WO2022162097A2 - Antibodies and uses thereof - Google Patents

Antibodies and uses thereof Download PDF

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Publication number
WO2022162097A2
WO2022162097A2 PCT/EP2022/051959 EP2022051959W WO2022162097A2 WO 2022162097 A2 WO2022162097 A2 WO 2022162097A2 EP 2022051959 W EP2022051959 W EP 2022051959W WO 2022162097 A2 WO2022162097 A2 WO 2022162097A2
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WO
WIPO (PCT)
Prior art keywords
antibody
atho
domain
aram
domain sequence
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PCT/EP2022/051959
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French (fr)
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WO2022162097A3 (en
Inventor
Anne Louise PALSER
Paul Kellam
Simon James Watson
Ilaria ANDREOZZI
Sara CIOCCOLO
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Kymab Limited
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Publication of WO2022162097A2 publication Critical patent/WO2022162097A2/en
Publication of WO2022162097A3 publication Critical patent/WO2022162097A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Cytomegalovirus and specifically, human cytomegalovirus (HCMV) belongs to the P-herpesvirus family of DNA viruses. It is estimated to have infected 50-90% of the world's population and causes a mild self-limiting infection in otherwise healthy children or adults.
  • HCMV is one of the most significant viral pathogens during pregnancy and in immunocompromised patients. In pregnancy HCMV is a more significant pathogen than all other types of congenital diseases.
  • HCMV congenital infection
  • congenital infection which is the most prominent infectious cause of congenital malformations, hearing loss and learning disabilities
  • HCMV retinitis in AIDS patients and HCMV syndrome gastrointestinal disease and pneumonia in organ transplant patients.
  • HCMV human cytomegalovirus
  • exemplary antibodies that bind human cytomegalovirus (HCMV)-related proteins, specifically antibodies that specifically bind UL16, antibodies that specifically bind UL141 and antibodies that specifically bind US28 are effective in killing cells infected with HCMV, particularly when measured using an Fc effector reporter assay (e.g. BATDA assay).
  • An aim of the present invention is to reduce the incidence or severity of HCMV infection, and to reduce the incidence or severity of HCMV -related diseases or conditions through the administration of such monoclonal antibodies.
  • the present invention provides an antibody that specifically binds to a UL16 viral protein.
  • the antibody specifically binds to the extracellular domain of a ULI 6 viral protein.
  • the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
  • the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
  • the antibody mediates killing of cells infected with HCMV. In one embodiment, the antibody mediates immune-mediated killing of cells infected with HCMV.
  • the antibody mediates NK-cell killing of cells infected with HCMV.
  • the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
  • the antibody has ADCP activity.
  • the antibody competes for binding to ULI 6 protein with MICB, ULBP1, ULBP2 and/or ULBP6.
  • the antibody blocks UL16 protein binding to MICB, ULBP1, ULBP2 and/or ULBP6.
  • the HCDR3 is the HCDR3 of antibody ATHO-OIOI
  • the HCDR3 is the HCDR3 of antibody ATHO-0102.
  • the HCDR3 is the HCDR3 of antibody ATHO-0104.
  • the HCDR3 is the HCDR3 of antibody ATHO-0105.
  • the HCDR3 is the HCDR3 of antibody ATHO-0106.
  • the HCDR3 is the HCDR3 of antibody ATHO-0109.
  • the HCDR3 is the HCDR3 of antibody ATHO-0111.
  • the HCDR3 is the HCDR3 of antibody ATHO-0112.
  • the HCDR3 is the HCDR3 of antibody ATHO-0113. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0114. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0115. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0116. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0201. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0301. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0302. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0303.
  • the HCDR3 is the HCDR3 of antibody ATHO-0401. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0501. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0601. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0701. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0801.
  • the present invention provides an anti-UL16 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801.
  • VH variable heavy
  • CDRs complementarity determining regions
  • LCDR1 variable light domain sequence
  • the antibody has the CDRs of antibody ATHO-0101. In one embodiment, the antibody has the CDRs of antibody ATHO-0102. In one embodiment, the antibody has the CDRs of antibody ATHO-0103. In one embodiment, the antibody has the CDRs of antibody ATHO-0104. In one embodiment, the antibody has the CDRs of antibody ATHO-0105. In one embodiment, the antibody has the CDRs of antibody ATHO-0106. In one embodiment, the antibody has the CDRs of antibody ATHO-0107. In one embodiment, the antibody has the CDRs of antibody ATHO-0108. In one embodiment, the antibody has the CDRs of antibody ATHO-0109.
  • the antibody has the CDRs of antibody ATHO-0303. In one embodiment, the antibody has the CDRs of antibody ATHO-0401. In one embodiment, the antibody has the CDRs of antibody ATHO-0501. In one embodiment, the antibody has the CDRs of antibody ATHO-0601. In one embodiment, the antibody has the CDRs of antibody ATHO-0701. In one embodiment, the antibody has the CDRs of antibody ATHO-0801.
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-O 106, ATHO-O 107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-O 115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-O 101, ATHO-O 102, ATHO-O 103, ATHO-
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0101, provided that the antibody has the CDRs of antibody ATHO-0101.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0102, provided that the antibody has the CDRs of antibody ATHO-0102.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0103, provided that the antibody has the CDRs of antibody ATHO-0103.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0105 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0105, provided that the antibody has the CDRs of antibody ATHO-0105.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0106 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0106, provided that the antibody has the CDRs of antibody ATHO-0106.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0107 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0107, provided that the antibody has the CDRs of antibody ATHO-0107.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0108 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0108, provided that the antibody has the CDRs of antibody ATHO-0108.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0109 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0109, provided that the antibody has the CDRs of antibody ATHO-0109.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-Ol lO and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-Ol lO, provided that the antibody has the CDRs of antibody ATHO-0110.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-O 111 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0111, provided that the antibody has the CDRs of antibody ATHO-O 111.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0112 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0112, provided that the antibody has the CDRs of antibody ATHO-0112.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0113 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0113, provided that the antibody has the CDRs of antibody ATHO-0113.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0114 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0114, provided that the antibody has the CDRs of antibody ATHO-0114.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0115 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0115, provided that the antibody has the CDRs of antibody ATHO-0115.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0116 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0116, provided that the antibody has the CDRs of antibody ATHO-0116.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0303, provided that the antibody has the CDRs of antibody ATHO-0303.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0401, provided that the antibody has the CDRs of antibody ATHO-0401.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0501, provided that the antibody has the CDRs of antibody ATHO-0501.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0601, provided that the antibody has the CDRs of antibody ATHO-0601.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0701, provided that the antibody has the CDRs of antibody ATHO-0701.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0801.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO- 0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0101.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0102.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0103.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0104.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0105.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0106.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0107.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0108.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0109.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0111.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0112.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0113.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0114.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0115.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0116.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0201.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0301. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0302.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0303.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0501.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0601.
  • the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0701.
  • the antibody is a human IgGl.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
  • the antibody is a human IgGl comprising an Fc effector enhanced constant region.
  • the antibody is a human IgGl having S239D and I332E mutations.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
  • the reference antibody may be defined by its function or by its structure (e.g. its HCDR3 sequence, its 6CDR sequences, its VH and VL sequences or its full heavy and light chain sequences) or a combination thereof as described anywhere herein.
  • the reference antibody is defined by the VH and VL sequences or by its full heavy and light chain sequences.
  • the antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient.
  • the patient is a transplant donor.
  • the patient is immunocompromised.
  • the patient has previously undergone balloon angioplasty.
  • said method further comprises administration of a further therapeutic agent.
  • said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
  • the further therapeutic agent is a further antibody.
  • the further antibody is an antibody that specifically binds to US28 protein as described anywhere herein.
  • the further therapeutic agent is an anti-viral agent.
  • the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
  • the antibody specifically binds to the extracellular domain of a UL141 viral protein.
  • the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
  • the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
  • the antibody mediates NK-cell killing of cells infected with HCMV.
  • the antibody reduces viral load of cells infected with HCMV.
  • the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
  • the antibody has CDC activity.
  • the antibody competes for binding to UL141 protein with CD 155, CD112 and/or TRAIL- R1/R2.
  • the antibody blocks UL141 protein binding to CD155, CD112 and/or TRAIL-R1/R2.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM- 0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
  • the HCDR3 is the HCDR3 of antibody ARAM-0101.
  • the HCDR3 is the HCDR3 of antibody ARAM-0102.
  • the HCDR3 is the HCDR3 of antibody ARAM-0201.
  • the HCDR3 is the HCDR3 of antibody ARAM-0202.
  • the HCDR3 is the HCDR3 of antibody ARAM-0203.
  • the HCDR3 is the HCDR3 of antibody ARAM-0301.
  • the HCDR3 is the HCDR3 of antibody ARAM-0303.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM- 0701, or ARAM-0801.
  • the antibody has the CDRs of antibody ARAM-0101.
  • the antibody has the CDRs of antibody ARAM-0103.
  • the antibody has the CDRs of antibody ARAM-0201.
  • the antibody has the CDRs of antibody ARAM-0202.
  • the antibody has the CDRs of antibody ARAM-0204.
  • the antibody has the CDRs of antibody ARAM-0301.
  • the antibody has the CDRs of antibody ARAM-0302.
  • the antibody has the CDRs of antibody ARAM-0303.
  • the antibody has the CDRs of antibody ARAM-0401.
  • the antibody has the CDRs of antibody ARAM-0501.
  • the antibody has the CDRs of antibody ARAM-0701.
  • the antibody has the CDRs of antibody ARAM-0801.
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM- 0601, ARAM-0701, or ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM- 0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-07
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0101, provided that the antibody has the CDRs of antibody ARAM-0101.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0102, provided that the antibody has the CDRs of antibody ARAM-0102.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0201, provided that the antibody has the CDRs of antibody ARAM-0201.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0202 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0202, provided that the antibody has the CDRs of antibody ARAM-0202.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0203 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0203, provided that the antibody has the CDRs of antibody ARAM-0203.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0204 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0204, provided that the antibody has the CDRs of antibody ARAM-0204.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0301, provided that the antibody has the CDRs of antibody ARAM-0301.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0302, provided that the antibody has the CDRs of antibody ARAM-0302.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0303, provided that the antibody has the CDRs of antibody ARAM-0303.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0401, provided that the antibody has the CDRs of antibody ARAM-0401.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0501, provided that the antibody has the CDRs of antibody ARAM-0501.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0601, provided that the antibody has the CDRs of antibody ARAM-0601.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0701, provided that the antibody has the CDRs of antibody ARAM-0701.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0801.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM- 0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0101.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0103.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0201.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0202.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0203.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0204.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0301.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0302.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0303. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0401.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0501.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0601.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0701.
  • the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0801.
  • the antibody is a human IgGl.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
  • the antibody is a human IgGl comprising an Fc effector enhanced constant region.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
  • the antibody comprises kappa (K) light chain constant regions.
  • an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein.
  • an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody selected from antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
  • an antibody that specifically binds to the same epitope on a UL141 protein as the epitope on a UL141 protein that is bound by a reference antibody where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein.
  • the antibody is linked to a cytotoxic agent.
  • a method of reducing frequency of HCMV virus reactivation in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein.
  • the further antibody is an antibody that specifically binds to US28 protein as described anywhere herein.
  • the cells are latently infected cells.
  • the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
  • the antibody has CDC activity.
  • the antibody has ADCP activity.
  • the HCDR3 is the HCDR3 of antibody PORT-0401.
  • the HCDR3 is the HCDR3 of antibody PORT-0501.
  • the HCDR3 is the HCDR3 of antibody PORT-0601.
  • the HCDR3 is the HCDR3 of antibody PORT-0701.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT- 0701, or PORT-0801.
  • VH variable heavy
  • CDRs complementarity determining regions
  • LCDR2 and LCDR3 variable light domain sequence
  • the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT- 0701, or PORT-0801.
  • the antibody has the CDRs of antibody PORT-0101, In one embodiment, the antibody has the CDRs of antibody PORT-0201, In one embodiment, the antibody has the CDRs of antibody PORT-0301, In one embodiment, the antibody has the CDRs of antibody PORT-0401, In one embodiment, the antibody has the CDRs of antibody PORT-0501, In one embodiment, the antibody has the CDRs of antibody PORT-0601, In one embodiment, the antibody has the CDRs of antibody PORT-0701, In one embodiment, the antibody has the CDRs of antibody PORT-0801.
  • the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0301, provided that the antibody has the CDRs of antibody PORT-0301.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0401, provided that the antibody has the CDRs of antibody PORT-0401.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0501, provided that the antibody has the CDRs of antibody PORT-0501.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT- 0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
  • the antibody comprises the VH domain and VL domain sequences of antibody PORT-0101. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0201. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0301. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0401. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0501. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0601. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0701. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0801.
  • the antibody is a human IgGl.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
  • the antibody is a human IgGl comprising an Fc effector enhanced constant region.
  • the antibody is a human IgGl having S239D and I332E mutations.
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
  • the antibody comprises kappa (K) light chain constant regions.
  • an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein.
  • an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody selected from antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801.
  • an antibody that specifically binds to the same epitope on a US28 protein as the epitope on a US28 protein that is bound by a reference antibody where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein.
  • the reference antibody may be defined by its function or by its structure (e.g. its HCDR3 sequence, its 6CDR sequences, its VH and VL sequences or its full heavy and light chain sequences) or a combination thereof as described anywhere herein.
  • the reference antibody is defined by the VH and VL sequences or by its full heavy and light chain sequences.
  • the antibody comprises VH and/or VL domain framework regions of human germline gene segment sequences.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-I*0I, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*0I, IGHVl-18*0I, IGHVl-8*0I, IGHV3-13*01, IGHV6-I*0I, or IGHV3- 21*03 with up to 1, 2, 3, 4, or 5 amino acid
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6- 1 * 01 , or IGHV 3 -21 * 03 , a human heavy chain D gene segment and a human heavy chain J gene segment, or comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations.
  • the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-I*0I, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*0I; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV3-10*01, IGKV
  • the antibody comprises an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV3- 10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and optionally the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01.
  • Example combinations of v and j gene segments for heavy and light chain variable domains are shown in Table 3, and these represent preferred combinations.
  • the heavy and light chain variable domains may optionally be derived from the v and j gene segments identified in Table 3 for any one individual PORT antibody identified in this Group C section.
  • the antibody is linked to a cytotoxic agent.
  • the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-1065, duocarmycins and anthracyclines.
  • the antibody is linked to an anti-viral agent.
  • the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X.
  • the anti-viral agent is valganciclovir.
  • the anti-viral agent is letermovir.
