowers; Mowing apparatus of harvesters characterised by features relating to the type of cutting apparatus having rotating cutters
    • A01D34/63—Mowers; Mowing apparatus of harvesters characterised by features relating to the type of cutting apparatus having rotating cutters having cutters rotating about a vertical axis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C07K2317/00—Immunoglobulins specific features
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    • C07K2317/622—Single chain antibody (scFv)
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
    • C12N2710/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • hCMV Human cytomegalovirus
  • hCMV Human cytomegalovirus
  • Hyperimmune globulins arc already commercialized for the prophylaxis of hCMV disease associated with transplantation and recent evidence indicates that they have therapeutic effect m pregnant women [9]
  • This therapeutic approach is limited by the low amount of neutralizing antibody that can be transferred and for this reason the availability of human antibodies (such as human monoclonal antibodies) with high neutralizing capacity would be highly desirable
  • human antibodies such as human monoclonal antibodies
  • some antibodies to gH, g ⁇ and UL128 and UL130 gene products have demonstrated in ⁇ ⁇ t ⁇ o neutralizing activities [7, 10, 11] and an antibody to gH was evaluated in clinical trials (that were discontinued due to lack of therapeutic effects)
  • the neutralizing potency of the antibodies isolated so far is modest Neutralization by these antibodies was observed at antibody concentrations ranging from 0 5 to 20 ⁇ g/ml
  • the current methods typically measure the neutralizing potency of anti-hCMV antibodies using fibroblasts as target cells
  • hCMV is also known to cause pathology by in
  • the invention comprises a heavy chain CDRl selected from the group consisting of SEQ ID NOs 188, 174, 65, 81, 97, 129, 145, 113, 1, 17, 33, and 49, a heavy chain CDR2 selected from the group consisting of SEQ ID NOs 189, 204, 175 66, 82, 98, 130, 146, 161, 2, 2, 18, 34, 50, and 114, and a heavy chain C DR3 selected from the group consisting of SEQ ID NOs 190, 205, 210, 176, 67, 83, 99, 131, 147, 162, 3, 19, 35, 51, and 115, wherein the antibody neutralizes hCMV infection
  • the invention comprises an antibody, or an antigen binding fragment thereof, comprising a light chain CDRl selected from the group consisting of SEQ ID NOs 191 177, 68, 84, 100, 132, 148 163, 4, 20, 36,
  • the invention comprises an antibody, or an antigen binding fragment thereof, wherein the antibody comp ⁇ ses a heavy chain variable region comprising the ammo acid sequence of SEQ ID NO 200 and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 201 , or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO 200 and a light chain variable region comprising the amino acid sequence of SEQ ID NO 213, or a heavy chain variable region comprising the ammo acid sequence of SEQ ID NO 208 and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 201, or a heavy chain variable region comprising the ammo acid sequence of SEQ ID NO 208 and a light chain variable region comprising the amino acid sequence of SEQ ID NO 213, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO 212 and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 201 , or a hea ⁇ y chain variable region
  • the invention comprises an antibody, or an antigen binding fragment thereof, that neutralizes infection of endothelial cells, epithelial cells, retinal cells, myeloid cells, dcndntic cells, fibroblasts, or mesenchymal stromal cells by a clinical isolate of hCMV, wherein the concentration of antibody required for 90% neutralisation of hCMV is 1 2 ⁇ g/ml or less
  • the invention compnses an antibody, or an antigen binding fragment thereof that neutralizes infection of endothelial cells, epithelial cells retinal cells, myeloid cells, dendritic cells, fibroblasts, or mesenchymal stromal cells by a clinical isolate of hCMV, wherein the concentration of antibody required for 90% neutralisation of hCMV is 10 ⁇ g/ml or less, and wherein the antibody is not MSL- 109 or 8F9
  • the invention comprises an antibody, or an antigen binding fragment thereof, comprising at least one CDR sequence at least 95% sequence identity to any one of SEQ ID NOs 216-221, 232-235, 149, 236, 246-251, 278-283, 296- 301, 312, 316-321, 332, 336-341, 352, 360, 361 or 262-267, wherein the antibody neutralizes hCMV infection
  • the invention comprises an antibody, or an antigen binding fragment thereof, comprising a heavy chain CDRl selected from the group consisting of SEQ ID NOs 216, 232, 246, 278, 296, 316, 336, 352, 360 and 262, a heavy chain CDR2 selected from the group consisting of SEQ ID NOs 217, 233, 247, 279, 297, 312, 317, 337 and 263 and a heavy chain CDR3 selected from the group consisting of SEQ TD NOs 218 234, 248, 280, 298, 318, 332, 338, and 264, wherein the antibody neutralizes hCMV infection
  • the invention comprises an antibody, or an antigen binding fragment thereof comprising a light chain CDRl selected from the group consisting of SEQ TD NOs 219, 235, 249, 281 , 299, 319, 339 and 265, a light chain CDR2 selected from the group consisting of SEQ TD NOs 220, 149, 250, 282, 300 320, 340 and 266, and a light chain CDR3 selected from the group consisting of SEQ ID NOs 221, 236, 251, 283, 301, 321, 341, 361 and 267, wherein the antibody neutralizes hCMV infection
  • the invention comprises an antibody, or an antigen binding fragment thereof, wherem the antibody comprises a heavy chain va ⁇ able region comprising the amino acid sequence of SEQ ID NO 228 and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 229, or a hea ⁇ y chain variable region comprising the ammo acid sequence of SEQ ID NO 242 and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 243, or a heavy chain variable region comprising the ammo acid sequence of SEQ TD NO 258 and a light chain variable region comprising the amino acid sequence of SEQ ID NO 259, or a heavy chain variable region comprising the ammo acid sequence of SEQ ID NO 290, and a light chain variable region comprising the ammo acid sequence of SEQ ID NO 291, or a heavy chain variable region comprising the ammo acid sequence of SEQ ID NO 294, and a light chain variable region comprising the amino acid sequence of SEQ ID NO 291, or a heavy chain va ⁇ able region comprising
  • the invention further comprises an antibody, or an antigen binding fragment thereof, produced by immortalised B cell done 8121, 2C 12, 8C 15, 4N10, 11B12, 3G16, 4H9, 6B4, 10C6, or 6L3 deposited with the Advanced Biotechnology Center (ABC), Largo Rossana Bcnzi 10, 16132 Genoa (Italy), under the terms of the Budapest Treaty, on July 9, 2008 (under Accession Numbers PD 08005, PD 08007, PD 08006, PD 08009, PD 08011, PD 08012, PD 08013, PD 08004 PD 08014, and PD 08010, respectn ely) and by immortalized B cell clone 7H3 deposited on July 16, 2008 under Accession Number PD 08017 Antibodies and antigen binding fragments thereof, with the same ammo acid sequence as those expressed from the aforementioned deposited immortalised B cells are also considered to be withm the scope of the invention
  • the invention comprises a nucleic acid
  • an antibody of the invention, or an antigen binding fragment thereof, a nucleic acid of the invention, an immunogenic polypeptide of the invention, or a pharmaceutical composition of the invention (i) in the manufacture of a medicament for the treatment of hCMV infection, (ii) in a vaccine, or (m) in diagnosis of hCMV infection is also contemplated to be within the scope of the invention
  • use of an antibody of the invention, or an antigen binding fragment thereof, for monitoring the quality of anti-hCMV vaccines by checking that the antigen of said vaccine contains the specific epitope in the correct conformation is also contemplated to be within the scope of the invention
  • the urvention comprises an epitope which specifically binds to an antibody of any one of the invention, or an antigen binding fragment thereof, for use (i) m therapy, (ii) in the manufacture of a medicament for treating hCMV infection, (in) as a ⁇ accine, or (iv) in screening for ligands able to neutralise hCMV infection
  • Figure 1 shows staining of HEK293T cells transfcctcd with hCMV UL128, UL130, UL131A, gH and gl_ genes, alone or in different combinations, by representative monoclonal antibodies (15D8, 2C 12 and 8121)
  • Figure 2 shows cross-competition experiments in which HEK293T cells transfected with hCMV gH (A) or gB (B) gene were first incubated with an unlabeled competitor antibody followed by staining with a biotmylated anti-gH or anti-gB antibody
  • FIG. 3 shows staining of HEK293T cells expressing either the wild type VRl 814 UL128 gene or a pan-mutated UL 128 gene by human monoclonal antibody 15D8 and a non-competing anti- UL 128 mouse monoclonal antibody
  • the pan-mutated UL 128 gene contains substitutions of the wild type VR 18 14 sequence with known va ⁇ ants described in other clinical isolates and laboratory strains of hCMV
  • the invention is based, in part, on the discovery of novel antibodies that neutralize hCMV infection with high potency as well as novel epitopes to which the antibodies of the invention bind Such antibodies are desirable, as only low concentrations are required in order to neutralize a grven amount of virus This facilitates higher levels of protection whilst administering lower amounts of antibody