  • the present invention also provides a pharmaceutical composition comprising an antibody that specifically binds to US28 as defined anywhere herein and a pharmaceutically acceptable excipient.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises at least one further therapeutic agent.
  • the further therapeutic agent is a further antibody.
  • the further antibody is selected from: an antibody that specifically binds to ULI 6 protein; an antibody that specifically binds to UL141 protein; an antibody that specifically binds to US28 protein; and an antibody that specifically binds to VEGF, for example bevacizumab.
  • the further antibody is an antibody that specifically binds the same target protein as the first antibody.
  • the further antibody is selected from: an antibody that specifically binds to ULI 6 protein as defined anywhere herein; an antibody that specifically binds to UL141 protein as defined anywhere herein; an antibody that specifically binds to US28 protein as defined anywhere herein; and an antibody that specifically binds to VEGF.
  • the pharmaceutical composition comprising a first antibody that specifically binds to US28 protein as defined anywhere herein and a second antibody that specifically binds to VEGF.
  • the further therapeutic agent is an anti-viral agent.
  • the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
  • the pharmaceutical composition further comprises two or more further therapeutic agents.
  • the two or more further therapeutic agents are two or more further antibodies.
  • the pharmaceutical composition is formulated for intravenous, intramuscular or subcutaneous administration.
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use as a medicament.
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient.
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient.
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient.
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating HCMV-positive glioblastoma multiforme (GBM), said method comprising administering the antibody or composition to a patient.
  • GBM HCMV-positive glioblastoma multiforme
  • the antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating congenital HCMV infection.
  • an antibody that specifically binds to US28 as defined anywhere herein or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV infection.
  • an antibody that specifically binds to US28 as defined anywhere herein or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV -positive glioblastoma multiforme (GBM) in a patient.
  • GBM glioblastoma multiforme
  • said method further comprises administration of chemotherapy or radiotherapy.
  • an antibody that specifically binds to US28 as defined anywhere herein or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof.
  • an antibody that specifically binds to US28 as defined anywhere herein or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating congenital HCMV infection.
  • a method of treating HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
  • a method of reducing HCMV viral load in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
  • a method of reducing frequency of HCMV virus reactivation in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
  • a method of treating HCMV -positive glioblastoma multiforme (GBM) in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
  • said method further comprises administration of chemotherapy or radiotherapy.
  • the patient shows one or more symptoms of HCMV infection.
  • the patient is a transplant recipient.
  • the patient is a transplant donor.
  • the transplant is a solid organ transplant.
  • the transplant is a stem cell transplant.
  • the transplant is a haematopoietic stem cell transplant (HSCT).
  • HSCT haematopoietic stem cell transplant
  • the patient is immunosuppressed.
  • the patient is HIV positive.
  • the patient has a HCMV infection which is refractory to at least one anti-viral agent.
  • the patient is a pregnant woman.
  • the HCMV infection is associated with an inflammatory disease.
  • the patient has atherosclerosis.
  • the patient has previously undergone balloon angioplasty. In one embodiment, the patient has glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • said method further comprises administration of a further therapeutic agent.
  • said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
  • the further therapeutic agent is a further antibody.
  • the further antibody is an antibody that specifically binds to UL141 protein as described anywhere herein.
  • the further antibody is a further antibody that specifically binds to US28 protein as described anywhere herein.
  • the further antibody is an antibody that specifically binds to VEGF, for example bevacizumab.
  • the further therapeutic agent is an anti-viral agent.
  • the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
  • said method further comprises administration of two or more further therapeutic agents.
  • said method further comprises administration of two or more further antibodies.
  • a nucleic acid may comprise a sequence that encodes a VH domain and/or an VL domain of an antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of an antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes the VH domain of an antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes the VL domain of an antibody as defined anywhere herein.
  • a vector may comprise the nucleic acid as defined anywhere herein; optionally wherein the vector is a CHO vector.
  • a host cell may comprise the nucleic acid as defined anywhere herein or the vector as defined anywhere herein.
  • kits may comprise the pharmaceutical composition as defined anywhere herein.
  • the kit may further comprise at least one further therapeutic agent.
  • the further therapeutic agent is a further pharmaceutical composition comprising at least one, preferably one or two, further antibodies.
  • the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein as defined anywhere herein; b. an antibody that specifically binds to UL141 protein as defined anywhere herein; c. an antibody that specifically binds to US28 protein as defined anywhere herein; and d. an antibody that specifically binds to VEGF.
  • the further therapeutic agent is an anti-viral agent.
  • the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X .
  • the anti-viral agent is valganciclovir.
  • the anti-viral agent is letermovir.
  • the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds ULI 6 as defined anywhere herein and a pharmaceutical composition comprising a second antibody that specifically binds US28 as defined anywhere herein.
  • the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds UL141 as defined anywhere herein and a pharmaceutical composition comprising a second antibody that specifically binds US28 as defined anywhere herein.
  • the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds ULI 6 as defined anywhere herein, a pharmaceutical composition comprising a second antibody that specifically binds UL141 as defined anywhere herein, and a pharmaceutical composition comprising a third antibody that specifically binds US28 as defined anywhere herein.
  • ADCC reporter assay showing the results from the 9 strongest binding anti-UL141 antibodies. Only one of these antibodies (ARAM-0601) shows ADCC activity in this assay.
  • Negative control is an isotype human IgGl and positive control is human immune globulin Cytotect.
  • ADCC reporter assay showing the results from 7 anti-US28 antibodies. Two of these antibodies (PORT- 0601 and PORT-0501) shows ADCC activity in this assay. Negative control is an isotype human IgGl and positive control is a hybridoma anti-US28 antibody TUB-45.
  • Figure 4A BATDA ADCC assay using UL16 antibody
  • BATDA ADCC assay showing NK mediated killing of ULI 6 expressing cells in the presence of antibody ATHO-0106.
  • Human isotype IgGl is used as a negative control.
  • FIG. 4B BATDA ADCC assay using anti-US28 antibodies
  • NK cells showed significant killing of target cells expressing US28 in the presence of anti-US28 antibodies PORT-0601 and PORT-0501.
  • Human isotype IgGl is used as a negative control and human immune globulin Cytotect is used as a positive control. Both antibodies showed greater NK mediated killing compared with Cytotect.
  • FIG. 5A ADCC activity of Fc modified and unmodified antibodies against UL16
  • Antibodies with a standard IgGl Fc region or that were mutated (S239D/I332E) in the Fc region were tested for activity using the reporter ADCC assay.
  • Antibodies containing the Fc modifications showed increased Fc receptor engagement compared to the unmodified antibodies (open symbols).
  • Figure 5B ADCC activity of Fc modified clones and unmodified antibodies against UL141
  • Antibodies with a standard IgGl Fc region or that were mutated (S239D/I332E) in the Fc region were tested for activity using the reporter ADCC assay.
  • Antibodies containing the Fc modifications showed increased Fc receptor engagement compared to the unmodified antibodies (open symbols).
  • Figure 6 Anti-UL16, anti-UL141 and anti-US28 antibodies bind to HCMV infected HFF cells
  • administer refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an antibody that specifically binds UL16, an antibody that specifically binds UL141 or an antibody that specifically binds US28 provided herein, or its encoding nucleic acid e.g. in an expression vector) into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, inhalation e.g. nebulisation and/or any other method of physical delivery described herein or known in the art.
  • administration of the substance typically occurs after the onset of the disease or symptoms thereof.
  • administration of the substance typically occurs before the onset of the disease or symptoms thereof.
  • antibody immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
  • a target such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
  • variable region refers to the amino-terminal domains of the heavy or light chain of the antibody.
  • the variable domains of the heavy chain and light chain may be referred to as "VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.
  • An example of antibodies are heavy chain-only (i.e., H2) antibodies that comprise a dimer of a heavy chain (5'- VH-(optional Hinge)-CH2-CH3-3') and are devoid of a light chain.
  • the antibodies described herein may be oligoclonal, polyclonal, monoclonal (including full-length monoclonal antibodies), camelised, chimeric, CDR-grafted, multi-specific, bi-specific (including dual-binding antibodies), catalytic, chimeric, humanized, fully human, anti-idiotypic, including antibodies that can be labelled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques.
  • An antibody may be from any species.
  • Antibodies described herein can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.
  • antigen binding domain refers to that portion of an antibody which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g. the complementarity determining regions (CDRs)).
  • the antigen binding region can be derived from any animal species, such as rodents (e.g. rabbit, rat or hamster) and humans. Preferably, the antigen binding region will be of human origin.
  • Antigen binding fragments described herein can include single-chain Fvs (scFv), single- chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (diabody), anti-idiotypic (anti-Id) antibodies (including, e.g. anti-Id antibodies to antibodies), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope -binding fragments of any of the above.
  • scFv single-chain Fvs
  • dsFv disulfide-stabilised variable region
  • dimeric variable region dimeric variable region
  • anti-Id anti-idiotypic antibodies
  • intrabodies linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope -binding fragments of any of the above.
  • antibodies and antibody fragments described herein can include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallize.
  • Fab when used herein refers to a fragment of an antibody that includes one constant and one variable domain of each of the heavy and light chains.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native- sequence Fc regions and variant Fc regions.
  • the "Fc fragment” refers to the carboxy-terminal portions of both H chains held together by disulfides.
  • the effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells. Digestion of antibodies with the enzyme, pepsin, results in a F(ab')2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites.
  • the F(ab')2 fragment has the ability to crosslink antigen.
  • Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • humanized antibody refers to a subset of chimeric antibodies in which a "hypervariable region" from a non-human immunoglobulin (the donor antibody) replaces residues from a hypervariable region in a human immunoglobulin (recipient antibody).
  • a humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the framework regions are those of a human immunoglobulin sequence, although the framework regions may include one or more substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc.
  • the bispecific molecule comprises an antibody which is fused to another non-Ig format, for example a T-cell receptor binding domain; an immunoglobulin superfamily domain; an agnathan variable lymphocyte receptor; a fibronectin domain (e.g. an AdnectinTM); an antibody constant domain (e.g.
  • a CH3 domain e.g., a CH2 and/or CH3 of an FcabTM
  • the constant domain is not a functional CHI domain; an scFv; an (scFv)2; an sc- diabody; an scFab; a centyrin and an epitope binding domain derived from a scaffold selected from CTLA-4 (EvibodyTM); a lipocalin domain; Protein A such as Z-domain of Protein A (e.g. an AffibodyTM or SpA); an A- domain (e.g. an AvimerTM or MaxibodyTM); a heat shock protein (such as and epitope binding domain derived from GroEI and GroES); a transferrin domain (e.g.
  • trans-body a trans-body
  • ankyrin repeat protein e.g. a DARPinTM
  • peptide aptamer e.g. a DARPinTM
  • C-type lectin domain e.g. TetranectinTM
  • human y- crystallin or human ubiquitin an affilin
  • a PDZ domain e.g. scorpion toxin
  • a kunitz type domain of a human protease inhibitor e.g. a trans-body
  • ankyrin repeat protein e.g. a DARPinTM
  • peptide aptamer e.g. TetranectinTM
  • C-type lectin domain e.g. TetranectinTM
  • human y- crystallin or human ubiquitin an affilin
  • a PDZ domain e.g., scorpion toxin
  • kunitz type domain of a human protease inhibitor e.g.
  • the bispecific antibody is a mAb2.
  • a mAb2 comprises a VH and VL domain from an intact antibody, fused to a modified constant region, which has been engineered to form an antigen-binding site, known as an “Fcab”.
  • the technology behind the Fcab/mAb2 format is described in more detail in W02008/003103, and the description of the mAb2 format is incorporated herein by reference.
  • a “bispecific antibody” does not include a FIT-Ig format. In one example, a “bispecific antibody” does not include a mAb2 format. In one example, a “bispecific antibody” does not include either a FIT-Ig format or a mAb2 format.
  • the bispecific antibody is a “dual binding antibody”.
  • the term “dual binding antibody” is a bispecific antibody wherein both antigen-binding domains are formed by a VH/VL pair, and includes FIT-Ig (see W02015/103072, incorporated herein by reference), mAb-dAb, dock and lock, Fab-arm exchange, SEEDbody, Triomab, LUZ-Y, Fcab, K/.-body.
  • CDR region refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops.
  • antigen binding sites of an antibody include six hypervariable regions: three in the VH (CDRH1, CDRH2, CDRH3), and three in the VL (CDRL1, CDRL2, CDRL3). These regions of the heavy and light chains of an antibody confer antigenbinding specificity to the antibody.
  • CDRs may be defined according to the Kabat system (see Kabat, E. A.et al., 1991, “Sequences of Proteins of Immunological Interest”, 5th edit., NIH Publication no. 91-3242, U.S. Department of Health and Human Services).
  • CDRs may be used to define CDRs, which as the system devised by Chothia et al (see Chothia, C. & Lesk, A. M., 1987, “Canonical structures for the hypervariable regions of immunoglobulins”, J. Mol. Biol., 196, 901-917) and the IMGT system (see Lefranc, M. P., 1997, “Unique database numbering system for immunogenetic analysis”, Immunol. Today, 18, 50).
  • An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs.
  • the term CDR or CDRs is used here to indicate one or several of these regions. A person skilled in the art is able to readily compare the different systems of nomenclature and determine whether a particular sequence may be defined as a CDR.
  • a "human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies and specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • the term "specifically binds to” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
  • an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
  • the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g. by a radioimmunoassay (RIA).
  • An antibody that specifically binds to a UE16 protein antigen, an antibody that specifically binds to a UE141 protein antigen or an antibody that specifically binds to US28 protein antigen can be identified, for example, by immunoassays, BIAcoreTM, or other techniques known to those of skill in the art.
  • An antibody binds specifically to a UE16 protein antigen when it binds to a UE16 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (EEISAs).
  • RIA radioimmunoassays
  • EEISAs enzyme-linked immunosorbent assays
  • an antibody binds specifically to a UL141 protein antigen when it binds to a UL141 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISAs).
  • an antibody binds specifically to a US28 protein antigen when it binds to a US28 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISAs).
  • a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times (such as more than 15 times, more than 20 times, more than 50 times or more than 100 times) background. See, e.g. Paul, ed., 1989, Fundamental Immunology Second Edition, Raven Press, New York at pages 332-336 for a discussion regarding antibody specificity.
  • authorization number or “marketing authorization number” refers to a number issued by a regulatory agency upon that agency determining that a particular medical product and/or composition may be marketed and/or offered for sale in the area under the agency’s jurisdiction.
  • regulatory agency refers to one of the agencies responsible for evaluating, e.g. the safety and efficacy of a medical product and/or composition and controlling the sales/marketing of such products and/or compositions in a given area.
  • the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EP A) in Europe are but two examples of such regulatory agencies.
  • Other non-limiting examples can include SDA, MPA, MHPRA, IMA, ANMAT, Hong Kong Department of Health-Drug Office, CDSCO, Medsafe, and KFDA.
  • carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • composition is intended to encompass a product containing the specified ingredients (e.g. an antibody) in, optionally, the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in, optionally, the specified amounts.
  • specified ingredients e.g. an antibody
  • the term "consisting essentially of' refers to those elements required for a given example. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that example.
  • an “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired effect, including a therapeutic or prophylactic result.
  • a “therapeutically effective amount” refers to the minimum concentration required to effect a measurable improvement or prevention of a particular disorder.
  • a therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at the dosages and for periods of time necessary, to achieve the desired prophylactic result.
  • the effective amount of an antibody is from about 0.1 mg/kg (mg of antibody per kg weight of the subject) to about 100 mg/kg.
  • an effective amount of an antibody provided therein is about 0. 1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, 3 mg/kg, 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg about 90 mg/kg or about 100 mg/kg (or a range therein).
  • “effective amount” as used herein also refers to the amount of an antibody to achieve a specified result (e.g. killing a cell expressing the UL16, UL141 and/or US28 protein).
  • epitope refers to a localized region on the surface of an antigen, such as a ULI 6, UL141, or US28 protein, that is capable of being bound to one or more antigen binding regions of an antibody, and that has antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human, that is capable of eliciting an immune response.
  • An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal.
  • An epitope having antigenic activity is a portion of a polypeptide to which an antibody specifically binds as determined by any method well known in the art, for example, by the immunoassays described herein.
  • a ULI 6, UL141 or US28 protein epitope is linear feature of aUL16, UL141, or US28 protein polypeptide respectively.
  • antibodies provided herein may specifically bind to an epitope of the UL16, UL141 or US28 protein in part by using an interaction with an N-linked glycan or another post-translational modification of the protein. Binding to the respective epitope thus might involve moving the N-linked glycan or post-translational modification away thereby removing or reducing steric hindrance that would otherwise prevent or hinder antibody binding.
  • Antibodies may be provided which bind to the same epitope as an ATHO, ARAM or PORT antibody disclosed herein.
  • excipients refers to inert substances which are commonly used as a diluent, vehicle, preservatives, binders, or stabilizing agent for drugs and includes, but not limited to, proteins (e.g. serum albumin, etc.), amino acids (e.g. aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g. alkyl sulfonates, caprylate, etc.), surfactants (e.g. SDS, polysorbate, non-ionic surfactant, etc.), saccharides (e.g.
  • proteins e.g. serum albumin, etc.
  • amino acids e.g. aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.
  • fatty acids and phospholipids e.g. alkyl sulfonates, caprylate, etc.
  • sucrose, maltose, trehalose, etc. sucrose, maltose, trehalose, etc.
  • polyols e.g. mannitol, sorbitol, etc.
  • fusion protein refers to a polypeptide that comprises an amino acid sequence of an antibody and an amino acid sequence of a heterologous polypeptide or protein (i.e. a polypeptide or protein not normally a part of the antibody (e.g. a non-anti-UL16, UL141 or US28 protein antigen antibody)).
  • fusion when used in relation to an antibody refers to the joining of a peptide or polypeptide, or fragment, variant and/or derivative thereof, with a heterologous peptide or polypeptide.
  • the fusion protein retains the biological activity of the antibody that specifically binds ULI 6 protein, the antibody that specifically binds UL141 protein, or the antibody that specifically binds US28 protein.
  • heavy chain when used with reference to an antibody refers to five distinct types, called alpha (a), delta (5), epsilon (a), gamma (y) and mu (p), based on the amino acid sequence of the heavy chain constant domain.
  • These distinct types of heavy chains are well known and give rise to five classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including two subclasses of IgA, namely IgAl and IgA2 and four subclasses of IgG, namely IgGl, IgG2, IgG3 and IgG4.
  • the heavy chain is a human heavy chain.
  • the antibodies disclosed herein comprise a heavy chain encoded by a IgGl constant region allele, which includes, but is not limited to, human IGHG1 *01, IGHG1*O2, IGHGl*03, IGHG1*O4 and IGHGl*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a protein encoded by a IgG4 constant region allele, which includes but is not limited to human IGHG4*01, IGHG4*02, IGHG4*03 and IGHG4*04 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the heavy chain is an IgA isotype, human IgAl or human IgA2, example amino acid sequences for which are shown in Table 2.
  • the heavy chain is a disabled IgG isotype, e.g. a disabled IgG4.
  • the antibodies comprise a human gamma 4 constant region.
  • the heavy chain constant region comprises a S239D mutation. In some examples, the heavy chain constant region comprises a I332E mutation. In some examples, the heavy chain constant region comprises the double mutation S239D/I332E. In some examples, the heavy chain constant region comprises the triple mutation S239D/I332E/A330L.
  • a first therapy can be administered before (e.g. 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently, or after (e.g.
  • injection device refers to a device that is designed for carrying out injections, an injection including the steps of temporarily fluidically coupling the injection device to a person's tissue, typically the subcutaneous tissue. An injection further includes administering an amount of liquid drug into the tissue and decoupling or removing the injection device from the tissue.
  • an injection device can be an intravenous device or IV device, which is a type of injection device used when the target tissue is the blood within the circulatory system, e.g. the blood in a vein.
  • IV device a type of injection device used when the target tissue is the blood within the circulatory system, e.g. the blood in a vein.
  • a common, but non-limiting example of an injection device is a needle and syringe.
  • instructions refers to a display of written, printed or graphic matter on the immediate container of an article, for example the written material displayed on a vial containing a pharmaceutically active agent, or details on the composition and use of a product of interest included in a kit containing a composition of interest. Instructions set forth the method of the treatment as contemplated to be administered or performed.
  • an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”).
  • heterologous protein also referred to herein as a “contaminating protein”.
  • the antibody is recombinantly produced, it is also preferably substantially free of culture medium, i.e. culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the antibody is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest.
  • antibodies are isolated or purified.
  • Kabat numbering and like terms are recognized in the art and refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al., (1971) Ann. NY Acad. Sci., 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242).
  • the hypervariable region typically ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3.
  • Label refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label, chemiluminescent label or a biotinyl group or gold.
  • Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, 115In, 1251, 1311, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, P-galactosidase, luciferase, alkaline phosphatase.
  • Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH”), alpha-D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes (e.g. cyanine dyes, e.g. Cy5TM, Cy5.5TM. or Cy7TM); additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein”), other fluorescent proteins (e.g.
  • fluorophores such as lanthanide cryptates and chelates e.g.
  • chemoluminescent labels or chemiluminescers such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5- bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, sap
  • light chain when used in reference to an antibody refers to the immunoglobulin light chains, of which there are two types in mammals, lambda (X) and kappa (K).
  • the light chain is a human light chain.
  • the light chain constant region is a human constant region. In the human population, multiple light chain constant region alleles exist.
  • the nucleotide and amino acid sequences of these allelic variants are accessible on publicly available databases such as IMGT, ENSEMBL, Swiss-Prot and Uniprot.
  • the antibodies disclosed herein comprise a protein encoded by a human K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*02, IGKC*03, IGKC*04 and IGKC*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a protein encoded by a human X constant region allele, which includes but is not limited to IGLC1*OI, IGLC1*O2, IGLC2*01, IGLC2*02, IGLC2*03, IGLC3*01, IGLC3*02, IGLC3*03, IGLC3*04, IGLC6*01, IGLC7*01, IGLC7*02, and IGLC7*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a light chain constant region encoded by a mouse K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*03 or IGKC*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a light chain constant region encoded by a mouse X constant region allele, which includes, but is not limited to, IGLCl*01, IGLC2*01 or IGLC3*01 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Percent (%) amino acid sequence identity with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEG ALIGNTM (DNASTAR) software. In one example, the % identity is about 70%. In one example, the % identity is about 75%.
  • the % identity is about 80%. In one example, the % identity is about 85%. In one example, the % identity is about 90%. In one example, the % identity is about 92%. In one example, the % identity is about 95%. In one example, the % identity is about 97%. In one example, the % identity is about 98%. In one example, the % identity is about 99%. In one example, the % identity is 100%.
  • naturally occurring or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to those which are found in nature and not manipulated by a human being.
  • pharmaceutically acceptable means being approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
  • nucleic acid molecule As used herein, the term “polynucleotide,” “nucleotide,” nucleic acid” “nucleic acid molecule” and other similar terms are used interchangeable and include DNA, RNA, mRNA and the like.
  • the terms “prevent”, “preventing”, and “prevention” refer to the total or partial inhibition of the development, recurrence, onset or spread of HCMV infection or a HCMV-related disease or condition, and/or symptom related thereto, resulting from the administration of a therapy or combination of therapies provided herein (e.g. a combination of prophylactic or therapeutic agents, such as an antibody).
  • a therapy or combination of therapies provided herein (e.g. a combination of prophylactic or therapeutic agents, such as an antibody).
  • soluble refers to a polypeptide that is lacking one or more transmembrane or cytoplasmic domains found in the native or membrane-associated form. In one example, the "soluble" form of a polypeptide lacks both the transmembrane domain and the cytoplasmic domain.
  • subject or “patient” refers to any animal, including, but not limited to, mammals.
  • mammal refers to any vertebrate animal that suckle their young and either give birth to living young (eutharian or placental mammals) or are egg-laying (metatharian or nonplacental mammals).
  • mammalian species include, but are not limited to, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats (including cotton rats) and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • surfactant refers to organic substances having amphipathic structures; namely, they are composed of groups of opposing solubility tendencies, typically an oil-soluble hydrocarbon chain and a water-soluble ionic group. Surfactants can be classified, depending on the charge of the surface -active moiety, into anionic, cationic, and non-ionic surfactants. Surfactants are often used as wetting, emulsifying, solubilizing, and dispersing agents for various pharmaceutical compositions and preparations of biological materials.
  • the term “tag” refers to any type of moiety that is attached to, e.g. a polypeptide and/or a polynucleotide that encodes an antibody that specifically binds ULI 6 protein, an antibody that specifically binds UL141 protein or an antibody that specifically binds US28 protein.
  • a polynucleotide that encodes an antibody that specifically binds ULI 6 protein, an antibody that specifically binds UL141 protein or an antibody that specifically binds US28 protein can contain one or more additional tag-encoding nucleotide sequences that encode e.g. a detectable moiety or a moiety that aids in affinity purification.
  • the tag and the antibody When translated, the tag and the antibody can be in the form of a fusion protein.
  • the term “detectable” or “detection” with reference to a tag refers to any tag that is capable of being visualized or wherein the presence of the tag is otherwise able to be determined and/or measured (e.g. by quantitation).
  • a non-limiting example of a detectable tag is a fluorescent tag.
  • treat refers to the reduction or amelioration of the progression, severity, and/or duration of a HCMV infection or HMCV-related disease or condition resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody). In specific examples, such terms refer to the inhibition or reduction of one or more symptoms associated with a HCMV infection or HMCV-related disease or condition.
  • HCMV is not eliminated by the immune system and instead establishes latency and persistence. Like other members of the herpesvirus family, it remains dormant in cells throughout the body and asymptomatic reactivation can occur throughout life.
  • the HCMV genome is maintained as a DNA episome with little or no major viral protein synthesis or virus production.
  • HCMV high species specificity productive infection can be established in nearly every tissue in humans.
  • HCMV infection or reactivation causes significant morbidity, some mortality and can limit organ engraftment. In-utero or peri/post- natal infection can cause significant disease and permanent damage to a child.
  • HCMV HCMV hematopoietic progenitor cells of the myeloid lineage.
  • HCMV has a double stranded DNA genome of 235-kb encoding for -170 genes.
  • cytomegalovirus gene products are of importance in cytomegalovirus immunity, for example multiple virally encoded glycoproteins such as glycoprotein B (gB) and glycoprotein H (gH) are the targets of neutralizing antibodies, and cytotoxic T-cell (CTL) responses exist against various HCMV proteins, the immune response is insufficient to prevent reinfection (superinfection) as demonstrated by the presence of extensive HCMV genetic recombination and is inadequate in preventing trans-placental infection, which can occur even in women who are HCMV seropositive.
  • gB glycoprotein B
  • gH glycoprotein H
  • CTL cytotoxic T-cell
  • Flow cytometry assays based on the difference in cell surface expression of certain proteins in the latent phase as compared to the lytic phase have been developed to determine whether HCMV infected cells are in the latent or lytic phase. Such assays have been described, for example in WO2015/073788, the contents of which are hereby incorporated by reference. Certain proteins for which plasma membrane expression was upregulated following HCMV infection were identified by cell surface proteomics in WO2015/073788.
  • the anti-UL16 antibody mediates killing of cells infected with HCMV. In an example, the anti- UL 16 antibody mediates killing of ULI 6 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody mediates killing of ULI 6 protein expressing cells lyrically infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of cells infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of UL16 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of ULI 6 protein expressing cells lytically infected with HCMV.
  • the antibody is selected from the group consisting of ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, and ATHO-0801.
  • the antibody is selected from the group consisting of ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, and ATHO-0116 (lineage 1 in Figures 2A and 2B).
  • the antibody is selected from the group consisting of ATHO-0301, ATHO-0302, and ATHO-0303 (lineage 2 in Figures 2C and 2D).
  • the antibody is selected from the group consisting of ATHO-0201, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, and ATHO-0801 (singletons in Figures 2E and 2F).
  • the antibody is ATHO-0101.
  • the antibody is ATHO-0102.
  • the antibody is ATHO-0103.
  • the antibody is ATHO-0104.
  • the antibody is ATHO- 0105.
  • the antibody is ATHO-0106.
  • the antibody is ATHO-0107.
  • the antibody is ATHO-0108.
  • the antibody is ATHO-0109. In one example the antibody is ATHO-0110. In one example the antibody is ATHO-0111. In one example the antibody is ATHO-0112.
  • the antibody is ATHO-0113. In one example the antibody is ATHO-0114. In one example the antibody is ATHO-0115. In one example the antibody is ATHO-0116. In one example the antibody is ATHO-0201. In one example the antibody is ATHO-0301. In one example the antibody is ATHO-0302. In one example the antibody is ATHO-0303. In one example the antibody is ATHO-0401. In one example the antibody is ATHO- 0501. In one example the antibody is ATHO-0601. In one example the antibody is ATHO-0701. In one example the antibody is ATHO-0801.
  • Antibody ATHO-0101 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 111, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 110.