  • the invention comprises a neutralizing antibody and antigen binding fragments thereof having high potency in neutralizing hCMV infection
  • Human monoclonal antibodies and the immortalised B cell clones that secrete such antibodies are also included withm the scope of the invention
  • fragment As used herein, the terms “fragment,” “antigen binding fragment” and “antibody fragment” are used interchangeably to refer to any fragment of an antibody of the invention that retains the antigen-bmdmg activity of the antibodies
  • Exemplary antibody fragments include, but are not limited to, a single chain antibody, Fab Fab', F(ab')2, Fv or scFv
  • high potency is used to refer to an antibody of the invention or an antigen binding fragment thereof that neutralizes hCMV infection with an IC 90 of less than about 2 ⁇ g/ml, (1 e the concentration of antibody required for 90% neutralisation of a clinical isolate of hCMV is about 2 ⁇ g/ml or less, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, 1 4, 1 3, 1 25, 1 2, 1 15, 1 1, or 1 05 ⁇ g/ml or less) Tn one embodiment, the antibody of the present invention, or antigen binding fragment thereof, has an IC 30 of 1 ⁇ g/ml or
  • the invention provides an antibody, or an antigen binding fragment thereof, that binds to an epitope formed by the hCMV proteins gH, gL, UL 128 and UL130, and neutralizes hCMV infection with an IC go of less than about 2 ⁇ g/ml, for example 1 9, 1 8, 1 75, 1 7,
  • the im cntion pro ⁇ idc s an antibody, or an antigen binding fragment thereof, that binds to an epitope formed by the hCMV proteins UL128, UL 130, and UL131A, and neutralizes hCMV infection with an IC 90 of less than about 2 ⁇ g/ml, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, 1 4, 1 3, 1 25, 1 2, 1 15, 1 1 , 1 05, 1, 0 95, 0 9, 0 85, 0 8, 0 75, 0 7, 0 6, 0 5, 0 4, 0 3, 0 2, 0 15, 0 125, 0 1 , 0 075, 0 05, 0 025, 0 02, 0 015, 0 0125, 0 01 , 0 0075, 0 005, 0 004, 0 00S, 0 002
  • the m ⁇ ention pro ⁇ ides an antibody, or an antigen binding fragment thereof, that binds to an epitope formed by the hCMV proteins UL130 and UL13 IA, and neutralizes hCMV infection with an TC 90 of less than about 2 ⁇ g/ml, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, I 4,
  • the invention provides an antibody, or an antigen binding fragment thereof, that binds to an epitope in the hCMV gH protein and neutralizes hCMV infection with an ICj 0 of less than about 2 ⁇ g/ml, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, 1 4, 1 3, 1 25, 1 2,
  • the invention pro ⁇ ides an antibody, or an antigen binding fragment thereof, that binds to an epitope m the hCMV gB protein and neutralizes hCMV infection with an IC 90 of less than about 2 ⁇ g/ml, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, 1 4, 1 3, 1 25, 1 2,
  • the im ention provides an antibody, or an antigen binding fragment thereof, that binds to an epitope formed by the hCMV proteins gM and gN and neutralizes hCMV infection w ith an IC 90 of less than about 2 ⁇ g / ml, for example 1 9, 1 8, 1 75, 1 7, 1 6, 1 5, 1 4, 1 3,
  • the antibodies of the invention and antigen binding fragments thereof bind to one or more hCMV proteins
  • the antibodies of the invention may bind to an epitope formed by a single hCMV protein or by a combination of two or more hCMV proteins
  • Exemplary hCMV proteins include, but are not limited to, products of viral genes UL55 (envelope glycoprotein B, "gB"), UL75 (envelope glycoprotein H, '"gH"), ULlOO (glycoprotein M, "gM”), UL73 (glycoprotein N, "gN"), ULl 15 (glycoprotein L, "gL"), UL74 (glycoprotein O, "g ⁇ "), UL128 (glycoprotein UL128, “UL128”), UL130 (glycoprotein UL130, "UL130”) or UL131A (glycoprotein UL131A, "UL 131 A”)
  • the antibodies of the invention bind to an epitope formed by a
  • the invention comprises an antibody, or an antibody fragment thereof, that binds to an epitope in the hCMV protein UL 128, or to an epitope formed by the hCMV proteins UL130 and UL131A, or to an epitope formed by the hCMV proteins UL128, UL130 and UL131A, or to an epitope formed by the hCMV proteins gH, gL, UL128, and UL130, or to an epitope in the hCMV protein gH, or the hCMV protein gB or to an epitope formed by the hCMV proteins gM and gN
  • the invention comprises an antibody, or an antibody fragment thereof, that binds to an epitope m UL128 In another embodiment, the invention comprises an antibody, or an antibody fragment thereof, that binds to an epitope formed by UL 130 and UL 13 IA As used herein, an epitope formed by UL 130 and UL 131 A means that the epitope may be formed by both UL130 and UL131A protein or may be formed by one of the two proteins, the presence of the other protein being necessary for antibody binding In yet another embodiment, the invention comprises an antibody, or an antibody fragment thereof, that binds to an epitope formed by UL128, UL130 and UL131A As used herein, an epitope formed by UL128, UL130 and UL 13 IA means that the epitope may be formed by all three proteins (UL 128, UL 130 and UL 131 A) or may be formed by one or more protem(s), the presence of the other protein(s) being necessary for antibody binding In still another embodiment, the invention comprises
  • the sequences of the heavy chains and light chains of several exemplary antibodies of the invention, each comprising three CDRs on the heavy chain and three CDRs on the light chain have been determined
  • the position of the CDR ammo acids are defined according to the IMGT numbe ⁇ ng system [ 12, 13, 14]
  • the sequences of the CDRs, heavy chains light chains as well as the sequences of the nucleic acid molecules encoding the CDRs, heavy chains, light chains are disclosed in the sequence listing.
  • Table 1 provides the SEQ ID NOs. for the sequences of the six CDRs of the exemplary antibodies of the invention.
  • the antibodies or antibody fragments of the invention comprise one or more heavy or light chain CDRs of the exemplary antibodies of the invention.
  • the antibodies or antibody fragments of the invention comprise an amino acid sequence selected from the group consisting of SEQ TD NOs: 188-193, 204-205, 210, 1 -6, 17-22, 33-38, 49-54, 113-118, 65-70, 81-86, 97-102, 129-134, 145-150, 174-178, and 161-164.
  • the antibodies of the invention comprise a heavy chain comprising an amino acid sequence of one or more of SEQ ID NOs: 188-190, 204, 205, 210, 1-3, 17-19, 33-35, 49-51 , 1 13- 1 15, 65-67, 81 -83, 97-99, 129- 131 , 145- 147, 174- 176, 161 or 162.
  • the antibodies of the invention comprise a heavy chain comprising SEQ ID NO: 188 for CDRHl, SEQ ID NO: 189 for CDRH2, SEQ ID NO: 190 for CDRH3; SEQ ID NO: 188 for CDRHl, SEQ ID NO; 204 for CDRH2, SEQ ID NO: 205 for CDRH3; SEQ ID NO; 188 for CDRHl, SEQ ID NO: 189 for CDRH2, SEQ ID NO: 210 for CDRH3; SEQ ID NO: 1 for CDRHl, SEQ ID NO: 2 for CDRH2, SEQ ID NO: 3 for CDRH3; SEQ TD NO; 17 for CDRH I , SEQ TD NO; 18 for CDRH2, SEQ TD NO: 19 for CDRH3; SEQ ID NO: 33 for CDRHl, SEQ ID NO: 34 for CDRH2, SEQ ID NO: 35 for CDRH3; SEQ ID NO 49 for CHRHl, SEQ ID NO: 50
  • the antibodies of the invention comprise a light chain comprising an amino acid sequence of one or more of SEQ ID NOs: 191-193, 4-6, 20-22, 36-38, 52-54, 116- 118, 68-70, 84-86, 100-102, 132-134, 148-150, 177, 178, 163, or 164.
  • the antibodies of the invention comprise a light chain comprising SEQ ID NO: 191 for CDRLl, SEQ ID NO: 192 for CDRL2; SEQ ID NO: 193 for CDRL3; SEQ ID NO: 4 for CDRLl, SEQ ID NO: 5 for CDRL2 and SEQ ID NO 6 for CDRI ⁇ SEQ TD NO 20 for CDRLl , SEQ TD NO 21 for CDRL2, SEQ TD NO 22 for CDRL3, SEQ ID NO, 36 for CDRLI, SEQ ID NO 37 for CDRL2, SEQ ID NO 38 for CDRL3, SEQ ID NO 52 for CDRLl, SEQ ID NO 53 for CDRL2, SEQ ID NO: 54 for CDRL3, SEQ ID NO: 116 for CDRLl, SEQ ID NO: 117 for CDRL2, SEQ ID NO 118 for CDRL3, SEQ ID NO 68 for CDRLl , SEQ ID NO 69 for CDRL2, SEQ ID NO 70 for CDRL3, SEQ ID NO 84 for CDRLl , SEQ ID NO 85 for CD
  • SEQ ID NO 132 for CDRLl SEQ ID NO 133 for CDRL2, SEQ ID NO 134 for CDRL3, SEQ ID NO 148 for CDRLl , SEQ ID NO 149 for CDRL2, SEQ ID NO. 150 for CDRL3, SEQ ID NO: 177 for CDRLl, SEQ ID NO. 149 for CDRL2, SEQ ID NO 178 for CDRL3, SEQ ID NO 163 for CDRLl, SEQ ID NO 149 for CDRL2 and SEQ ID NO 164 for CDRL3
  • the antibodies of the invention comprise a heavy chain with an ammo acid sequence that is at least 70% identical to those of SEQ ID NOs 200, 208, 212, 13, 29, 45, 61, 125, 77, 93, 109, 141, 157, 184, or 170, and neutralize hCMV infection
  • the antibody binds to an epitope in the hCMV UL128 protein and comprises a heavy chain having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at Least 85%, at least 90%, at least 95%, at least 98%, or at Least 99% identical to the ammo acid sequence of SEQ ID NO 200, 208 or 212, and neutralizes hCMV infection
  • an antibody according to the invention comprises a heavy chain having the sequence recited in SEQ TD NO 200, 208 or 212, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins UL130 and UL131A and comprises a heavy chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO 13, 29, 45, 61 or 125, and neutralizes hCMV infection
  • an antibody according to the invention comprises a heavy chain having the sequence recited in SEQ ID NO 13, 29, 45, 61 or 125, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins UL 128, ULl 30 and UL131A and comprises a heavy chain having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO.