  • Antibody ATHO-0101 has a light chain variable region (VL) amino acid sequence of Seq ID No: 116, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 115.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0102 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 121, comprising the CDRH1 amino acid sequence of Seq ID No: 122 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 123 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 120.
  • Antibody ATHO-0102 has a light chain variable region (VL) amino acid sequence of Seq ID No: 125, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 124.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0103 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 128, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 127.
  • Antibody ATHO-0103 has a light chain variable region (VL) amino acid sequence of Seq ID No: 130, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 129.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0104 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 132, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 133 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 134 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 131.
  • Antibody ATHO-0104 has a light chain variable region (VL) amino acid sequence of Seq ID No: 136, comprising the CDRL1 amino acid sequence of Seq ID No: 137 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 138 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 135.
  • the VH domain may be combined with any ofthe heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0105 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 140, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 139.
  • Antibody ATHO-0105 has a light chain variable region (VL) amino acid sequence of Seq ID No: 142, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 143 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 141.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0107 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 150, comprising the CDRH1 amino acid sequence of Seq ID No: 151 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 152 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 149.
  • Antibody ATHO-0107 has a light chain variable region (VL) amino acid sequence of Seq ID No: 154, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 153.
  • the VH domain may be combined with any ofthe heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0108 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 156, comprising the CDRH1 amino acid sequence of Seq ID No: 157 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 123 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 158 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 155.
  • Antibody ATHO-0109 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 163, comprising the CDRH1 amino acid sequence of Seq ID No: 164 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 165 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 166 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 162.
  • Antibody ATHO-0109 has a light chain variable region (VL) amino acid sequence of Seq ID No: 168, comprising the CDRL1 amino acid sequence of Seq ID No: 169 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 167.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0110 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 171, comprising the CDRH1 amino acid sequence of Seq ID No: 172 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 170.
  • Antibody ATHO-0110 has a light chain variable region (VL) amino acid sequence of Seq ID No: 174, comprising the CDRL1 amino acid sequence of Seq ID No: 175 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 173.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0111 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 177, comprising the CDRH1 amino acid sequence of Seq ID No: 178 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 179 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 180 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 176.
  • Antibody ATHO-0112 has a light chain variable region (VL) amino acid sequence of Seq ID No: 188, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 143 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 187.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0114 has a light chain variable region (VL) amino acid sequence of Seq ID No: 197, comprising the CDRL1 amino acid sequence of Seq ID No: 169 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 198 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 196.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0115 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 200, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 201 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 199.
  • Antibody ATHO-0115 has a light chain variable region (VL) amino acid sequence of Seq ID No: 203, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 138 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 202.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0116 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 205, comprising the CDRH1 amino acid sequence of Seq ID No: 206 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 204.
  • Antibody ATHO-0116 has a light chain variable region (VL) amino acid sequence of Seq ID No: 208, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 207.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0201 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 210, comprising the CDRH1 amino acid sequence of Seq ID No: 211 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 212 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 213 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 209.
  • Antibody ATHO-0201 has a light chain variable region (VL) amino acid sequence of Seq ID No: 215, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 217 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 218 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 214.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0301 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 220, comprising the CDRH1 amino acid sequence of Seq ID No: 221 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 222 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 223 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 219.
  • Antibody ATHO-0301 has a light chain variable region (VL) amino acid sequence of Seq ID No: 225, comprising the CDRL1 amino acid sequence of Seq ID No: 226 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 227 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 228 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 224.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ATHO-0302 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 230, comprising the CDRH1 amino acid sequence of Seq ID No: 231 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 232 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 233 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 229.
  • Antibody ATHO-0501 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 255, comprising the CDRH1 amino acid sequence of Seq ID No: 256 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 257 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 258 (IMGT).
  • VH heavy chain variable region
  • IMGT CDRH1 amino acid sequence of Seq ID No: 256
  • IMGT CDRH2 amino acid sequence of Seq ID No: 257
  • IMGT CDRH3 amino acid sequence of Seq ID No: 258
  • Antibody ATHO-0601 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 265, comprising the CDRH1 amino acid sequence of Seq ID No: 266 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 267 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 268 (IMGT).
  • VH heavy chain variable region
  • IMGT CDRH1 amino acid sequence of Seq ID No: 266
  • IMGT CDRH2 amino acid sequence of Seq ID No: 267
  • IMGT CDRH3 amino acid sequence of Seq ID No: 268
  • Antibody ATHO-0801 has a light chain variable region (VL) amino acid sequence of Seq ID No: 288, comprising the CDRL1 amino acid sequence of Seq ID No: 289 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 217 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 290 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 287.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the present disclosure describes antibodies of the invention that specifically bind to a ULI 6 protein and which are defined by their function and/ or by their structure.
  • the invention also provides antibodies that compete with those antibodies described herein for binding to the target ULI 6 protein. Such competition may be due, for example, to the antibody binding to an identical or overlapping epitope of the ULI 6 protein as the reference antibody. Such a ‘competing’ antibody may retain the same function as the reference antibody with which it competes.
  • An antibody that binds to an identical (same) epitope can be expected to have the same function as the reference antibody with which it competes.
  • the present inventors are the first to discover ‘active’ epitopes on ULI 6 protein which can be targeted with an antibody for cell killing.
  • An antibody of the present invention may be one which binds to the same epitope on a ULI 6 protein as any antibody described herein, such as ATHO-0101, ATHO-0102, ATHO-O 103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801 as defined herein.
  • an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody binds to the same epitope on a ULI 6 protein as a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a ULI 6 protein.
  • Antibodies that specifically bind ULI 6 described herein are therefore useful as medicaments.
  • antibodies that specifically bind ULI 6 described herein may be useful in treating HCMV infection.
  • antibodies that specifically bind ULI 6 described herein may be useful in a method of reducing HCMV viral load in a patient.
  • antibodies that specifically bind ULI 6 described herein may be useful in a method of reducing frequency of HCMV virus reactivation in a patient is also provided.
  • antibodies that specifically bind ULI 6 described herein may be useful in a method of preventing HCMV infection in a patient at risk of thereof.
  • antibodies that specifically bind ULI 6 described herein may be useful in a method of treating congenital HCMV infection is also provided.
  • prophylaxis against HCMV infection in HCMV seronegative pregnant women in the first trimester to prevent high risk transmission of HCMV to foetus.
  • prophylaxis against HCMV infection in HCMV seropositive pregnant women in the first trimester to prevent transmission of HCMV to foetus leading to asymptomatic infection at birth.
  • NK activating ligands from the cell surface on infected cells markedly inhibits NK killing of those cells 2,3 .
  • Recent structural studies have shown high affinity dimeric binding to TRAIL-R2 and CD 155 (and low affinity binding to TRAIL-R1) forming a heterotetrameric complex 6,7 .
  • UL141 is located in the UL/b’ region of the HCMV genome that is frequently deleted in extensively passaged laboratory strains of HCMV 2,4,7 .
  • Table 4 shows the amino acid sequences for ligands of UL141.
  • Antibodies that specifically bind UL141 protein are provided.
  • An antibody of the present invention may be one which competes for binding to the UL141 protein with any ARAM antibody described herein, such as ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM- 0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
  • the antibody is selected from the group consisting of ARAM-0201, ARAM-0202, ARAM- 0203, and ARAM-0204, (lineage 2 in Figures 21 and 2J). In one example, the antibody is selected from the group consisting of ARAM-0301, ARAM-0302 and ARAM-0303 (lineage 3 in Figures 2K and 2L). In one example, the antibody is selected from the group consisting of ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, and ARAM-0801 (singletons in Figures 2M and 2N). In one example the antibody is ARAM- 0101. In one example the antibody is ARAM-0102. In one example the antibody is ARAM-0103.
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 14.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 6.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0201 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 21, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 20.
  • Antibody ARAM-0201 has a light chain variable region (VL) amino acid sequence of Seq ID No: 26, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 25.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0202 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 31, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 30.
  • Antibody ARAM-0202 has a light chain variable region (VL) amino acid sequence of Seq ID No: 33, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 32.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0203 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 35, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 34.
  • Antibody ARAM-0203 has a light chain variable region (VL) amino acid sequence of Seq ID No: 37, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 38 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 36.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0204 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 40, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 39.
  • Antibody ARAM-0204 has a light chain variable region (VL) amino acid sequence of Seq ID No: 42, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 41.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0301 has a light chain variable region (VL) amino acid sequence of Seq ID No: 49, comprising the CDRL1 amino acid sequence of Seq ID No: 50 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 52 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 48.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0302 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 54, comprising the CDRH1 amino acid sequence of Seq ID No: 45 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 46 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 47 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 53.
  • Antibody ARAM-0302 has a light chain variable region (VL) amino acid sequence of Seq ID No: 49, comprising the CDRL1 amino acid sequence of Seq ID No: 50 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 52 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 48.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0303 has a light chain variable region (VL) amino acid sequence of Seq ID No: 61, comprising the CDRL1 amino acid sequence of Seq ID No: 62 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 63 (IMGT).
  • VL light chain variable region
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 60.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0701 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 94, comprising the CDRH1 amino acid sequence of Seq ID No: 95 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 4 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 96 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 93.
  • Antibody ARAM-0701 has a light chain variable region (VL) amino acid sequence of Seq ID No: 98, comprising the CDRL1 amino acid sequence of Seq ID No: 99 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 17 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 100 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 97.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody ARAM-0801 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 102, comprising the CDRH1 amino acid sequence of Seq ID No: 103 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 104 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 105 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is Seq ID No: 101.
  • Antibody ARAM-0801 has a light chain variable region (VL) amino acid sequence of Seq ID No: 107, comprising the CDRL1 amino acid sequence of Seq ID No: 108 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 109 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is Seq ID No: 106.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the present disclosure describes antibodies of the invention that specifically bind to a UL141 protein and which are defined by their function and/ or by their structure.
  • the invention also provides antibodies that compete with those antibodies described herein for binding to the target UL141 protein. Such competition may be due, for example, to the antibody binding to an identical or overlapping epitope of the UL141 protein as the reference antibody. Such a ‘competing’ antibody may retain the same function as the reference antibody with which it competes.
  • An antibody that binds to an identical (same) epitope can be expected to have the same function as the reference antibody with which it competes.
  • the present inventors are the first to discover ‘active’ epitopes on UL141 protein which can be targeted with an antibody for cell killing.
  • an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein.
  • an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody selected from antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801 as defined by the VH and VL sequences.
  • the reference antibody is in IgGl format.
  • the reference antibody is in ScFv format.
  • an antibody that specifically binds to a UL141 protein is provided, wherein said antibody binds to the same epitope on a UL141 protein as a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein.
  • Antibodies that specifically bind UL141 described herein are therefore useful as medicaments.
  • antibodies that specifically bind UL141 described herein may be useful in treating HCMV infection.
  • antibodies that specifically bind UL141 described herein may be useful in a method of reducing HCMV viral load in a patient.
  • antibodies that specifically bind UL141 described herein may be useful in a method of reducing frequency of HCMV virus reactivation in a patient is also provided.
  • antibodies that specifically bind UL141 described herein may be useful in a method of preventing HCMV infection in a patient at risk of thereof.
  • antibodies that specifically bind UL141 described herein may be useful in a method of treating congenital HCMV infection is also provided.
  • the patient shows one or more symptoms of HCMV infection.
  • the patient is a transplant recipient.
  • the patient is a transplant donor.
  • the transplant is a solid organ transplant.
  • the transplant is a stem cell transplant.
  • the transplant is a haematopoietic stem cell transplant (HSCT).
  • the patient is immunosuppressed.
  • the patient is immunocompromised.
  • the patient is HIV positive.
  • the patient has previously been treated with an anti-viral agent.
  • the patient has a HCMV infection which is refractory to at least one anti-viral agent.
  • the patient is a pregnant woman.
  • the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty.
  • the patient has glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • Antibodies that specifically bind US28 protein are provided.
  • the antibodies specifically bind the extracellular domain of the US28 protein.
  • Such antibodies binding the extracellular domain of US28 may or may not compete with one or more of the respective ligands for binding to US28 respectively and thus may or may not directly inhibit binding of US28 to the ligand.
  • antibodies that specifically bind to US28 protein which mediate killing of HCMV infected cells are provided.
  • the antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region.
  • An effector enabled antibody may recruit natural killer cells to infected cells to achieve ADCC.
  • the anti-US28 antibody mediates NK-cell killing of cells infected with HCMV. In an example, the anti-US28 antibody mediates NK-cell killing of US28 protein expressing cells infected with HCMV. In an example, the anti-US28 antibody mediates NK-cell killing of US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells.
  • an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein.
  • an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody selected from antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801 as defined by the VH and VL sequences.
  • the reference antibody is in IgGl format.
  • the reference antibody is in ScFv format.
  • prophylaxis against HCMV infection in HCMV seronegative pregnant women in the first trimester to prevent high risk transmission of HCMV to foetus prophylaxis against HCMV infection in HCMV seropositive pregnant women in the first trimester to prevent transmission of HCMV to foetus leading to asymptomatic infection at birth.
  • An efficacious antibody that specifically binds US28 should reduce the prevalence of HCMV disease providing an associated reduction in morbidity and improved allograft outcomes.
  • the prevention of HCMV infection is a potential goal in seronegative recipients, but the key outcome would be reduction in disease.
  • KD is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction. Affinity of antibody-antigen binding may be determined, e.g., by SPR. Affinity may also be determined by bio-layer interferometry.
  • an antibody may bind to a UL 16, UL 141 or US28 protein with an affinity (KD) of 1 mM or less, preferably less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, as determined by SPR.
  • the antibody may bind to a ULI 6, UL141 or US28 protein with a KD of less than 10 nM (e.g.
  • an antibody may bind to a UL16, UL141 or US28 protein with KD of O.lnM or less, as determined by SPR. In some examples, an antibody may bind to a UL16, UL141 or US28 protein with a KD of 50pM or less, as determined by SPR. Binding and binding affinity can be determined to various purified UL16, UL141 or US28 proteins and sub-domains, for example, the extracellular domain of UL16, UL141 or US28, or mutations to UL16, UL141 or US28 proteins observed in clinical isolates. If the antibody epitope is a linear continuous epitope, then binding and binding affinity can be determined using synthetic purified peptide sequences.
  • Regeneration of the capture surface can be carried out with 3 M magnesium chloride solution. This removes the captured test antibody and allows the surface to be used for another interaction.
  • the binding data can be fitted to 1 : 1 model inherent using standard techniques, e.g. using analysis software such as Biacore Insight Evaluation Software.
  • Cells express ULI 6, UL141 and/or US28 as a consequence of infection with HCMV, thus the antibodies described herein may be useful in killing HCMV infected cells, specifically HCMV infected cells expressing ULI 6, UL141 and/or US28 proteins, thus being useful in therapy and prophylaxis to prevent infection with HCMV.
  • the antibody mediates killing of cells infected with HCMV. In an example, the antibody mediates killing of UL16, UL141 or US28 protein expressing cells infected with HCMV. In an example, the antibody mediates killing of UL16, UL141 or US28 protein expressing cells lytically infected with HCMV. In one example, the killing of cells infected with HCMV is immune-mediated. In one example, the killing of cells infected with HCMV is mediated by NK cells.
  • ADCC is a killing mechanism by which antibodies target specific cells for elimination.
  • the classic protocol relies on the use of primary human Natural Killer (NK) cells isolated from blood donors that have, on their surface, FCyRIIIa receptors, which can bind the Fc portion of an antibody and activate the NK cell to kill the target cell to which the antibody is bound.
  • NK Natural Killer
  • the cells expressing the target of interest E.g HEK cells expressing US28 or Uli 6 or UL141 on their surface, or possibly cells infected with HCMV in vitro
  • effector NK cells which express FcyRIIIa, that in the presence of an ADCC-enabled antibody will induce cell killing.
  • the ADCC activity is calculated as a fold induction by dividing the well sample signal by the control wells, where no antibody was added to the target and effector cells.
  • Fluorescent (BADTA), colourimetric or radioactive (eg chromium-51 release) substrates can be used as the readout to measure cell killing in these assays.
  • human NK cells (either as PBMCs or purified NK cells) are incubated with cells expressing the target of interest (e.g HEK cells expressing US28 or U116 or UL141 on their surface) and in the presence of an ADCC-enabled antibody NK cells are activated and express markers of degranulation which can be detected using fluorescent antibodies in flow cytometry.
  • the ADCC activity can be expressed as the percent of NK cells that are positive for degranulation markers, such as CD 107a.
  • the antibodies kill infected cells with an IC50 of lOnM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of InM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 500pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of lOOpM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 50pM or lower (e.g.
  • the antibodies kill infected cells with an IC50 of lOnM or lower (e.g. as determined in aNK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of InM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 500pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of lOOpM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 50pM or lower (e.g.
  • the antibodies may kill infected cells with an activity level which is greater than a reference antibody.
  • the reference antibody may be Cytotect.
  • the antibodies may kill infected cells with an activity level which is greater than the reference antibody expressed as fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 2-fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 25-fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 50-fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 100-fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 500-fold change relative to the reference antibody.
  • the antibody may kill infected cells with an activity level greater than a 1000-fold change relative to the reference antibody.
  • the cell line to be used for measuring the activity level as compared to a reference antibody such as the polyclonal antibody Cytotect will vary depending on the antibody being tested and the target prtein to which it binds. This is due to differential protein expression of different cell lines. Recombinant, overexpressing cell lines such as HEK293 cells or HFF (human foreskin fibroblast) cells overexpressing the target viral protein suitably may be used. Cytotect is particularly suitable as a refemce antibody for anti-US28 antibodies due to high levels of anti-US28 antibodies in the polyclonal antibody. (iv) Fc Effector Function
  • the antibodies of the invention may have ADCC, CDC or ADCP activity.
  • the antibodies may have ADCC activity.
  • ADCC is an immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing tumor- or pathogen-derived antigens on their surface. ADCC is largely mediated by NK cells through the CD 16 (FcyRIII) receptor that binds the Fc portion of IgG antibodies triggering the lysis of targeted cells. In humans, ADCC effector function generally is highest for IgGl.
  • CDC is triggered by binding of antibody - antigen complexes to the complement component Clq.
  • antibodies of the IgG subclasses IgGl, IgG2 and IgG3 as well as IgM antibodies are generally capable of initiating the classical complement pathway.
  • ADCC Activity and Measurement The antibodies described herein may have ADCC activity.
  • ADCC activity may be measure in, for example, an Fc Effector Reporter Assay.
  • the ADCC activity of the antibody is sufficient to achieve at least 50% inhibtion in an Fc effector reporter assay.
  • the ADCC activity of the antibody is sufficient to achieve at least 50% killing of infected cells (e.g. as determined in an Fc effector reporter assay).
  • NK Natural Killer
  • FCyRIIIa receptors which can bind the Fc portion of an antibody and activate the NK cell to kill the target cell to which the antibody is bound.
  • Reporter assays provide a simpler and more cost effecive alternative to primary assays.
  • the cells expressing the target of interest E.g HEK cells expressing US28 or U116 or UL141 on their surface
  • effector cells expressing human FcyRIIIa that in the presence of an ADCC-enabled antibody produce luciferase in a concentration dependent manner.
  • ADCC activity is calculated as a fold induction by dividing the well sample signal by the control wells, where no antibody was added to the target and effector cells.
  • the antibodies described herein may have ADCP activity.
  • ADCP activity may be measure in, for example, an Fc Effector Reporter Assay.
  • target-expressing cells are incubated with an antibody, in the presence of human serum containing either active or heat-inactivated complement.
  • Dead-cell protease activity which is released from cells that have lost membrane integrity, is measured as an indicator of cell lysis.
  • Other readouts of cell lysis could include radioactive signal or flow cytometry.
  • Assays can also be performed with recombinant complement proteins in place of primary human serum.
  • preventing or inhibiting binding of US28 to CX3C chemokine fractalkine/CX3CLl also can be expected to be advantageous.
  • Chemokine binding to US28 can induce an array of cellular responses which may favour virus replication.
  • Table 4 shows the amino acid sequences for ligands of US28.
  • the antibodies provided may inhibit the UL16, UL141 or US28 protein binding to one or more of their respective ligands.
  • an antibody specifically binds to the extracellular domain of the UL16, UL141 or US28 protein, wherein the antibody partially or completely inhibits the UL16, UL141 or US28 protein binding to one or more of the respective ligands for UL16, UL141 or US28.
  • the antibody partially or completely inhibits binding of UL16, UL141 or US28 to soluble versions of one or more of the respective ligands.
  • inhibition may be by competition for binding of UL16, UL141 or US28 protein to one or more of the respective ligands for UL16, UL141 or US28 (whether for the same epitope or by steric hindrance).
  • the epitope to which the antibody binds completely blocks the binding site of the UL16, UL141 or US28 protein to its ligand, then ligand binding is completely prevented (which may be a physical blocking - in the case of overlapping epitopes - or steric blocking - where the antagonist is large such that it prevents the ligand binding to its distinct epitope). If the epitope to which the antibody binds partially blocks the binding site of the UL16, UL141 or US28 protein to its ligand, the ligand may be able to bind, but only weakly (in the case of partial inhibition), or in a different orientation to the natural binding interaction.
  • Whether an antibody competes with one or more of the respective ligands for UL 16, UL 141 or US28 for binding to UL16, UL141 or US28 protein may be measured using a competition assay.
  • Competition may be determined by surface plasmon resonance (SPR), such techniques being readily apparent to the skilled person.
  • SPR may be carried out using BiacoreTM, ProteonTM or another standard SPR technique.
  • Such competition may be due, for example, to the antibodies or fragments binding to identical or overlapping epitopes of the ULI 6, UL141 or US28 protein to that which the one or more of the respective ligands for UL16, UL141 or US28 binds.
  • competition is determined by ELISA, such techniques being readily apparent to the skilled person.
  • competition is determined by homogenous time resolved fluorescence (HTRF), such techniques being readily apparent to the skilled person.
  • competition is determined by fluorescence activated cell sorting (FACS), such techniques being readily apparent to the skilled person.
  • FACS fluorescence activated cell sorting
  • competition is determined by ForteBio Octet® Bio-Layer Interferometry (BLI) such techniques being readily apparent to the skilled person.
  • the antibody competes (e.g. in a dose-dependent manner) with one or more of the respective ligands for UL16, UL141 or US28 (or a fusion protein thereof) for binding to UL16, UL141 or US28.
  • the one or more respective ligands may be in a soluble form or may be expressed on the surface of cells.
  • the antibody is a monoclonal antibody.
  • Methods of making monoclonal antibodies are known and include, for example, fusing myeloma cells with the cells from an animal that was immunized with the desired antigen.
  • the monoclonal antibodies may be generated using recombinant DNA technology.
  • the antibody is a monoclonal antibody that specifically binds UL16, UL141 or US28 protein.
  • the antibody is a fully human monoclonal antibody.
  • the antibody is a human antibody. In one example, the antibody is a fully human antibody.
  • the antibody is a fully human monoclonal antibody.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of any one of the antibodies described herein and set out in Table 1.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% (preferably 95%, more preferably 98%) identity to the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, provided that the antibody has the CDRs of said antibody described herein and set out in Table 1.
  • antibody sequences were recovered from antigen-binding B cells or from plasma cells from immunised mice as described elsewhere herein, and grouped into the clusters shown in Figure 2 using bioinformatics analysis. It will be understood that antibodies in the same cluster ( Figure 2) share a degree of sequence identity and/ or conserved sequences. As such, antibodies in the same cluster might be considered as ‘sibling antibodies’. Sibling antibodies are within the scope of the present invention.
  • the present invention provides an expanded group of antibodies consisting of any antibody disclosed herein together with its sibling antibodies.
  • the present invention provides an expanded group of antibodies consisting of any group of antibodies disclosed herein together with their sibling antibodies.
  • the present invention also provides antibodies having at least 90% (preferably 95%, more preferably 98%) identity to the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, provided that any substitutions in the VH and VL domain sequences are to amino acid residues present in a sibling antibody in the same cluster disclosed herein.
  • the present invention also provides antibodies comprising a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, optionally with 1, 2, 3, 4 or 5 amino acid substitutions in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid substitutions in the variable light (VL) domain sequence, provided that any substitutions in the VH and VL domain sequences are to amino acid residues present in a sibling antibody in the same cluster disclosed herein.
  • an antibody may comprise the VH and VL domain of an ATHO, ARAM or PORT antibody disclosed herein, with one or more substitutions in framework regions, where those one or more substitutions are at positions shown to be variable in the cluster (optionally, at positions that vary between siblings obtained from antigen-binding B cells in the cluster and/or siblings for which assay data are presented herein).
  • the substituted residue is the amino acid residue present in the sibling sequence (preferably, the sequence of a sibling obtained from an antigen-binding B cell or a sibling for which assay data are presented herein).
  • sibling sequence preferably, the sequence of a sibling obtained from an antigen-binding B cell or a sibling for which assay data are presented herein.
  • siblings which were recovered from plasma cells (i.e., not recovered via antigen-binding of their expressing B cell) and for which assay data are not shown herein may optionally be discounted for this analysis.
  • the clusters are shown in Figure 2.
  • the resulting antibody may be tested (e.g., in one or more assays described herein) to confirm that affinity and/or potency are retained.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1.
  • variable heavy chain VH only of any antibody described herein.
  • variable light chain (VL) only of any antibody described herein. (viii) Sequence Identity
  • the antibody comprises an amino acid sequence which has a high level of sequence identity to the amino acid sequence of one of the exemplary antibodies described herein and set out in Table 1.
  • the amino acid sequence is at least 70% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 75% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 95% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 96% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 97% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 98% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 99% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 99.5% identical to the specified SEQ ID No.
  • the antibody comprises amino acid substitutions.
  • Amino acid substitutions include alterations in which an amino acid is replaced with a different naturally- occurring amino acid residue. Such substitutions may be classified as “conservative", in which case an amino acid residue contained in a polypeptide is replaced with another naturally occurring amino acid of similar character either in relation to polarity, side chain functionality or size. Such conservative substitutions are well known in the art. Substitutions encompassed by the present invention may also be "non-conservative", in which an amino acid residue which is present in a peptide is substituted with an amino acid having different properties, such as naturally-occurring amino acid from a different group (e .g . substituting a charged or hydrophobic amino; acid with alanine), or alternatively, in which a naturally-occurring amino acid is substituted with a non- conventional amino acid.
  • the conservative amino acid substitutions are as described herein.
  • the substitution may be of Y with F, T with S or K, P with A, E with D or Q, N with D or G, R with K, G with N or A, T with S or K, D with N or E, I with L or V, F with Y, S with T or A, R with K, G with N or A, K with R, A with S, K or P.
  • the conservative amino acid substitutions may be wherein Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, S with A or T and A with S, G, T or V.
  • amino acid substitutions are located outside the CDR sequences.
  • the antibody comprises a kappa light chain.
  • Kappa light chain constant region amino acid and nucleotide sequences are set out in SEQ ID Nos: 395-404.
  • the light chain may be a lambda light chain. Lambda light chain constant region amino acid and nucleotide sequences can be found in SEQ ID Nos: 405-428.
  • the antibodies described herein may comprise a constant region, such as a human constant region.
  • An antibody of the invention may have any suitable constant region sequence.
  • Table 2 shows exemplary constant region sequences either in terms of amino acid sequence or nucleic acid sequence encoding the constant region amino acid sequence.
  • the constant region is wild-type human IgGl. In one embodiment, the constant region comprises an amino acid sequence as shown in SEQ ID No: 363.
  • the antibody has natural effector function.
  • the constant region is engineered for enhanced effector function.
  • the constant region is engineered for enhanced ADCC and/or CDC and/or ADCP activity.
  • the human IgG heavy chain constant region is a variant human IgGl heavy chain constant region comprising the S239D and I332E amino acid mutations (EU index numbering system).
  • the constant region comprises an amino acid sequence as shown in SEQ ID No: 364.
  • the antibodies described herein facilitate the killing of an infected cell via antibody dependent cellular cytotoxicity (ADCC), where antibodies bind to infected cells and allow immune cells to kill them.
  • ADCC antibody dependent cellular cytotoxicity
  • the antibodies described herein facilitate the killing of an infected cell via antibodydependent cellular phagocytosis (ADCP).
  • ADCP antibodydependent cellular phagocytosis
  • the antibodies described herein facilitate the killing of an infected cell via complementdependent cytotoxicity (CDC).
  • an appropriate format for the antibody e.g., IgG4 or IgGl
  • the antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region.
  • Fc effector function e.g., an IgGl constant region.
  • An effector enhanced or enabled antibody may recruit natural killer cells to infected cells to achieve ADCC.
  • the antibody may comprise modifications that enhance the ability of the antibody to cluster and therefore be a better substrate for complement fixation.
  • the Fc domain of IgGl may be mutated for example at E345 or E430 to reinforce inter-antibody Fc:Fc interactions, stimulating formation of hexamers, which enhances the induction of CDC and ADCC of target cells (de Jong et al., PloS Biol 14(1) e 1002344 2016). Hexamer formation is optionally combined with a bispecific antibody format.