  • an antibody according to the invention comprises a heavy chain having the sequence recited in SEQ ID NO 77, 93, 109, 141, 157, or 170, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins gH, gL, UL 128 and UL 130 and comprises a heavy chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO 184, and neutralizes hCMV infection
  • an antibody according to the invention comprises a heavy chain having the sequence recited m SEQ ID NO 184, and neutralizes hCM V infection
  • the antibodies of the invention comprise a light chain with an
  • the antibody binds to an epitope in the hCMV UL 128 protein and comp ⁇ ses a light chain having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 201or 213, and neutralizes hCMV infection
  • an antibody according to the invention comprises a light chain having the sequence recited in SEQ ID NO 201 or 213, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins UL130 and UL131A and comprises a light chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 14, 30, 46, 62 or 126, and neutralizes
  • the antibody binds to an epitope formed by the hCMV proteins UL128, UL130 and UL131A and comprises a light chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO 78, 94, 110, 142, 158, or 171, and neutralizes hCMV infection
  • an antibody according to the invention comprises a light chain having the sequence recited in SEQ ID NO 78, 94, 110, 142, 158, or 171, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hC MV proteins gH, gL, UL128 and UL130 and comprises a light chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO 185, and neutralizes hCMV infection
  • an antibody according to the invention comprises a light chain having the sequence recited in SEQ ID NO 185, and neutralizes hCMV infection
  • the antibodies or antibody fragments of the invention comprise one or more heavy or light chain CDRs of the exemplary antibodies of the invention
  • the antibodies or antibody fragments of the invention comprise an ammo acid sequence selected from the group consisting of SEQ ID NOs 316-321, 332, 336-341, 278-283, 352, 296-301, 312, 232-236, 149, 216-221, 246-251 , 360, 361 and 262-267, and neutralize hCMV infection
  • the antibodies of the invention comprise a heavy chain comprising an ammo acid sequence of one or more of SEQ ID NOs 316-318, 332, 336-338, 278- 280, 352, 296-298, 312, 232-234, 216-218, 246-248, 360, 361 and 262-264
  • the antibodies of the invention comprise a heavy chain comprising SEQ ID NO 316 for CDRHl, SEQ ID NO 317 for CDRH2, SEQ ID NO 318 for CDRH3, SEQ ID NO 316 for C
  • the antibodies of the invention comprise a light chain comprising an amino acid sequence of one or more of SEQ ID NOs 319-321, 339-341 , 281-283, 299-301, 149, 235, 236, 219-221, 249-251, 265-267
  • the antibodies of the invention comprise a light chain comprising SEQ ID NO 319 for CDRLl, SEQ ID NO 320 for CDRL2, SEQ ID NO 321 for CDRL3, SEQ ID NO 339 for CDRLl , SEQ ID NO 340 for CDRL2, SEQ ID NO 341 for C DRL3, SEQ ID NO 281 for C DRLl, SEQ ID NO 282 for C DRL2, SEQ ID NO 283 for CDRL3, SEQ ID NO 299 for CDRLl , SEQ ID NO 300 for CDRL2, SEQ ID NO 301 for CDRL3, SEQ ID NO 235 for CDRLl, SEQ ID NO 149 for CDRL2, SEQ ID NO 2
  • SEQ ID NO 219 for CDRLl SEQ ID NO 220 for CDRL2, SEQ ID NO 221 for CDRL3, SEQ ID NO 249 for CDRLl , SEQ TD NO 250 for CDRL2, SEQ TD NO 251 for CDRL3 and SEQ ID NO 281 for CDRLl, SEQ ID NO 282 for CDRL2, SEQ ID NO 361 for CDRL3, and SEQ ID NO 265 for CDRLl, SEQ ID NO 266 for CDRL2, SEQ ID NO 267 for CDRL3
  • the antibodies of the invention comprise a heavy chain with an ammo acid sequence that is at least 70% identical to those of SEQ TD NOs 328, 334, 348, 290, 294, 357, 308, 314, 242, 228, 258, 367 or 274, and neutralizes hCMV infection
  • the antibody binds to an epitope in the hCMV gB protein and comprises a heavy chain ha ⁇ mg an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO 328, 334, 348, 290, 294, 308, 357, 314 or 367, and neutralizes hCMV infection
  • an antibody according to the invention comprises a heavy chain having the sequence recited m SEQ ID NO 328, 334, 348, 290, 294, 308, 357, 314 or 367 and neutralize
  • the antibody binds to an epitope in the hCMV gH protein and comprises a heavy chain having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 242, 228, or 258, and neutralizes hCMV infection
  • an antibody according to the invention comprises a heavy chain having the sequence recited in SEQ ID NO 242, 228, or 258, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins gM and gN and comprises a heavy chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ TD NO 274, and neutralizes hCMV infection Tn
  • an antibody according to the invention comprises a heavy chain having the sequence recited in SEQ ID NO 274, and neutralizes hCMV infection
  • the antibodies of the mvention comprise a light chain with an ammo acid sequence that is at least 70% identical to those of SEQ ID NOs 329, 349, 291, 309, 243, 229, 259, 368 or 275, and neutralize hCMV infection
  • the antibody binds to an epitope in the hCMV gB protein and comprises a light chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 329, 349 291 , 309, or 368 and neutralizes hCMV infection Tn one embodiment, an antibody according to the invention comprises a light chain having the sequence recited in SEQ ID NO 329, 349, 291, 309 or 368, and neutralizes hCMV infection
  • the antibody binds to an epitope in the hCMV gH protein and comp ⁇ ses a light chain having an ammo acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 243, 229, or 259, and neutralizes hCMV infection
  • an antibody according to the invention comprises a light chain having the sequence recited in SEQ ID NO 243, 229, or 259, and neutralizes hCMV infection
  • the antibody binds to an epitope formed by the hCMV proteins gM and gN and comprises a light chain having an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the ammo acid sequence of SEQ ID NO 275, and neutralizes hCMV infection
  • an antibody according to the mvention comp ⁇ ses a light chain ha ⁇ mg the sequence recited m SEQ ID NO 275, and neutralizes hCMV infection
  • the antibody of the mvention is not MSL-109, 8F9, 3E3 or R551A In another embodiment, the antibody of the invention is not IFl 1 , 2F4, 5A2 or 6G4, disclosed in U S Application Nos 11/ 969,104 and 12/174,568
  • Exemplary antibodies of the invention include, but arc not limited to, 15D8, 4N10, 10F7, 10P3, 4122, 8L13, 2C12, 8C15, 916, 7B13, 8J16, 8121, 7113, 7H3, 6B4, 5Fl, 10C6, 4H9, 2Bl 1 , 11B12, 13H11 , 3G16 and 6L3
  • Variants of 15D8 that neutralize hCMV infection consist of a heavy chain variant ha ⁇ ing ammo acid sequence recited in SEQ ID NO 208 ("15D8 variant 1"), and SEQ ID NO 212 ("15D8 variant 2"), and a light chain ha ⁇ mg the ammo acid sequence recited m SEQ ID NO 213 (15D8 variant 2)
  • the nucleic acid sequences encoding the variant heavy chain variants are recited in SEQ ID NO 209 (15D8 variant 1) and SEQ ID NO 214 (15D8 variant 2)
  • 15D8 is used to refer to any and/or all variants of 15D8 that neutralize hCMV infection, for example, those -with heavy chains corresponding to SEQ ID NO 208 and 212 and light chains corresponding to SEQ ID NO, 213
  • a variant of 7H3 that neutralizes hCMV infection consists of a heavy chain having the amino acid sequence recited in SEQ ID NO 334 ("7H3 variant 1")
  • the nucleic acid sequence encoding the variant heavy chain is recited in SEQ ID NO 335
  • antibodies comprising the 7H3 variant heavy chain (SEQ ID NO 334) that neutralize hCMV infection are included withm the scope of the invention
  • the term ' 7H3 is used to refer to any and/or all ⁇ anants of 7H3 that neutralize hCMV infection, for example, those with heav y chains corresponding to SEQ ID NO 334
  • a variant of 5Fl that neutralizes hCMV infection consists of a heavy chain having the ammo acid sequence recited in SEQ TD NO 294 (' 5F l variant 1 ")
  • the nucleic acid sequence encoding the variant heavy chain is recited m SEQ ID NO 295
  • antibodies comprising the 5Fl variant heavy chain (SEQ ID NO 294) that neutralize hCMV infection are included withm the scope of the invention
  • the term ' 5F l " is used to refer to any and/or all variants of 5F 1 that neutralize hCMV infection, for example, those with heavy chains corresponding to SEQ ID NO 294
  • a variant of 4H9 that neutralizes hCMV infection consists of a heavy chain having the ammo acid sequence recited m SEQ ID NO 314 ("4H9 variant 1")
  • the nucleic acid sequence encoding the variant heavy chain is recited in SEQ ID NO 315
  • antibodies comprising the 4H9 variant heavy chain (SEQ TD NO 314), that neutralize hCMV infection are included within the scope of the invention
  • the term “4H9” is used to refer to any and/or all ⁇ ariants of 4H9 that neutralize hCMV infection, for example, those with heavy chains corresponding to SEQ ID NO 314