  • the heavy chain constant region may be . an IgG4 constant region or an IgGl constant region, optionally wherein the constant region is IgG4-PE (SEQ ID Nos: 389-394 and 429-430), or a disabled IgGl as defined in SEQ ID Nos: 373-374.
  • the heavy chain constant region may be a wild-type human IgGl constant region (SEQ ID Nos: 363 or 365- 372).
  • the IgG4 constant region may be any of the IgG4 constant region amino acid sequences, or encoded by any of the nucleic acid sequences (SEQ ID Nos: 383-388).
  • a heavy chain constant region may be an IgG4 comprising both the Leu235Glu mutation and the Ser228Pro mutation.
  • the heavy chain constant region may be an IgGl *01 allele comprising the L235A and/or G237A mutations (e.g. LAGA, SEQ ID Nos: 373-374).
  • the antibodies or antibody fragments disclosed herein comprise an IgGl heavy chain constant region, wherein the sequence contains alanine at position 235 and/or 237 (EU index numbering).
  • ADCP antibody-dependent cell phagocytosis
  • the potency of Fc-mediated effects may be enhanced by engineering the Fc domain by various established techniques. Such methods increase the affinity for certain Fc-receptors or decrease the affinity for inhibitory Fc-receptors, thus creating potential diverse profiles of activation enhancement. This can be achieved by modification of one or several amino acid residues (e.g. as described in Lazar et al., 2006, Proc. Natl. Acad. Sci. U.S.A., Mar 14; 103(11):4005-10; the modifications disclosed therein are incorporated herein by reference). Human IgGl constant regions containing specific mutations or altered glycosylation on residue Asn297 (e.g. N297Q, EU index numbering) have been shown to enhance binding to certain Fc receptors.
  • such mutations are one or more of the residues selected from 239, 332 and 330 for human IgGl constant regions (or the equivalent positions in other IgG isotypes) .
  • the antibody or fragment comprises a human IgGl constant region having one or more mutations independently selected from N297Q, S239D, I332E and A330L (EU index numbering).
  • the antibody or fragment comprises a human IgGl constant region having an S239D mutation (EU index numbering).
  • the antibody or fragment comprises a human IgGl constant region having an I332E mutation (EU index numbering).
  • the antibody or fragment comprises a human IgGl constant region having S239D and I332E mutations (EU index numbering).
  • the antibody or fragment comprises the human IgGl constant region sequence of SEQ ID NO: 364.
  • SEQ ID NO: 364 comprises the S239D and I332E mutations.
  • the increase in affinity for Fc-receptors is achieved by altering the natural glycosylation profile of the Fc domain by, for example, generating under fucosylated or de-fucosylated variants (as described in Natsume et al., 2009, Drug Des. Devel. Ther., 3:7-16 or by Zhou Q., Biotechnol. Bioeng., 2008, Feb 15, 99(3):652-65, the modifications described therein are incorporated herein by reference).
  • Non-fucosylated antibodies harbour a tri-mannosyl core structure of complex-type N-glycans of Fc without fucose residue.
  • glycoengineered antibodies that lack core fucose residue from the Fc N-glycans may exhibit stronger ADCC than fucosylated equivalents due to enhancement of FcyRIIIa binding capacity.
  • residues in the hinge region can be altered to increase binding to Fc-yRIII (see, for example, Shields et al., 2001, J. Biol. Chem., Mar 2; 276(9):6591-604; the modifications described therein are incorporated herein by reference).
  • the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild-type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human Fey receptors selected from the group consisting of FcyRIIB and FcyRIIA with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fey receptors.
  • the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human FcyRIIB with higher affinity than the wild type human IgG heavy chain constant region binds to human FcyRIIB.
  • the variant human IgG heavy chain constant region is a variant human IgGl, a variant human IgG2, or a variant human IgG4 heavy chain constant region.
  • the variant human IgG heavy chain constant region comprises one or more amino acid mutations selected from G236D, P238D, S239D, S267E, L328F, and L328E (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S267E and L328F; P238D and L328E; P238D and one or more substitutions selected from the group consisting of E233D, G237D, H268D, P271G, and A330R; P238D, E233D, G237D, H268D, P271G, and A330R; G236D and S267E; S239D and S267E; V262E, S267E, and L328F; and V264E, S267E, and L328F (EU index numbering system).
  • the variant human IgG heavy chain constant region further comprises one or more amino acid mutations that reduce the affinity of the IgG for human FcyRIIIA, human FcyRIIA, or human FcyRI.
  • the FcyRIIB is expressed on a cell selected from the group consisting of macrophages, monocytes, B-cells, dendritic cells, endothelial cells, and activated T-cells.
  • the variant human IgG heavy chain constant region comprises one or more of the following amino acid mutations G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305I, A330L, I332E, E333A, K334A, A339T, and P396L (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S239D; T256A; K290A; S298A; I332E; E333A; K334A; A339T; S239D and I332E; S239D, A330L, and I332E; S298A, E333A, and K334A; G236A, S239D, and I332E; and F243L, R292P, Y300L, V305I, and P396L (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a S239D, A330L, or I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region comprises an S239D and I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region is a variant human IgGl heavy chain constant region comprising the S239D and I332E amino acid mutations (EU index numbering system).
  • the antibody or fragment comprises the human IgGl constant region sequence of SEQ ID NO: 364. As set out in Table 2, SEQ ID NO: 364 comprises the S239D and I332E mutations. In one example, the antibody or fragment comprises an afiicosylated Fc region. In another example, the antibody or fragment thereof is defucosylated. In another example, the antibody or fragment is under fucosylated.
  • the antibodies and fragments disclosed herein may comprise a triple mutation (M252Y/S254T/T256E) which enhances binding to FcRn. See Dall’Aqua et al., Immunol 2002; 169:5171-5180 for a discussion of mutations affection FcRn binding in table 2, the mutations described therein are incorporated herein by reference.
  • the enhancement of CDC may be achieved by amino acid changes that increase affinity for Clq, the first component of the classic complement activation cascade (see Idusogie et al., J. Immunol., 2001, 166:2571— 2575; the modifications described are incorporated herein by reference).
  • Another approach is to create a chimeric Fc domain created from human IgGl and human IgG3 segments that exploit the higher affinity if IgG3 for Clq (Natsume et al., 2008, Cancer Res., 68: 3863-3872; the modifications are incorporated herein by reference).
  • the antibody or antibody fragments disclosed herein may comprise mutated amino acids at residues 329, 331 and/or 322 to alter the C Iq binding and/or reduced or abolished CDC activity.
  • the antibodies or antibody fragments disclosed herein may contain Fc regions with modifications at residues 231 and 239, whereby the amino acids are replaced to alter the ability of the antibody to fix complement.
  • the antibody or fragment has a constant region comprising one or more mutations selected from E345K, E430G, R344D and D356R, in particular a double mutation comprising R344D and D356R (EU index numbering system).
  • the antibodies disclosed herein are modified to increase or decrease serum half-life.
  • one or more of the following mutations: T252L, T254S or T256F are introduced to increase biological half-life of the antibody.
  • Biological half-life can also be increased by altering the heavy chain constant region CHI domain or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Numbers. 5,869,046 and 6,121,022, the modifications described therein are incorporated herein by reference.
  • the Fc hinge region of an antibody or antigen-binding fragment of the invention is mutated to decrease the biological half-life of the antibody or fragment.
  • One or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody or fragment has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • Other methods of increasing serum half-life are known to those skilled in the art.
  • the antibody or fragment is PEGylated.
  • the antibody or fragment is fused to an albumin-binding domain, e.g. an albumin binding single domain antibody (dAb).
  • the antibody or fragment is PASylated (i.e. genetic fusion of polypeptide sequences composed of PAS (XL-Protein GmbH) which forms uncharged random coil structures with large hydrodynamic volume).
  • the antibody or fragment is XTENylated®/rPEGylated (i.e. genetic fusion of non-exact repeat peptide sequence (Amunix, Versartis) to the therapeutic peptide).
  • the antibody or fragment is ELPylated (i.e. genetic fusion to ELP repeat sequence (PhaseBio)).
  • the antibody may have a modified constant region which increases stability.
  • the heavy chain constant region comprises a Ser228Pro mutation.
  • the antibodies and fragments disclosed herein comprise a heavy chain hinge region that has been modified to alter the number of cysteine residues. This modification can be used to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the antibody comprises VH and/or VL domain and framework regions of human germline gene segment sequences.
  • Gene segment sequences from which the exemplary antibodies described herein are derived are set out in Table 3.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-34*01, IGHV4-31*03, IGHV3-ll*01, IGHVl-3*01, IGHV4- 59*01, or IGHV3-30* 18; and/or the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4- 34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations,
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4- 31*03, or IGHV3-48*02; and/or the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59* 01 , IGHV4-4* 02, IGHV5 -51*01, IGHV4-31 * 03 , or IGHV3 -48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4- 31*03, IGHV4-59*0I, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-I*0I, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6- 1*01, or IGHV3-21*03with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*OI, IGLV3-I0*0I, IGLV2-8*0I, IGLVl-5I*0I, IGKV1D-39*OI, or IGKVl-9*dOI, and/or the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-I0*0I, IGLV2-8*0I, IGLV1-5I*OI, IGKV1D-39*OI, orIGKVl-9*dOI with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D- 39*01, or IGKVl
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV2-23*dO2, IGLVl-51*01, IGKV3-l l*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01, and/or the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-I I*0I, IGLV3-I9*0I, IGKV2-24*0I, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGLV2-23*dO2, IGLV 1-51*01, IGKV3- 11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01.
  • the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGLV3- 10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene
  • Antibodies that compete with a reference antibody for binding to a target UL16, UL141 or US28 protein are described in this disclosure. Any suitable method may be used to determine whether an antibody competes with a reference antibody for binding to a target UL16, UL141 or US28 protein. Such methods are well known in the art.
  • Whether an antibody competes with a reference antibody for binding to UL16, UL141 or US28 protein may be measured using a competition assay.
  • Competition may be determined by surface plasmon resonance (SPR), such techniques being readily apparent to the skilled person. SPR may be carried out using BiacoreTM, ProteonTM or another standard SPR technique.
  • SPR may be carried out using BiacoreTM, ProteonTM or another standard SPR technique.
  • competition is determined by ELISA, such techniques being readily apparent to the skilled person.
  • competition is determined by homogenous time resolved fluorescence (HTRF), such techniques being readily apparent to the skilled person.
  • competition is determined by fluorescence activated cell sorting (FACS), such techniques being readily apparent to the skilled person.
  • competition is determined by ForteBio Octet® Bio-Layer Interferometry (BLI) such techniques being readily apparent to the skilled person.
  • Nucleic acids that encode a VH domain and/or a VL domain of any one of the antibodies described herein are also provided.
  • the nucleic acid sequences encoding each of the VH and VL domains of each the exemplary antibodies described herein are set out in Table 1.
  • the nucleic acid sequence is at least 70% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 80% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 90% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 95% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 96% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 97% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 98% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 99% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 99.5% identical to the specified SEQ ID NO.
  • the nucleic acid encodes a heavy chain of any one of the antibodies described herein. In another example, the nucleic acid encodes a light chain of any one of the antibodies described herein.
  • the nucleic acid is an isolated and purified nucleic acid.
  • Vectors comprising the nucleic acids described above are also provided.
  • the vector may be a CHO vector.
  • the vector may be a HEK293 vector.
  • physiologically acceptable excipient examples include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as Ethylenediaminetetraacetic acid (EDTA); sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • CMV in Transplantation is the most common and single most important viral infection in solid organ transplant recipients. CMV infection usually develops during the first few months after transplantation and is associated with clinical infectious disease (e.g., fever, pneumonia, GI ulcers, hepatitis) and acute and/or chronic graft injury and dysfunction. Sources of CMV infection in transplant recipients include reactivation of preexisting latent infections, donor-transmitted virus, and virus present in donor WBCs. 20% to 60% of all transplant recipients develop symptomatic CMV infection. The patients at highest risk for symptomatic disease are the CMV-seropositive donor/CMV-seronegative recipient (D+/R-) who often develop a primary infection after transplantation.
  • D+/R- CMV-seropositive donor/CMV-seronegative recipient
  • the second antibody specifically binds ULI 6 protein.
  • the second antibody specifically binds VEGF, for example bevacizumab.

Abstract

The present invention relates to antibodies that specifically bind UL16 protein, antibodies that specifically bind UL141 protein and antibodies that specifically bind US28 protein. The present invention also provides methods of treatment, uses, pharmaceutical compositions and kits comprising the antibodies.

Description

ANTIBODIES AND USES THEREOF
I. FIELD OF THE INVENTION
The present invention relates to antibodies that bind human cytomegalovirus (HCMV)-related proteins, specifically antibodies that specifically bind UL16, antibodies that specifically bind UL141 and antibodies that specifically bind US28, and their use in diagnosis, prevention and treatment of HCMV infections and HCMV- related diseases or conditions.
II. BACKGROUND OF THE INVENTION
Cytomegalovirus (CMV), and specifically, human cytomegalovirus (HCMV) belongs to the P-herpesvirus family of DNA viruses. It is estimated to have infected 50-90% of the world's population and causes a mild self-limiting infection in otherwise healthy children or adults. However, HCMV is one of the most significant viral pathogens during pregnancy and in immunocompromised patients. In pregnancy HCMV is a more significant pathogen than all other types of congenital diseases.
The most important clinical diseases linked to HCMV are congenital infection, which is the most prominent infectious cause of congenital malformations, hearing loss and learning disabilities; HCMV retinitis in AIDS patients and HCMV syndrome, gastrointestinal disease and pneumonia in organ transplant patients. Even in immunocompetent hosts development of autoimmune, cardiovascular and proliferative diseases have consistently been associated with HCMV infection.
There is no treatment for congenital infection and the significant morbidity associated with this disease is increasingly of public concern, particularly in the USA. The US Institute of Medicine (the health arm of the National Academy of Sciences) has ranked congenital CMV infection as its highest ranked project for prophylaxis development and Trellis Biosciences Inc. in the USA (http://www.trellisbio.eom/therapeutics.html#virusStart) has stated that congenital CMV infection as its first target indication for an anti-CMV antibody in development.
The management of CMV infection in transplant patients has improved with the introduction of antiviral prophylactic or pre-emptive therapy. To date much work has focused on antiviral drugs targeting HCMV proteins involved in genome replication or the development of a protective vaccine based around glycoprotein B (gB) or glycoprotein H (gH). Valganciclovir, a pro-drug of ganciclovir, is used as an antiviral prophylactic or pre-emptive therapy in high and moderate risk patients despite the significant side effects and dose limiting toxicities of the drugs used. CMV pneumonia remains difficult to treat, even with the antivirals now available. The mortality rate of CMV pneumonia in bone marrow transplants that requires mechanical ventilation is high, despite treatment with ganciclovir and immune globulin. Poor clinical outcomes are also observed in patients who are also infected with community respiratory viruses (e.g., parainfluenza, influenza, respiratory syncytial virus) and those who have received allogeneic marrow transplants.
Ganciclovir-resistant CMV infection has been observed in 0%, 0.3%, 1%, 9%, and 13% among liver, heart, kidney, lung, and combined pancreas-kidney transplant recipients, respectively and represents an increasing problem. The overall incidence of ganciclovir-resistant CMV infection is 2.1%, but this varies widely among transplant groups, with the highest incidence among recipients of lung and combined kidney-pancreas transplants.
To date most HCMV treatment using valganciclovir suffers from toxicity, especially myelosuppression which limits utility in HSCT. New drugs such as Letermovir however, have much more acceptable toxicity profiles and Letermovir is predicted to become the main drug of choice within HCMV disease. One potential limitation of Letermovir, especially in the transplantation setting is the generation of drug resistant HCMV. It is known that naturally occurring drug resistant variants, albeit rare, occur in drug naive people, suggesting that the pathways to resistance may have low genetic barriers and be phenotypically neutral with respect to virus fitness and virulence.
To date there are no effective vaccines against HCMV and the barriers to development are biological, with limited knowledge as to the virus proteins and types of immune response required for eliciting long term protection. There is limited evidence that a vaccine strategy will provide the specific immunity needed to protect in utero, as the majority of congenital infections occur where the woman has pre-existing HCMV immunity or protect people with comorbidities requiring organ transplantation. Finally, in such patient groups, with an incomplete knowledge of immune responses, there is a safety issue related to infection or pathology enhancing immunity.
There is therefore considerable unmet need for development of new therapeutics.
All references cited herein are incorporated by reference in their entirety. III. SUMMARY OF THE INVENTION
We have discovered antibodies that bind human cytomegalovirus (HCMV)-related proteins, specifically antibodies that specifically bind UL16 protein, antibodies that specifically bind UL141 protein and antibodies that specifically bind US28 protein, and have properties suitable for development as medicaments for treating or preventing HCMV infection and diseases or conditions associated with HCMV infection. We demonstrate herein that exemplary antibodies that bind human cytomegalovirus (HCMV)-related proteins, specifically antibodies that specifically bind UL16, antibodies that specifically bind UL141 and antibodies that specifically bind US28, are effective in killing cells infected with HCMV, particularly when measured using an Fc effector reporter assay (e.g. BATDA assay).
An aim of the present invention is to reduce the incidence or severity of HCMV infection, and to reduce the incidence or severity of HCMV -related diseases or conditions through the administration of such monoclonal antibodies.
Administration of monoclonal antibodies of the invention may be used either as a prophylactic or as a therapeutic. Monoclonal antibodies of the invention may also be used in diagnosis.
GROUP A - ULI 6 antibodies:
In a first aspect, the present invention provides an antibody that specifically binds to a UL16 viral protein.
In one embodiment, the antibody specifically binds to the extracellular domain of a ULI 6 viral protein.
In one embodiment, the antibody is a monoclonal antibody.
In one embodiment, the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
In one embodiment, the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
In one embodiment, the antibody mediates killing of cells infected with HCMV. In one embodiment, the antibody mediates immune-mediated killing of cells infected with HCMV.
In one embodiment, the antibody mediates NK-cell killing of cells infected with HCMV.
In one embodiment, the antibody reduces viral load of cells infected with HCMV.
In one embodiment, the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
In one embodiment, the antibody has CDC activity.
In one embodiment, the antibody has ADCP activity.
In one embodiment, the antibody competes for binding to ULI 6 protein with MICB, ULBP1, ULBP2 and/or ULBP6.
In one embodiment, the antibody blocks UL16 protein binding to MICB, ULBP1, ULBP2 and/or ULBP6.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ATHO-OIOI, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-080I.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-OIOI
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0102.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0103.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0104.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0105.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0106.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0107.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0108.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0109.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0110.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0111.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0112.
In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0113. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0114. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0115. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0116. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0201. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0301. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0302. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0303. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0401. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0501. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0601. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0701. In one embodiment, the HCDR3 is the HCDR3 of antibody ATHO-0801.
In one embodiment, the present invention provides an anti-UL16 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-OIOI, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801.
In one embodiment, the antibody has the CDRs of antibody ATHO-0101. In one embodiment, the antibody has the CDRs of antibody ATHO-0102. In one embodiment, the antibody has the CDRs of antibody ATHO-0103. In one embodiment, the antibody has the CDRs of antibody ATHO-0104. In one embodiment, the antibody has the CDRs of antibody ATHO-0105. In one embodiment, the antibody has the CDRs of antibody ATHO-0106. In one embodiment, the antibody has the CDRs of antibody ATHO-0107. In one embodiment, the antibody has the CDRs of antibody ATHO-0108. In one embodiment, the antibody has the CDRs of antibody ATHO-0109.
In one embodiment, the antibody has the CDRs of antibody ATHO-0110. In one embodiment, the antibody has the CDRs of antibody ATHO-O 111. In one embodiment, the antibody has the CDRs of antibody ATHO-0112. In one embodiment, the antibody has the CDRs of antibody ATHO-0113. In one embodiment, the antibody has the CDRs of antibody ATHO-0114. In one embodiment, the antibody has the CDRs of antibody ATHO-0115. In one embodiment, the antibody has the CDRs of antibody ATHO-0116. In one embodiment, the antibody has the CDRs of antibody ATHO-0201. In one embodiment, the antibody has the CDRs of antibody ATHO-0301. In one embodiment, the antibody has the CDRs of antibody ATHO-0302. In one embodiment, the antibody has the CDRs of antibody ATHO-0303. In one embodiment, the antibody has the CDRs of antibody ATHO-0401. In one embodiment, the antibody has the CDRs of antibody ATHO-0501. In one embodiment, the antibody has the CDRs of antibody ATHO-0601. In one embodiment, the antibody has the CDRs of antibody ATHO-0701. In one embodiment, the antibody has the CDRs of antibody ATHO-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ATHO-O 101, ATHO-O 102, ATHO-O 103, ATHO-O 104, ATHO-O 105, ATHO-O 106, ATHO-O 107, ATHO-O 108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-O 101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).,
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0112, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0112, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0113, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0113, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0115, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0115, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-O 106, ATHO-O 107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-O 115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-O 101, ATHO-O 102, ATHO-O 103, ATHO-O 104, ATHO-O 105, ATHO-O 106, ATHO-O 107, ATHO-O 108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0101, provided that the antibody has the CDRs of antibody ATHO-0101.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0102, provided that the antibody has the CDRs of antibody ATHO-0102.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0103, provided that the antibody has the CDRs of antibody ATHO-0103.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0104 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0104, provided that the antibody has the CDRs of antibody ATHO-0104.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0105 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0105, provided that the antibody has the CDRs of antibody ATHO-0105.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0106 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0106, provided that the antibody has the CDRs of antibody ATHO-0106.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0107 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0107, provided that the antibody has the CDRs of antibody ATHO-0107.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0108 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0108, provided that the antibody has the CDRs of antibody ATHO-0108.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0109 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0109, provided that the antibody has the CDRs of antibody ATHO-0109. In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-Ol lO and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-Ol lO, provided that the antibody has the CDRs of antibody ATHO-0110.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-O 111 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0111, provided that the antibody has the CDRs of antibody ATHO-O 111.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0112 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0112, provided that the antibody has the CDRs of antibody ATHO-0112.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0113 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0113, provided that the antibody has the CDRs of antibody ATHO-0113.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0114 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0114, provided that the antibody has the CDRs of antibody ATHO-0114.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0115 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0115, provided that the antibody has the CDRs of antibody ATHO-0115.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0116 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0116, provided that the antibody has the CDRs of antibody ATHO-0116.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0201, provided that the antibody has the CDRs of antibody ATHO-0201.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0301, provided that the antibody has the CDRs of antibody ATHO-0301. In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0302, provided that the antibody has the CDRs of antibody ATHO-0302.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0303, provided that the antibody has the CDRs of antibody ATHO-0303.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0401, provided that the antibody has the CDRs of antibody ATHO-0401.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0501, provided that the antibody has the CDRs of antibody ATHO-0501.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0601, provided that the antibody has the CDRs of antibody ATHO-0601.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0701, provided that the antibody has the CDRs of antibody ATHO-0701.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO- 0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0101.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0102.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0103.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0104.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0105.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0106.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0107.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0108.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0109.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0110.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0111.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0112.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0113.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0114.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0115.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0116.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0201.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0301. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0302.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0303.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0401.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0501.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0601.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0701.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ATHO- 0801.
In one embodiment, the antibody is a human IgGl.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
In one embodiment, the antibody is a human IgGl comprising an Fc effector enhanced constant region.
In one embodiment, the antibody is a human IgGl having S239D and I332E mutations.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
In one embodiment, the antibody comprises kappa (K) light chain constant regions.
In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody competes for binding to a ULI 6 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a ULI 6 protein. In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody competes for binding to a ULI 6 protein with a reference antibody selected from antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-080I. In one embodiment, an antibody that specifically binds to the same epitope on a ULI 6 protein as the epitope on a ULI 6 protein that is bound by a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a ULI 6 protein.
The reference antibody may be defined by its function or by its structure (e.g. its HCDR3 sequence, its 6CDR sequences, its VH and VL sequences or its full heavy and light chain sequences) or a combination thereof as described anywhere herein. Preferably, the reference antibody is defined by the VH and VL sequences or by its full heavy and light chain sequences.
In one embodiment, the antibody comprises VH and/or VL domain framework regions of human germline gene segment sequences.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-34*01, IGHV4-31*03, IGHV3-ll*01, IGHVl-3*01, IGHV4- 59*01, or IGHV3-30* 18; and/or the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-34*0I, IGHV4-31*03, IGHV3-I I*0I, IGHVl-3*01, IGHV4-59*0I, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-I I*0I, IGHVl-3*01, IGHV4-59*0I, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3- 11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4- 59*01, or IGHV3-30* 18, a human heavy chain D gene segment and a human heavy chain J gene segment, or comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3- 30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with 1, 2, 3, 4 or 5 amino acid alterations. In one embodiment, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01, and/or the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKVlD-39*01, orIGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLV1-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGKJl*01, IGLJ2*01, or IGKJ3*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGKV1- 12*01, IGLV3-I0*0I, IGLV2-8*0I, IGLVl-5I*0I, IGKVID-39*01, or IGKVI-9*d01, and optionally the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01.
Example combinations of v and j gene segments for heavy and light chain variable domains are shown in Table 3, and these represent preferred combinations. The heavy and light chain variable domains may optionally be derived from the v and j gene segments identified in Table 3 for any one individual ATHO antibody identified in this Group A section.
In one embodiment, the antibody is linked to a cytotoxic agent.
In one embodiment, the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-I065, duocarmycins and anthracyclines.
In one embodiment, the antibody is linked to an anti-viral agent.
In one embodiment, the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
The present invention also provides a pharmaceutical composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein and a pharmaceutically acceptable excipient. The present invention also provides a pharmaceutical composition comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein and a pharmaceutically acceptable excipient.
In one embodiment, the pharmaceutical composition further comprises at least one further therapeutic agent.
In one embodiment, the further therapeutic agent is a further antibody.
In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein; an antibody that specifically binds to UL141 protein; and an antibody that specifically binds to US28 protein.
In one embodiment, the further antibody is an antibody that specifically binds the same target protein as the first antibody.
In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein as defined anywhere herein; an antibody that specifically binds to UL141 protein as defined anywhere herein; and an antibody that specifically binds to US28 protein as defined anywhere herein.
In one embodiment, the pharmaceutical composition comprises a first antibody that specifically binds to ULI 6 as defined anywhere herein and a second antibody that specifically binds to US28 as defined anywhere herein.
In one embodiment, the pharmaceutical composition comprises a first antibody that specifically binds to ULI 6 as defined anywhere herein, a second antibody that specifically binds to UL141 as defined anywhere herein, and a third antibody that specifically binds to US28 as defined anywhere herein.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. . In one embodiment, the anti-viral agent is letermovir.
In one embodiment, the pharmaceutical composition further comprises two or more further therapeutic agents.
In one embodiment, the two or more further therapeutic agents are two or more further antibodies. In one embodiment, the pharmaceutical composition is formulated for intravenous, intramuscular or subcutaneous administration.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein may be provided for use as a medicament.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, may be provided for use in a method of treating congenital HCMV infection. Also provided is the use of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV infection.
Also provided is the use of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient.
Also provided is the use of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient.
Also provided is the use of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof.
Also provided is the use of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating congenital HCMV infection.
A method of treating HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein.
A method of reducing HCMV viral load in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein. A method of reducing frequency of HCMV virus reactivation in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL 16 as defined anywhere herein.
A method of preventing HCMV infection in a patient at risk of thereof may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL 16 as defined anywhere herein.
A method of treating congenital HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to ULI 6 as defined anywhere herein, or the composition comprising an antibody that specifically binds to ULI 6 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to ULI 6 as defined anywhere herein.
In one embodiment, the patient shows one or more symptoms of HCMV infection.
In one embodiment, the patient is a transplant recipient.
In one embodiment, the patient is a transplant donor.
In one embodiment, the transplant is a solid organ transplant.
In one embodiment, the transplant is a stem cell transplant.
In one embodiment, the transplant is a haematopoietic stem cell transplant (HSCT).
In one embodiment, the patient is immunosuppressed.
In one embodiment, the patient is immunocompromised.
In one embodiment, the patient is HIV positive.
In one embodiment, the patient has previously been treated with an anti-viral agent. In one embodiment, the patient has a HCMV infection which is refractory to at least one anti-viral agent.
In one embodiment, the patient is a pregnant woman.
In one embodiment, the HCMV infection is associated with an inflammatory disease.
In one embodiment, the patient has atherosclerosis.
In one embodiment, the patient has previously undergone balloon angioplasty.
In one embodiment, said method further comprises administration of a further therapeutic agent.
In one embodiment, said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
In one embodiment, the further therapeutic agent is a further antibody.
In one embodiment, the further antibody is a further antibody that specifically binds to ULI 6 protein as described anywhere herein.
In one embodiment, the further antibody is an antibody that specifically binds to UL141 protein as described anywhere herein.
In one embodiment, the further antibody is an antibody that specifically binds to US28 protein as described anywhere herein.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one embodiment, said method further comprises administration of two or more further therapeutic agents.