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 15D8 as listed in Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the m ⁇ ention, or antigen binding fragment thereof comprises all of the CDRs of antibody 15D8 variant 1 as listed in Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 15D8 variant 2 as listed in Table 1, and neutralizes hCMV infection m a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 8121 as listed m Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 4N10 as listed in Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 10F7 as listed m Table 1 , and neutralizes hCMV infection in a human host Tn another embodiment an antibody of the invention or antigen binding fragment thereof, comprises all of the CDRs of antibody 10P3 as listed in Table 1, and neutralizes hCMV infection m a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 4122 as listed in Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 8Ll 3 as listed in Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 2C 12 as listed m Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 8Cl 5 as listed in Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 916 as listed in Table 1 , and neutralizes hCMV infection m a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 7B 13 as listed in Table 1 , and neutralizes hC M V infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 8J16 as listed m Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 7H3 as listed in Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 7H3 variant 1 as listed in Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 6B4 as listed m Table 1, and neutralizes hCMV infection m a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 5F I as listed in Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 1OC 6 as listed m Table 1 , and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 11B12 as listed m Table 1, and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 13H1 I as listed in Table 1 and neutralizes hCMV infection in a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 3G16 as listed in Table 1, and neutralizes hCMV infection m a human host
  • an antibody of the invention, or antigen binding fragment thereof comprises all of the CDRs of antibody 6L3 as listed m Table I , and neutralizes hCMV infection in a human host
  • the invention further comprises an antibody, or fragment thereof, that binds to an epitope capable of binding to an antibody of the invention, or an antibody that competes with an antibody of the invention
  • Antibodies of the invention also include hybrid antibody molecules that comprise one or more CDRs from an antibody of the invention and one or more CDRs from another antibody to the same epitope
  • such hybrid antibodies comprise three CDRs from an antibody of the invention and three CDRs from another antibody to the same epitope
  • Exemplary hybrid antibodies comp ⁇ se i) the three light chain CDRs from an antibody of the invention and the three heavy chain CDRs from another antibody to the same epitope, or 11) the three heavy chain CDRs from an antibody of the invention and the three light chain CDRs from another antibody to the same epitope
  • nucleic acid sequences according to the invention include nucleic acid sequences having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to the nucleic acid encoding a heavy or light chain of an antibody of the invention
  • a nucleic acid sequence of the uxvention has the sequence of a nucleic acid encoding a heavy or light chain CDR of an antibody of the invention
  • a nucleic acid sequence according to the invention comprises a sequence that is at least 75% identical to the nucleic acid sequences of SEQ ID NOs 7-12, 15, 16, 23-28, 31, 32, 39-44, 47, 48, 55-60, 63, 64, 71-76, 79, 80, 87-92, 95, 96, 103-108,
  • variants of the sequences recited in the application are also included within the scope of the invention.
  • variants mcludc natural variants generated by somatic mutation in ⁇ ⁇ o during the immune response or in i itro upon culture of immortalized B cell clones are also included within the scope of the invention.
  • variants may arise due to the degeneracy of the genetic code, as mentioned above or may be produced due to errors m transcription or translation
  • antibody sequences having improved affinity and/or potency may be obtained using methods known m the art and are included withm the scope of the invention
  • ammo acid substitutions may be used to obtain antibodies with further improved affinity
  • codon optimisation of the nucleotide sequence may be used to improve the efficiency of translation in expression systems for the production of the antibody
  • polynucleotides comprising a sequence optimized for antibody specificity or neutralizing activity by the application of a directed evolution method to any of the nucleic acid sequences of the invention are also within the scope of the invention
  • variant antibody sequences that neutralize hCMV infection may share 70% or more (i e 75%, 80%, 85% 90% 95%, 97%, 98%, 99% or more) ammo acid sequence identity w ith the sequences recited m the application In some embodiments such sequence identity is calculated with regard to the full length of the reference sequence ⁇ e the sequence recited m the application) In some further embodiments, percentage identity, as referred to herein, is as determined using BLAST version 2 1 3 using the default parameters specified by the NCBI (the National Center for Biotechnology Information) [Blosum 62 matrix, gap open penalty" 1 1 and gap extension penalty- 1]
  • vectors for example expression vectors, comprising a nucleic acid sequence according to the invention
  • Cells transformed with such vectors are also included within the scope of the m ⁇ ention
  • examples of such cells include but are not limited to, cukaryotic cells, e g yeast cells, animal cells or plant cells
  • the cells are mammalian, e g human, CHO, HEK293T, PER C6, NSO, myeloma or hyb ⁇ doma cells
  • the invention also relates to monoclonal antibodies that bind to an epitope capable of binding the antibodies of the invention, including, but not limited to a monoclonal antibody selected from the group consisting of 15D8, 4N10 10F7, 10P3, 4122, 8L13 2C12, 8C15 916 7B13, 8J16, 8121, 7113, 7H3, 6B4, 5Fl, 10C6, 4H9, 11B12, 13H11, 3G16, 2B11 and 6L3
  • Monoclonal and recombinant antibodies are particularly useful in identification and purification of the individual polypeptides or other antigens against which they are directed
  • the antibodies of the invention have additional utility in that they may be employed as reagents in immunoassays, radioimmunoassays (RIA) or enzyme -linked immunosorbent assays (ELISA) In these applications, the antibodies can be labelled with an analytically-detectable reagent such as a radioisotope, a fluorescent molecule or an enzyme
  • the antibodies may also be used for the molecular identification and characterisation (epitope mapping) of antigens
  • Antibodies of the invention can be coupled to a drug for delivery to a treatment site or coupled to a detectable label to facilitate imaging of a site comprising cells of interest, such as cells infected with hCMV
  • Methods for coupling antibodies to drugs and detectable labels are well known m the art, as are methods for imaging using detectable labels
  • Labelled antibodies may be employed in a wide variety of assays, employing a wide variety of labels
  • Detection of the formation of an antibody-antigen complex between an antibody of the invention and an epitope of interest (an hCMV epitope) can be facilitated by attaching a detectable substance to the antibody
  • Suitable detection means include the use of labels such as radionuclides enzymes, coenzymes, fluorescers, chemiluminescers, chromogens, enzyme substrates or co-factors, enzyme inhibitors, prosthetic group complexes, free radicals, particles, dyes, and the luce
  • suitable enzymes include horseradish peroxida
  • an antibody according to the invention may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent, or a radioactive metal ion or radioisotope
  • a therapeutic moiety such as a cytotoxin, a therapeutic agent, or a radioactive metal ion or radioisotope
  • radioisotopes include, but are not limited to, 1-131 , 1-123, 1-125, Y-90, Re-188, Re-186, At-211, Cu-67, Bi-212, Bi-213, Pd-109, Tc-99, In-111, and the like
  • the drug moiety is not to be construed as limited to classical chemical therapeutic agents
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity
  • proteins may include, for example, a toxin such as abnn, ⁇ cm A, pseudomonas exotoxin, or diphtheria toxm
  • Antibodies of the invention may also be attached to a solid support
  • the PEG has a terminal hydroxy group
  • it is the terminal hydroxy group which is activated to react with a free ammo group on the inhibitor
  • the type and amount of the reactive groups may be varied to achieve a covalently conjugated PEG/antibody of the present invention
  • Water-soluble polyoxyethylated polyols are also useful m the present invention. They include polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxyethylated glycerol (POG), and the like In one embodiment.
  • POG is used Without being bound by any theory, because the glycerol backbone of polyoxyethylated glycerol is the same backbone occurring naturally in, for example, animals and humans in mono-, di-, triglycerides, this branching would not necessarily be seen as a foreign agent in the body.
  • POG has a molecular weight in the same range as PEG
  • the structure for POG is shown in reference 28, and a discussion of POG/IL-2 conjugates is found in reference 24
  • liposome Another drug delivery system that can be used for increasing circulatory half-life is the liposome Methods of preparing liposome delivery systems are discussed m references 29, 30 and 31 Other drug delivery systems are known in the art and are described in, for example, references 32 and 33
  • Antibodies of the invention may be provided in purified form Typically, the antibody will be present in a composition that is substantially free of other polypeptides e.g. where less than 90% (by weight), usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides
  • Antibodies of the invention may be immunogenic in non-human (or heterologous) hosts e g m mice.
  • the antibodies may have an idiotope that is immunogenic in non-human hosts, but not in a human host
  • Antibodies of the invention for human use include those that cannot be easily isolated from hosts such as mice, goats, rabbits, rats, non-primate mammals, etc and cannot generally be obtained by humanisation or from xcno-micc
  • Antibodies of the invention can be of any isotype (e g. IgA, IgG, IgM i e an ⁇ , ⁇ or ⁇ heavy chain), but will generally be IgG. Within the IgG isotype, antibodies may be IgGl , IgG2, IgG3 or IgG4 subclass Antibodies of the invention may have a K or a ⁇ light chain.
  • Monoclonal antibodies according to the invention can be made by any method known in the art
  • the general methodology for making monoclonal antibodies using hyb ⁇ doma technology is well known [34, 35]
  • the alternative EBV immortalisation method described in reference 36 is used
  • B cells producing the antibody of the invention can be transformed with EBV in the presence of a polyclonal B cell activator Transformation with EBV is a standard technique and can easily be adapted to include polyclonal B cell activators Additional stimulants of cellular growth and differentiation may optionally be added du ⁇ ng the transformation step to further enhance the efficiency These stimulants may be cytokines such as IL-2 and IL- 15 In one aspect, IL-2 is added during the immortalisation step to further improve the efficiency of immortalisation, but its use is not essential The immortalised B cells produced using these methods can then be cultured using methods known in the art and antibodies isolated therefrom
  • the antibodies of the invention can also be made by culturmg single plasma cells m microwell culture plates using the method described in UK Patent Application 0819376 5 Further, from single plasma cell cultures RNA can be extracted and single cell PCR can be performed using methods known in the art
  • the VH and VL regions of the antibodies can be amplified by RT-PCR, sequenced and cloned into an expression vector that is then transfected into HEK293T cells or other host cells
  • the cloning of nucleic acid in expression vectors, the transfection of host cells, the culture of the transfected host cells and the isolation of the produced antibody can be done using any methods known to one of skill in the art
  • Monoclonal antibodies may be further purified, if desired, using filtration, centrifugation and various chromatographic methods such as HPLC or affinity chromatography Techniques for purification of monoclonal antibodies, including techniques for producing pharmaceutical-grade antibodies, are well known in the art
  • Fragments of the monoclonal antibodies of the invention can be obtained from the monoclonal antibodies by methods that include digestion with enzymes, such as pepsm or papain, and/or by cleavage of disulfide bonds by chemical reduction Alternatively, fragments of the monoclonal antibodies can be obtained by cloning and expression of part of the sequences of the heavy or iight chains
  • Antibody "fragments" may include Fab, Fab', F(ab')2 and Fv fragments
  • the invention also encompasses single-chain Fv fragments (scFv) de ⁇ ved from the heavy and light chains of a monoclonal antibody of the invention e g the in ⁇ ention includes a scFv comprising the CDRs from an antibody of the invention
  • heavy or light chain monomers and dimers as well as single chain antibodies, e g single chain Fv in which the heavy and light chain variable domains arc joined by a peptide linker
  • DNA sequences coding for the antibodies or fragments of the antibodies of the present invention Desired DNA sequences may be synthesised completely or in part using oligonucleotide synthesis techniques Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate
  • Any suitable host cell/vector system may be used for expression of the DNA sequences encoding the antibody molecules of the present invention or fragments thereof
  • Bacterial, for example E coh, and other microbial systems may be used, in part, for expression of antibody fragments such as Fab and F(ab')2 fragments, and especially Fv fragments and single chain antibody fragments, for example, single chain Fvs
  • Eukaryotic, e g mammalian, host cell expression systems may be used for production of larger antibody molecules, including complete antibody molecules
  • Suitable mammalian host cells include CHO, HEK293T, PER C6, NSO, myeloma or hybridoma cells
  • the present invention also provides a process for the production of an antibody molecule according to the present invention comprising culturing a host cell comprising a vector of the present invention under conditions suitable for leading to expression of protein from DNA encoding the antibody molecule of the present invention, and isolating the antibody molecule
  • the antibody molecule may comprise only a heavy or light chain polypeptide, in which case only a heavy chain or light chain polypeptide coding sequence needs to be used to transfect the host cells
  • the cell line may be transfected with two vectors, a first vector encoding a light chain polypeptide and a second vector encoding a heavy chain polypeptide
  • a single vector may be used, the vector 0 including sequences encoding light chain and heavy chain polypeptides
  • the screening step may be carried out by ELISA, by staining of tissues or cells (including transfcctcd cells), a neutralisation assay or one of a number of other methods known in the art for identifying desired antigen specificity
  • the assay may select on the basis of simple antigen0 recognition, or may select on the additional basis of a desired function e g to select neutralizing antibodies rather than just antigen binding antibodies, to select antibodies that can change characteristics of targeted cells, such as their signalling cascades, their shape, their growth rate, their capability of influencing other cells, their response to the influence by other cells or by other reagents or by a change in conditions, their differentiation status, etc *)
  • the cloning step for separating indrvidual clones from the mixture of positive cells may be carried out using limiting dilution, micromanipulation, single cell deposition by cell sorting or another method known in the art
  • the epitopes recognised by the antibodies of the present invention may a number of uses
  • the epitope and mimotopes thereof m purified or synthetic form can be used to raise immune responses (z e as a vaccine, or for the production of antibodies for other uses) or for screening patient serum for antibodies that immunoreact with the epitope or mimotopes thereof
  • such an epitope or mimotope, or antigen comprising such an epitope or mimotope may be used as a vaccme for raising an immune response
  • the antibodies and antibody fragments of the invention can also be used m a method of monitoring the quality of vaccines
  • the antibodies can be used to check that the antigen in a vaccme contains the specific immunogenic epitope in the correct conformation
  • the immortalised B memory cells of the invention may also be used as a source of nucleic acid for the cloning of antibody genes for subsequent recombinant expression
  • Expression from recombinant sources is more common for pharmaceutical purposes than expression from B cells or hyb ⁇ domas e g for reasons of stability, reproducibility, culture ease, etc
  • the invention provides a method for preparing a recombinant cell, comprising the steps of (i) sequencing nucleic acid(s) from the B cell clone that encodes the antibody of interest, and (ii) using the sequence information from step (i) to prepare nucleic acid(s) for insertion into an expression host m order to permit expression of the antibody of interest in that host
  • the nucleic acid may, but need not, be manipulated between steps (i) and (11) to introduce restriction sites, to change codon usage, and/or to optimise transcription and/or translation regulatory sequences
  • the invention also provides a method of preparing a recombinant cell, comprising the step of transforming a host cell with one or more nucleic acids that encode a monoclonal antibody of interest, wherein the nucleic acids are nucleic acids that were derived from an immortalised B cell clone of the invention
  • the procedures for first preparing the nucleic acid(s) and then using it to transform a host cell can be performed at different times by different people in different places (e g in different countries).
  • These recombinant cells of the invention can then be used for expression and culture purposes They are particularly useful for expression of antibodies for large-scale pharmaceutical production They can also be used as the active ingredient of a pharmaceutical composition.
  • Any suitable culture techniques can be used, including but not limited to static culture, roller bottle culture, ascites fluid, hollow-fiber type bioreactor cartridge, modular minifermenter, stirred tank, microcar ⁇ cr culture, ceramic core perfusion, etc
  • the expression host is preferably a eukaryotic cell, including yeast and animal cells, particularly mammalian cells (e g CHO cells, NSO cells, human cells such as PER C6 [Crucell, reference 38] or HKB-11 [Bayer; references 39 & 40] cells, myeloma cells [41 & 42], etc ), as well as plant cells.
  • mammalian cells e g CHO cells, NSO cells, human cells such as PER C6 [Crucell, reference 38] or HKB-11 [Bayer; references 39 & 40] cells, myeloma cells [41 & 42], etc
  • Preferred expression hosts can glycosylate the antibody of the invention, particularly with carbohydrate structures that are not themselves immunogenic m humans
  • the expression host may be able to grow in scrum-frcc media
  • the expression host may be able to grow in culture without the presence of animal -derived products
  • the expression host may be cultured to give a cell line.
  • the invention also provides a method of preparing nucleic acid molecule(s) that encodes an antibody of interest, comprising the step of obtaining the nucleic acid from a B cell clone that was obtained from a transformed B cell of the invention
  • a method of preparing nucleic acid molecule(s) that encodes an antibody of interest comprising the step of obtaining the nucleic acid from a B cell clone that was obtained from a transformed B cell of the invention
  • the invention provides a method for preparing an antibody (e g for pharmaceutical use), comprising the steps of (i) obtaining and/or sequencing one or more nucleic acids (e g heavy and light chain genes) from the selected B cell clone expressing the antibody of interest, (ii) inserting the nucleic acids (e g heavy and light chain genes) from the selected B cell clone expressing the antibody of interest, (ii) inserting the nucleic acids (e g heavy and light chain genes) from the selected B cell clone expressing the antibody of interest, (ii) inserting the
  • cell lines expressing exemplary antibodies of the m ⁇ ention, 4N 10, 2C l 2, 8C l 5, 8121, 6B4, 10C6, 4H9, 11B12, 3G16, and 6L3 were deposited with the Advanced Biotechnology Center (ABC), Largo Rossana Benzi 10, 16132 Genoa (Italy), under the terms of the Budapest Treaty, on July 9, 2008, (under Accession Numbers PD 08009, PD 08007, PD 08006, PD 08005, PD 08004, PD 08014, PD 08013, PD 08011 , PD 08012, and PD 08010, respectively) and an immortalized B cell line expressing 7H3 w as deposited on July 16, 2008 under Accession Number PD 08017
  • An antibody, or an antigen binding fragment thereof, expressed from the above cell lines as well as antibodies, and antigen binding fragments thereof, with the same ammo acid sequence as those expressed from the above cell lines are also considered to be within the scope of the invention
  • compositions The invention provides a pharmaceutical composition containing the antibodies and/or antibody fragments of the invention and/or nucleic acid encoding such antibodies and/or immortalised B cells that express such antibodies and'or the epitopes recognised by the antibodies of the invention
  • a pharmaceutical composition may also contain a pharmaceutically acceptable carrier to allow administration
  • the carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic
  • Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers and inactrv c virus particles
  • Pharmaceutically acceptable salts can be used, for example mineral acid salts, such as hydrochlorides, hydrobromides, phosphates and sulphates, or salts of organic acids, such as acetates, propionates malonates and benzoates
  • forms of administration may include those forms suitable for parenteral administration, e g by injection or infusion, for example by bolus injection or continuous infusion
  • the product may take the form of a suspension, solution or emulsion m dn oily or aqueous ⁇ ehicle and it may contain formuldtory agents, such as suspending, preservative, stabilising and/or dispersing agents
  • the antibody molecule may be m dry form, for reconstitution before use with an appropriate sterile liquid
  • compositions of the invention can be administered directly to the subject
  • compositions are adapted for administration to human subjects
  • compositions of the invention may be prepared in ⁇ v arious forms
  • the compositions may be prepared as in
  • Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared (t g a lyophilised composition, like SynagisTM and HerceptmTM, for reconstitution with sterile water containing a preservative)
  • the composition may be prepared for topical administration e g as an ointment, cream or powder
  • the composition may be prepared for oral administration e g as a tablet or capsule, as a spray, or as a syrup (optionally flavoured)
  • the composition may be prepared for pulmonary administration e g as an inhaler, using a fine powder or a spray
  • the composition may be prepared as a suppository or pessary
  • the composition may be prepared for nasal, aural or ocular administration eg as drops
  • the composition may be in kit form, designed such that a
  • the active ingredient in the composition will be an antibody molecule, an antibody fragment or variants and derivatives thereof As such, it will be susceptible to degradation m the gastrointestinal tract
  • the composition will need to contain agents which protect the antibody from degradation but which release the antibody once it has> been absorbed from the gastrointestinal tract
  • compositions of the invention generally have a pH between 5 5 and 8 5, in some embodiments this may be between 6 and 8, and in further embodiments about 7
  • the pH may be maintained by the use of a buffer
  • the composition may be sterile and/or pyrogen free
  • the composition may be isotonic with respect to humans
  • pharmaceutical compositions of the invention are supplied in hermetically-sealed containers
  • compositions will include an effective amount of one or more antibodies of the invention and/or one or more immortalised B cells of the invention and/or a polypeptide comprising an epitope that binds an antibody of the invention i e an amount that is sufficient to treat, ameliorate or pre ⁇ ent a desired disease or condition, or to exhibit a detectable therapeutic effect
  • Therapeutic effects also include reduction in physical symptoms
  • the precise effective amount for any particular subject w ill depend upon their size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration The effective amount for a given situation is determined by routine experimentation and is w ithin the ] udgment of a clinician
  • an effective dose will generally be from about 0 Olmg'kg to about 50mg/kg, or about 0 05 mg/kg to about 10 mg/kg of the compositions of the present invention m the individual to which it is administered
  • Known antibody- based pharmaceuticals provide guidance in this respect e g HerceptinTM is administered by intra ⁇
  • compositions can include more than one (e g 2, 3, 4, 5, etc ) antibody of the invention to provide an additive or synergistic therapeutic effect
  • the composition may comprise one or more (e g 2, 3, 4, 5, etc ) antibody of the invention and one or more (e g 2, 3, 4, 5, etc ) additional antibodies that neutralize hCMV infection
  • one antibody may bind to an epitope in the hCMV UL128 protein, an epitope formed by the hCMV proteins UL 130 and UL 131 A, an epitope formed by the hCMV proteins UL128, UL130 and UL131A, an epitope formed by the hCMV proteins gH, gL, UL128 and UL130, an epitope m the hCMV gB protein, an epitope m the hCMV gH protein, or an epitope formed by the hCMV proteins gM and gN, while another may bind to a different epitope in
  • the invention ⁇ ro ⁇ ides a pharmaceutical composition comprising two or more antibodies, wherein the first antibody is specific for a first UL 128 epitope, and the second antibody is specific for a second UL128 epitope, a combination of UL130 and UL131A, a combination of UL128, UL130 and UL131A, a combination of gH, gL, UL128 and UL130, gB, gH, gL
  • the invention provides a pharmaceutical composition comprising two or more antibodies, wherein the first antibody is specific for a first gB epitope, and the second antibody is specific for UL128, a combination of UL130 and UL13 IA, a combination of UL128, UL130 and UL131A, a combination of gH, gL, UL128 and UL130, a second gB epitope, gH, gL, gM, gN, g ⁇ , or a combination of gM and gN
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising two or more antibodies, wherein the first antibody is specific for a first gH epitope, and the second antibody is specific for UL128, a combination of UL130 and UL13 IA, a combination of UL128, UL130 and UL131A, a combination of gH, gL, UL128 and UL130, gB, a second gH epitope, gL, gM, gN, g ⁇ , or a combination of gM and gN
  • the invention a pharmaceutical composition comprising two or more antibodies, wherein the first antibody is specific for a first epitope on a combination of gM and gN, and the second antibody is specific for UL 128, a combination of UL 130 and ULl 3 IA, a combination of UL128, UL130 and UL131A, a combination of gH, gL, UL128 and UL130, gB, gH, gL, gM, gN, g ⁇ , or a second epitope on a combination of gM and gN
  • Exemplary antibodies of the invention for use in a pharmaceutical composition that bind to an epitope in the hCMV UL 128 protein include, but are not limited to, 15D8
  • Exemplary antibodies of the invention for use m a pharmaceutical composition that bind an epitope formed by the hCMV proteins UL130 and ULBlA include, but are not limited to, 4N10, 10F7, 10P3, 4122, 8
  • the invention provides a pharmaceutical composition comprising the antibody 15D8 or an antigen binding fragment thereof, and d pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 15D8 variant lor an antigen binding fragment thereof and a pharmaceutically acceptable earner Tn
  • the invention provides a pharmaceutical composition comprising the antibody 15D8 variant 2or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 8121 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention pro ⁇ ides a pharmaceutical composition comprising the antibody 2C 12 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 8Cl 5 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the imention provides a pharmaceutical composition comprising the antibody 916 or an antigen bindmg fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 7Bl 3 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 8Jl 6 or an antigen binding fragment thereof, and a pharmaceutical Iy acceptable carrier Tn another embodiment, the invention provides a pharmaceutical composition comprising the antibody 7113 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 4N 10 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the indention provides a pharmaceutical composition comprising the antibody 10F7 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the indention provides a pharmaceutical composition comprising the antibody 10P3 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 4T22 or an antigen binding fragment thereof, and a pharmaceutically acceptable earner
  • the invention provider a pharmaceutical composition comprising the antibody 8Ll 3 or an antigen binding fragment thereof, and a pharmaceutically acceptable earner
  • the invention provides a pharmaceutical composition comprising the antibody 7H3 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 7H3 variant 1 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 10C6 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 5Fl or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 6B4 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 4H9 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 4H9 variant 1 or an antigen binding fragment thereof, and d pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising the antibody 2
  • the pharmaceutical compositions of the invention may comprise the above antibodies or antigen binding fragments thereof, as the sole active ingredient
  • the pharmaceutical composition may comprise 2 or more, e g , 2, 3, 4, 5, 6, 7, 8, or more of the above antibodies or antigen binding fragment thereof
  • the pharmaceutical compositions of the invention may also comprise one or more antibodies, or antigen binding fragment thereof, and a second antibody, or antigen binding fragment thereof, that neutralises hCMV infection
  • Antibodies of the invention may be administered (either combined or separately) with other therapeutics e g with chemotherapeutic compounds, with radiotherapy, etc
  • Preferred therapeutic compounds include anti-viral compounds such as ganciclovir, foscarnet and cidoftrwr
  • Such combination therapy provides an additive or synergistic improvement in therapeutic efficacy relative to the individual therapeutic agents when administered alone
  • the term "synergy" is used to describe a combined effect of two or more actrv e agents that is greater than the sum of the individual effects of each respective active agent
  • Antibodies may be administered to those patients who have previously shown no response to treatment for hCMV infection, i e have been shown to be refractrv e to anti-hCMV treatment
  • Such treatment may include previous treatment with an anti-vrral agent This may be due to, for example, infection w ith an anti- viral resistant strain of hC M V
  • compositions of the invention that include antibodies of the invention, the antibodies may make up at least 50% by weight (e g 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or more) of the total protein m the composition
  • the antibodies are thus m purified form
  • the invention provides a method of preparing a pharmaceutical, comprising the steps of (i) preparing an antibody of the invention, and (ii) admixing the purified antibody with one or more pharmaceutically-acceptable earners
  • the invention also provides a method of preparing a pharmaceutical, comprising the step of admixing an antibody with one or more pharmaccutically-acccptablc carriers, wherein the antibody is a monoclonal antibody that was obtained from a transformed B cell of the invention
  • the procedures for first obtaining the monoclonal antibody and then preparing the pharmaceutical can be performed at very different times by different people in different places (e g in different countries)
  • nucleic acid typically DNA
  • Suitable gene therapy and nucleic acid delivery vectors are known in the art
  • compositions of the invention may be immunogenic compositions, and in some embodiments may be vaccine compositions comprising an antigen comprising an epitope in the hCMV UL128 protein, formed by the hCMV proteins UL130 and 131A, formed by the hCMV proteins UL128, UL130 and UL131A formed by the hCMV proteins gH, gL, UL128 and UL130, in the hCMV gB protein, in the hCMV gH protein, or formed by the hCMV proteins gM and gN
  • Alternative compositions may comprise (i) an antigen comprising an epitope formed by a combination of hC MV proteins UL 128, UL 130 and UL131A, and (ii) an antigen comprising an epitope found on gB, gH, gL, gM, gN, g ⁇ , UL128, UL130 or UL131A, or a combination thereof
  • compositions of the invention may also comprise one or more immunoregulatory agents Ia one embodiment, one or more of the immunoregulatory agents mclude(s) an adjuvant
  • the epitope compositions of the invention may elicit both a cell mediated immune response as well as a humoral immune response in order to effectively address a hCMV infection
  • This immune response may induce long lasting (e g neutralizing) antibodies and a cell mediated immunity that can quickly respond upon exposure to hCMV Medical treatments and uses
  • the antibodies antibody fragments of the invention or derivatives and variants thereof may be used for the treatment of hCMV infection, for the prevention of hCMV infection or for the diagnosis of hCMV infection
  • Methods of diagnosis may include contacting an antibody or an antibody fragment with a sample
  • samples may be tissue samples taken from, for example, salivary glands, lung liver, pancreas, kidney, ear, eye placenta, alimentary tract, heart, ovaries, pituitary, adrenals, thyroid, brain or skin
  • the methods of diagnosis may also include the detection of an antigen/antibody complex
  • the invention therefore provides (i) an antibody, an antibody fragment, or variants and de ⁇ vatnes thereof according to the invention, (ii) an immortalised B cell clone according to the invention, (in) an epitope capable of binding an antibody of the invention or (iv) a ligand, preferably an antibody, capable of binding an epitope that binds an antibody of the invention for use in therapy
  • Also provided is a method of treating a patient comprising administering to that patient (i) an antibody, an antibody fragment, or variants and derivatives thereof according to the invention, or, a ligand, preferably an antibody, capable of binding an epitope that binds an antibody of the invention
  • the invention also provides the use of (i) an antibody, an antibody fragment, or variants and derivatives thereof according to the invention, (n) an immortalised B cell clone according to the invention, (m) an epitope capable of binding an antibody of the invention, or (i ⁇ ) a ligand, preferably an antibody, that binds to an epitope capable of binding an antibody of the invention, in the manufacture of a medicament for the prevention or treatment of hCMV infection
  • the invention provides a composition for use as a medicament for the prevention or treatment of an hCMV infection Tt also provides the use of an antibody and/or a protein comprising an epitope to which such an antibody binds m the manufacture of a medicament for treatment of a patient and/or diagnosis in a patient It also provides a method for treating a sub
  • Antibodies of the invention and dntigen-bidmg fragments thereof can also be used in passive immunisation Further, as described in the present invention, they may also be used in a kit for the diagnosis of hCMV infection Epitopes capable of binding an antibody of the m ⁇ ention, e g , the monoclonal antibodies
  • 15D8, 4N10, 10F7, 10P3, 4122, 8L13, 2C12, 8C15, 916, 7B13, 8J16, 8121, 7113, 7H3, 6B4, 5Fl, 10C6, 4H9, 2Bl 1, 11B12, 13Hl 1, 3G16, and 6L3, may be used in a kit for monitoring the efficacy of vaccination procedures by detecting the presence of protective anti hCMV antibodies
  • Antibodies, antibody fragment, or variants and derivatives thereof, as described in the present invention may also be used in a kit for monitoring vaccine manufacture with the desired immunogemcity
  • the invention also provides a method of preparing a pharmaceutical, comprising the step of admixing a monoclonal antibody with one or more pharmaccutically-acccptablc carriers, wherein the monoclonal antibody is a monoclonal antibody that was obtained from an expression host of the invention
  • the procedures for first obtaining the monoclonal antibody (e g expressing it and/or purifying it) and then admixing it with the pharmaceutical carner(s) can be performed at very different times by different people in different places (e g in different countries)
  • the above methods further comprise techniques of optimisation (e g affinity maturation or optimisation) applied to the nucleic acids encoding the antibody
  • optimisation e g affinity maturation or optimisation
  • the invention encompasses all cells, nucleic acids, vectors, sequences, antibodies etc used and prepared during such steps
  • the nucleic acid used in the expression host may be manipulated to insert, delete or amend certain nucleic acid sequences Changes from such manipulation include, but are not limited to, changes to introduce restriction sites, to amend codon usage, to add or optimise transcription and'Or translation regulatory sequences, etc It is also possible to change the nucleic acid to alter the encoded ammo acids For example, it may be useful to introduce one or more (e g 1, 2, 3, 4, 5, 6, 7 8, 9, 10, etc ) amm
  • composition comprising X may consist exclusively of X or may include something additional e g X + Y
  • word “substantially” does not exclude “completely” e g a composition which is
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life
  • patient means all mammals including humans Examples of patients include humans, cows, dogs, cats, horses, goats sheep, pigs, and rabbits Generally, the patient is a human
  • Memory B cells were isolated and immortalised using EBV and CpG as described in reference 36 Briefly, memory B cells were isolated by negative selection using CD22 beads, followed by removal of IgM , IgD IgA B cells using specific antibodies and cell sorting The sorted cells (IgG ) were immortalized with EBV in the presence of CpG 2006 and irradiated allogeneic mononuclear cells
  • Table 5 A shows the neutralization of a hCMV clinical isolate (VRl 814) on both a fibroblastic cell line (MRC-9) and a human retinal epithelial cell line (ARPE)
  • Some antibodies neutralized hCMV infection of epithelial cells (ARPE) but they did not neutralize infection of fibroblasts (MRC-9)
  • Most of these antibodies which are specific for one or more proteins of the gH/gL/UL 128/ULnO 7 UL H l A protein complex, neutralized hCMV infection of epithelial cells at very low concentrations (50% reduction of hCMV infection at concentrations ranging from 0 01 ⁇ g/ml and 0 001 ⁇ g/ml)
  • Other antibodies which arc specific for the hCMV protein gB, gH or a combination of gM and gN, neutralized hCMV infection of fibroblast
  • Table 5B shows an independent experiment performed using purified antibodies The results show that Group 2 antibodies neutralized infection of epithelial cells with IC 90 values (i c the concentration of antibody required to give 90% reduction of viral infection) rangmg from 0 007 ⁇ g/ml to 0 003 ug/ml while Group 1 antibodies neutralized infection of both fibroblasts and epithelial cells with IC90 values ranging from 0 1 ug/ml to 30 ⁇ g/ml Group 2 antibodies also neutralized infection of endothelial cells (HUVEC) and myeloid cells (monocyte- de ⁇ ved dendritic cells) (data not shown) Group 1 antibodies also neutralized infection of endothelial cells (HUVEC), myeloid cells (monocytc-dc ⁇ vcd dendritic cells) and bone marrow me
  • antibodies that neutralize infection of different cell types may be combined to bring about an additive or synergistic neutralization effect when the different cell types are present during infection.
  • a neutralizing antibody such as 15D8 which is potent in neutralizing infection of epithelial cells but does not neutralize infection of fibroblasts might be combined with 3G16 which does have virus neutralizing activity on fibroblasts.
  • a neutralizing antibody such as 916 which is potent in neutralizing infection of epithelial cells but does not neutralize infection of fibroblasts, might be combined with 6B4 which does have virus neutralizing activity on fibroblasts.
  • HEK293T cells were transfected with one or more vectors encoding full length hCMV proteins UL128, UL130, UL131A, gH, gL, gB, gM, and gN
  • cells were fixed, pcrmcabilizcd and stained with the human monoclonal antibodies followed by goat anti-human IgG
  • Figure 1 shows the binding of representative antibodies to HEK293T cells expressing one or more hCMV proteins.
  • Table 6 shows the staining pattern of all the different antibodies to hCMV gene-transfected HEK293T cells.
  • All these antibodies also stained HEK293T cells transfected with all genes forming the gH/gL/UL128-130 complex.
  • Group 1 antibodies three (11B12, 13Hl 1 and 3G16) stained cells expressing the hCMV protein gH, six (7H3, 10C6, 5Fl , 6B4, 4H9 and 2Bl 1) stained cells expressing the hCMV protein gB and one (6L3) stained cells cocxprcssing the hCMV proteins gM and gN.
  • At least seven distinct antigenic sites can be distinguished on the hCMV complex formed by gH, gL, UL128 and UL130 (Table 8)
  • Site 1 is present in UL128 and is defined by antibody 15D8
  • Sites 2 to 4 are formed by the combination of UL130 and UL13 IA and are defined by the antibodies 10F7 4I22, 8L 13 IFI l and 2F4 (site 2) by 4N10 and 5 A2 (site 3), and by 10P3 (site 4), respectively
  • Sites 5 and 6 arc formed by the combination of UL128, UL130 and UL131A and are defined by antibodies 2C12, 7B13, 8C 15, 8J16, 916 and 6G4 (site 5) and by 7113 (site 6), respectively
  • site 7 is formed by the combination of gH, gL, UL128 and UL130 and is defined by the antibody 8121 Antibodies defining site 7 and site 3 partially competed with each other, suggesting that these sites may
  • HEK293T cells were transfected with a vector encoding full length gH to examine the cross-competition binding of the anti-gH antibodies As can be seen in Figure 2A and Table 9, at least two different binding sites were identified in the hCMV gH protein.
  • Antibody 6B4 (recognizing gB site 1) reacted by ELISA with the gB 69-78 peptide (EC 50 of 0 044 ⁇ g'ml) It is anticipated that antibodies that target different sites even on the same target molecule can be used in combination to achieve robust virus neutralization It is anticipated that antibodies that target different sites even on the same target molecule can be used in combination to achieve robust virus neutralization.
  • 15D8 binds, to an epitope m UL 128 that is distinct from the epitope recognized by 2C12, 7B13, 6G4 (all specific for a combination of UL128, UL130 and UL131A) and from the epitope recognized by 8121 (specific for a combination of gH, gL, UL128 and UL130)
  • binding of 15D8 to its epitope is not inhibited by 4N10, 10F7, 10P3 and IFl 1 (all specific for a combination of UL130 and UL131A)
  • 10F7 binds to an epitope -which requires expression of UL130 and UL131 A that is the same or largely overlapping to the epitope(s) recognized by 4T22, 8L13, I Fl 1 and 2F4 but distinct from epitope(s) recognized by 4N10 and 5A2 (both specific for a combination of UL130 and UL131A) as well as distinct from epitopes recognized by 2C12 and 6G4 (both specific for a combination of UL128, UL130 and UL13 IA)
  • binding of 10F7 to its epitope is not inhibited by 15D8 (specific for UL128) or by 13Hl 1 (specific for gH) 4122 binds to an epitope which requires expression of UL130 and UL131A and that is the same or partially overlapping to epitope(s) recognized by 2F4, IFl 1 and 10F7 but distinct from epitope(s) recognized by 4N10, 10P3 and 5A2 (all specific for a
  • 2C12 binds to an epitope which requires expression of hCMV UL128, UL130 and UL131A gene products and that is the same or largely to e ⁇ itope(s) recognized by 7B 13, 8C 15, 8Jl 6, 916 and 6G4 but distinct from the epitope recognized by 7113 (all specific for a combination of UL128, UL130 and UL131A) and distinct from epitope(s) recognized by 15D8 (specific for UL128), 4N10, 10F7, 10P3, 4122, 8L13, IFl 1, 2F4, 5A2 (all specific for a combination of UL130 and UL131 A) and 8121 (specific for a combination of gH, gL, UL128 and UL130) In addition binding of 2C12 to its epitope is not inhibited by 3G16 (specific for gH)
  • 8C15 binds to an epitope which requires expression of hCMV UL128, UL130 and UL131A gene products and that is the same or largely overlapping to epitope(s) recognized by 2C12, 7B13, 8J16, 916 and 6G4 but distinct from the epitope recognized by 7113 (all specific for a combination of UL128 UL130 and UL131A)
  • 8J16 binds to an epitope which requires expression of hCMV UL128, UL130 and UL131A gene products and that is the same or largely overlapping to epitope(s) recognized by 2C12, 7B13, 8C15, 916 and 6G4, but distinct from the epitope recognized by 7113 (all specific for a combination of UL128, UL130 and UL13 IA) and from the epitope recognized by 4122 (specific for a combination of UL130 and UL131A)
  • 916 binds to an epitope which requires expression of hCMV UL128, UL130 and UL131A gene products and that is the same or largely overlapping to epitope(s) recognized by 2C12, 7B13, 8C15, 8Jl 6 and 6G4 but distinct from the epitope recognized by 7113 (all specific for a combination of UL128, UL130 and UL13 IA) and from the epitope(s) recognized by 2F4 and 5A2 (specific for a combination of UL130 and UL131A)
  • 8121 binds to an epitope which requires expression of hCMV gH, gL, UL128 and UL130 gene products and that may be partially overlapping to epitope(s) recognized by 4N10 and 5A2 (both specific for a combination of UL130 and UL131A) but distinct from epitopes recognized by 15D8 (specific UL128), 10F7, 10PS, 4122, 1Fl 1 , 2F4 (all specific for a combination of ULHO and UL131 A) 2C12, 7B13 7113 8C 15, SJ16 916 and 6G4 (all specific for a combination of LJL128, LJL130 and UL131A) In addition binding of 8121 to its epitope is not inhibited by 3G16 (specific for gH)
  • 3G16 binds to an epitope in gH that is distinct from the epito ⁇ e(s) recognized by 1 IB 12 and 13H I 1 (both specific for gH)
  • 11B12 binds to an epitope in gH that is the same or largely overlapping to the epitope recognized by 13Hl 1 and distinct from the epitopes recognized by 3G16 (both specific for gH)
  • 13H11 binds to an epitope in gH that is the same or largely overlapping to the epitope recognized by 11B12 and distinct from the epitopes recognized by 3G16 (both specific for gH) 6B4 recognizes an epitope in gB that is distinct from the cpitopc(s) recognized by 7H3, 4H9,
  • 7H3 binds to an epitope m gB that is distinct from the e ⁇ itope(s) recognized by 6B4, 7H3, 4H9, 5Fl, 10C6 and 2Bl 1 (all specific for gB)
  • 10C6 bindt> to an epitope in gB that is the same or partially overlapping to the epitope(s) recognized by 5Fl, 4H9 and 2Bl 1, but distinct from the e ⁇ itope(s) recognized by 7H3 and 6B4 (all specific for gB)
  • 5Fl binds to an epitope in gB that is the same or largely overlapping to the cpitopc(s) recognized by 10C6, 4H9 and 2Bl 1 but distinct from the epitope(s) recognized by 6B4 and 7H3 (all specific for gH)
  • 4H9 binds to an epitope m gB that is the same or largely overlapping to the epito ⁇ e(s) recognized by 5Fl, 1OC 6 and 2Bl 1, but distinct from the epitope(s) recognized by 6B4 and 7H3 (all specific for gH)
  • 2Bl 1 binds to an epitope in gB that is the same or largely overlapping to the epitope(s) recognized by 5F I 10C6 and 4H9 but distinct from the epito ⁇ e(s) recognized by 6B4 and 7H3 (all specific for gH)
  • ULl 28 is the most conserved gene of the ULl 32-128 locus
  • sequences derived from several clinical isolates revealed the existence of 10 variants with one or more mutations when compared to the VRl 814 sequence Wc therefore inv estigated whether the binding of the UL 128- specific antibody 15D8 would be affected by any of these mutations
  • published ammo acid sequences of variants of UL128 from clinical isolates VR4603 M, VR4836 M, VR5001 M, VR4254-M VR4969-M, VR4313-M, VR4116-M VR5235-T, VR5055-T, VR4168-A, VRl 814- PCR
  • laboratory strains Two-derived from clinical isolates
  • a gene was synthesized encoding a protein that includes alL ammo acid substitutions described as well as an additional, mutation that we found to be generated at ⁇ ery high frequency in i itro upon
  • HEK293T cells were transfected with the original UL128 from VR1814 or with the pan- 5 mutated gene and stained with serial dilutions of 15D8 antibody As shown in Figure 3, the original and the pan mutated ULl 28 protein were recognized by 15D8 with comparable efficiency (saturated staining at ⁇ 0 2 ⁇ g/ml) These findings indicate that 15D8 recognize a highly conserved epitope in the UL128 encoded protein

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BRPI0916443A2 (pt) 2017-10-31
IL232861A0 (en) 2014-07-31
EA201170205A1 (ru) 2011-08-30
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US9365636B1 (en) 2016-06-14
JP2015145412A (ja) 2015-08-13
US20160145319A1 (en) 2016-05-26
PE20141398A1 (es) 2014-10-18
CN106924729A (zh) 2017-07-07
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JP6345753B2 (ja) 2018-06-20
CN106924729B (zh) 2021-03-02
US20160280770A1 (en) 2016-09-29
PE20140882A1 (es) 2014-07-25
ES2654543T3 (es) 2018-02-14
GT201100011AA (es) 2017-09-14
KR101356350B1 (ko) 2014-01-27
US9491906B2 (en) 2016-11-15
JP2017055765A (ja) 2017-03-23
US8603480B2 (en) 2013-12-10
SG191699A1 (en) 2013-07-31
CN103980363B (zh) 2017-04-12
ZA201600335B (en) 2017-11-29
IL238421A (en) 2016-06-30
ES2682596T3 (es) 2018-09-21
PE20141432A1 (es) 2014-10-18
US20140193428A1 (en) 2014-07-10
IL232863A0 (en) 2014-07-31
GT201100011BA (es) 2017-09-14
US8124093B2 (en) 2012-02-28
US9725502B2 (en) 2017-08-08
SG10201608381SA (en) 2016-11-29
EP3009449A1 (en) 2016-04-20
NZ619953A (en) 2015-06-26
US10414817B2 (en) 2019-09-17
IL232863A (en) 2016-06-30
ECSP11010827A (es) 2011-07-29
US9796771B2 (en) 2017-10-24
SG10201706350PA (en) 2017-09-28
PE20141433A1 (es) 2014-10-19
IL232861A (en) 2016-06-30
US8298539B2 (en) 2012-10-30
US20170081391A1 (en) 2017-03-23
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CU23953B1 (es) 2013-10-29
MX338067B (es) 2016-04-01
HK1220981A1 (en) 2017-05-19
KR20110052585A (ko) 2011-05-18
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CN102203133B (zh) 2015-01-07
US20180371062A1 (en) 2018-12-27
JP5807050B2 (ja) 2015-11-10
US20120128692A1 (en) 2012-05-24
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US20120128691A1 (en) 2012-05-24
US9221897B2 (en) 2015-12-29
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US20170334972A1 (en) 2017-11-23
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US20160280769A1 (en) 2016-09-29
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ECSP11010826A (es) 2011-07-29
US10889632B2 (en) 2021-01-12
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US20130302350A1 (en) 2013-11-14
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