In one embodiment, said method further comprises administration of two or more further antibodies. GROUP B - UL141 antibodies:
In a second aspect, the present invention provides an antibody that specifically binds to a UL141 viral protein.
In one embodiment, the antibody specifically binds to the extracellular domain of a UL141 viral protein.
In one embodiment, the antibody is a monoclonal antibody.
In one embodiment, the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
In one embodiment, the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
In one embodiment, the antibody mediates killing of cells infected with HCMV.
In one embodiment, the antibody mediates immune-mediated killing of cells infected with HCMV.
In one embodiment, the antibody mediates NK-cell killing of cells infected with HCMV.
In one embodiment, the antibody reduces viral load of cells infected with HCMV.
In one embodiment, the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
In one embodiment, the antibody has CDC activity.
In one embodiment, the antibody has ADCP activity.
In one embodiment, the antibody competes for binding to UL141 protein with CD 155, CD112 and/or TRAIL- R1/R2.
In one embodiment, the antibody blocks UL141 protein binding to CD155, CD112 and/or TRAIL-R1/R2. In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM- 0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0101.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0102.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0103.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0201.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0202.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0203.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0204.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0301.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0302.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0303.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0401.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0501.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0601.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0701.
In one embodiment, the HCDR3 is the HCDR3 of antibody ARAM-0801.
In one embodiment, the present invention provides an anti -UL 141 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM- 0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM- 0701, or ARAM-0801. In one embodiment, the antibody has the CDRs of antibody ARAM-0101.
In one embodiment, the antibody has the CDRs of antibody ARAM-0102.
In one embodiment, the antibody has the CDRs of antibody ARAM-0103.
In one embodiment, the antibody has the CDRs of antibody ARAM-0201.
In one embodiment, the antibody has the CDRs of antibody ARAM-0202.
In one embodiment, the antibody has the CDRs of antibody ARAM-0203.
In one embodiment, the antibody has the CDRs of antibody ARAM-0204.
In one embodiment, the antibody has the CDRs of antibody ARAM-0301.
In one embodiment, the antibody has the CDRs of antibody ARAM-0302.
In one embodiment, the antibody has the CDRs of antibody ARAM-0303.
In one embodiment, the antibody has the CDRs of antibody ARAM-0401.
In one embodiment, the antibody has the CDRs of antibody ARAM-0501.
In one embodiment, the antibody has the CDRs of antibody ARAM-0601.
In one embodiment, the antibody has the CDRs of antibody ARAM-0701.
In one embodiment, the antibody has the CDRs of antibody ARAM-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM- 0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM- 0601, ARAM-0701, or ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM- 0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0101, provided that the antibody has the CDRs of antibody ARAM-0101.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0102, provided that the antibody has the CDRs of antibody ARAM-0102.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0103, provided that the antibody has the CDRs of antibody ARAM-0103.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0201, provided that the antibody has the CDRs of antibody ARAM-0201.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0202 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0202, provided that the antibody has the CDRs of antibody ARAM-0202.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0203 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0203, provided that the antibody has the CDRs of antibody ARAM-0203.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0204 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0204, provided that the antibody has the CDRs of antibody ARAM-0204.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0301, provided that the antibody has the CDRs of antibody ARAM-0301.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0302, provided that the antibody has the CDRs of antibody ARAM-0302.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0303, provided that the antibody has the CDRs of antibody ARAM-0303.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0401, provided that the antibody has the CDRs of antibody ARAM-0401.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0501, provided that the antibody has the CDRs of antibody ARAM-0501.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0601, provided that the antibody has the CDRs of antibody ARAM-0601.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0701, provided that the antibody has the CDRs of antibody ARAM-0701.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM- 0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0101.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0102.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0103.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0201.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0202.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0203.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0204.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0301.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0302.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0303. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0401.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0501.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0601.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0701.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody ARAM- 0801.
In one embodiment, the antibody is a human IgGl.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
In one embodiment, the antibody is a human IgGl comprising an Fc effector enhanced constant region.
In one embodiment, the antibody is a human IgGl having S239D and I332E mutations.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
In one embodiment, the antibody comprises kappa (K) light chain constant regions.
In one embodiment, an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein. In one embodiment, an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody selected from antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
In one embodiment, an antibody that specifically binds to the same epitope on a UL141 protein as the epitope on a UL141 protein that is bound by a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein.
The reference antibody may be defined by its function or by its structure (e.g. its HCDR3 sequence, its 6CDR sequences, its VH and VL sequences or its full heavy and light chain sequences) or a combination thereof as described anywhere herein. Preferably, the reference antibody is defined by the VH and VL sequences or by its full heavy and light chain sequences.
In one embodiment, the antibody comprises VH and/or VL domain framework regions of human germline gene segment sequences.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4- 31*03, or IGHV3-48*02; and/or the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*0I, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*0I, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4- 31*03, or IGHV3-48*02, a human heavy chain D gene segment and a human heavy chain J gene segment, or comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-31*03, IGHV4-59*0I, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3- 48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-l l*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-I5*0I, and/or the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*0I, IGKJ3*01, or IGKJl*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-I I*0I, IGLV3-I9*0I, IGKV2-24*0I, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV2-23*dO2, IGLV1-51*O1, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3- 11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV2- 23*d02, IGLVl-51*01, IGKV3-l l*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01, and optionally the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01.
Example combinations of v and j gene segments for heavy and light chain variable domains are shown in Table 3, and these represent preferred combinations. The heavy and light chain variable domains may optionally be derived from the v and j gene segments identified in Table 3 for any one individual ARAM antibody identified in this Group B section.
In one embodiment, the antibody is linked to a cytotoxic agent.
In one embodiment, the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-1065, duocarmycins and anthracyclines.
In one embodiment, the antibody is linked to an anti-viral agent.
In one embodiment, the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
The present invention also provides a pharmaceutical composition comprising an antibody that specifically binds to UL141 as defined anywhere herein and a pharmaceutically acceptable excipient.
The present invention also provides a pharmaceutical composition comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein and a pharmaceutically acceptable excipient.
In one embodiment, the pharmaceutical composition further comprises at least one further therapeutic agent.
In one embodiment, the further therapeutic agent is a further antibody. In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein; an antibody that specifically binds to UL141 protein; and an antibody that specifically binds to US28 protein.
In one embodiment, the further antibody is an antibody that specifically binds the same target protein as the first antibody.
In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein as defined anywhere herein; an antibody that specifically binds to UL141 protein as defined anywhere herein; and an antibody that specifically binds to US28 protein as defined anywhere herein.
In one embodiment, the pharmaceutical composition comprises a first antibody that specifically binds to UL141 protein as defined anywhere herein and a second antibody that specifically binds to US28 protein as defined anywhere herein.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one embodiment, the pharmaceutical composition further comprises two or more further therapeutic agents.
In one embodiment, the two or more further therapeutic agents are two or more further antibodies.
In one embodiment, the pharmaceutical composition is formulated for intravenous, intramuscular or subcutaneous administration.
The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use as a medicament. The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient.
The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, may be provided for use in a method of treating congenital HCMV infection.
Also provided is the use of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV infection.
Also provided is the use of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient.
Also provided is the use of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient.
Also provided is the use of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof.
Also provided is the use of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating congenital HCMV infection.
A method of treating HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to UL 141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein.
A method of reducing HCMV viral load in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to UL 141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein.
A method of reducing frequency of HCMV virus reactivation in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein. A method of preventing HCMV infection in a patient at risk of thereof may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein.
A method of treating congenital HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to UL141 as defined anywhere herein, or the composition comprising an antibody that specifically binds to UL141 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to UL141 as defined anywhere herein.
In one embodiment, the patient shows one or more symptoms of HCMV infection.
In one embodiment, the patient is a transplant recipient.
In one embodiment, the patient is a transplant donor.
In one embodiment, the transplant is a solid organ transplant.
In one embodiment, the transplant is a stem cell transplant.
In one embodiment, the transplant is a haematopoietic stem cell transplant (HSCT).
In one embodiment, the patient is immunosuppressed.
In one embodiment, the patient is immunocompromised.
In one embodiment, the patient is HIV positive.
In one embodiment, the patient has previously been treated with an anti-viral agent.
In one embodiment, the patient has a HCMV infection which is refractory to at least one anti-viral agent.
In one embodiment, the patient is a pregnant woman.
In one embodiment, the HCMV infection is associated with an inflammatory disease. In one embodiment, the patient has atherosclerosis.
In one embodiment, the patient has previously undergone balloon angioplasty.
In one embodiment, said method further comprises administration of a further therapeutic agent.
In one embodiment, said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
In one embodiment, the further therapeutic agent is a further antibody.
In one embodiment, the further antibody is an antibody that specifically binds to ULI 6 protein as described anywhere herein.
In one embodiment, the further antibody is a further antibody that specifically binds to UL141 protein as described anywhere herein.
In one embodiment, the further antibody is an antibody that specifically binds to US28 protein as described anywhere herein.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one embodiment, said method further comprises administration of two or more further therapeutic agents.
In one embodiment, said method further comprises administration of two or more further antibodies. GROUP C - US28 antibodies:
In a third aspect, the present invention provides an antibody that specifically binds to a US28 viral protein.
In one embodiment, the antibody specifically binds to the extracellular domain of a US28 viral protein.
In one embodiment, the antibody is a monoclonal antibody.
In one embodiment, the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
In one embodiment, the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
In one embodiment, the antibody mediates killing of cells infected with HCMV.
In one embodiment, the antibody mediates immune-mediated killing of cells infected with HCMV.
In one embodiment, the antibody reduces viral load of cells infected with HCMV.
In one embodiment, the cells are lytically infected cells.
In one embodiment, the cells are latently infected cells.
In one embodiment, the antibody reduces frequency of viral reactivation in cells latently infected with HCMV.
In one embodiment, the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
In one embodiment, the antibody has CDC activity.
In one embodiment, the antibody has ADCP activity.
In one embodiment, the antibody competes for binding to US28 protein with CX3CL1 and/or other chemokines.
In one embodiment, the antibody blocks US28 protein binding to CX3CL1 and/or other chemokines. In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0101.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0201.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0301.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0401.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0501.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0601.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0701.
In one embodiment, the HCDR3 is the HCDR3 of antibody PORT-0801.
In one embodiment, the present invention provides an anti-US28 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT- 0701, or PORT-0801.
In one embodiment, the antibody has the CDRs of antibody PORT-0101, In one embodiment, the antibody has the CDRs of antibody PORT-0201, In one embodiment, the antibody has the CDRs of antibody PORT-0301, In one embodiment, the antibody has the CDRs of antibody PORT-0401, In one embodiment, the antibody has the CDRs of antibody PORT-0501, In one embodiment, the antibody has the CDRs of antibody PORT-0601, In one embodiment, the antibody has the CDRs of antibody PORT-0701, In one embodiment, the antibody has the CDRs of antibody PORT-0801. In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). In one embodiment, the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT- 0601, PORT-0701, or PORT-0801, provided that the antibody has the CDRs of antibody PORT-0101, PORT- 0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0101, provided that the antibody has the CDRs of antibody PORT-0101.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0201, provided that the antibody has the CDRs of antibody PORT-0201.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0301, provided that the antibody has the CDRs of antibody PORT-0301.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0401, provided that the antibody has the CDRs of antibody PORT-0401.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0501, provided that the antibody has the CDRs of antibody PORT-0501.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0601, provided that the antibody has the CDRs of antibody PORT-0601. In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0701, provided that the antibody has the CDRs of antibody PORT-0701.
In one embodiment, the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0801, provided that the antibody has the CDRs of antibody PORT-0801.
In one embodiment, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT- 0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0101. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0201. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0301. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0401. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0501. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0601. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0701. In one embodiment, the antibody comprises the VH domain and VL domain sequences of antibody PORT-0801.
In one embodiment, the antibody is a human IgGl.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363.
In one embodiment, the antibody is a human IgGl comprising an Fc effector enhanced constant region.
In one embodiment, the antibody is a human IgGl having S239D and I332E mutations.
In one embodiment, the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364.
In one embodiment, the antibody comprises kappa (K) light chain constant regions.
In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein. In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody selected from antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801.
In one embodiment, an antibody that specifically binds to the same epitope on a US28 protein as the epitope on a US28 protein that is bound by a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein.
The reference antibody may be defined by its function or by its structure (e.g. its HCDR3 sequence, its 6CDR sequences, its VH and VL sequences or its full heavy and light chain sequences) or a combination thereof as described anywhere herein. Preferably, the reference antibody is defined by the VH and VL sequences or by its full heavy and light chain sequences.
In one embodiment, the antibody comprises VH and/or VL domain framework regions of human germline gene segment sequences.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-I*0I, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*0I, IGHVl-18*0I, IGHVl-8*0I, IGHV3-13*01, IGHV6-I*0I, or IGHV3- 21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV2- 5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6- 1 * 01 , or IGHV 3 -21 * 03 , a human heavy chain D gene segment and a human heavy chain J gene segment, or comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations. In one embodiment, the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-I*0I, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*0I; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-l*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ4*01, or IGLJ2*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one embodiment, the antibody comprises an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV3- 10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and optionally the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01.
Example combinations of v and j gene segments for heavy and light chain variable domains are shown in Table 3, and these represent preferred combinations. The heavy and light chain variable domains may optionally be derived from the v and j gene segments identified in Table 3 for any one individual PORT antibody identified in this Group C section.
In one embodiment, the antibody is linked to a cytotoxic agent.
In one embodiment, the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-1065, duocarmycins and anthracyclines.
In one embodiment, the antibody is linked to an anti-viral agent.
In one embodiment, the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir. The present invention also provides a pharmaceutical composition comprising an antibody that specifically binds to US28 as defined anywhere herein and a pharmaceutically acceptable excipient.
The present invention also provides a pharmaceutical composition comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein and a pharmaceutically acceptable excipient.
In one embodiment, the pharmaceutical composition further comprises at least one further therapeutic agent.
In one embodiment, the further therapeutic agent is a further antibody.
In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein; an antibody that specifically binds to UL141 protein; an antibody that specifically binds to US28 protein; and an antibody that specifically binds to VEGF, for example bevacizumab.
In one embodiment, the further antibody is an antibody that specifically binds the same target protein as the first antibody.
In one embodiment, the further antibody is selected from: an antibody that specifically binds to ULI 6 protein as defined anywhere herein; an antibody that specifically binds to UL141 protein as defined anywhere herein; an antibody that specifically binds to US28 protein as defined anywhere herein; and an antibody that specifically binds to VEGF.
In one embodiment, the pharmaceutical composition comprising a first antibody that specifically binds to US28 protein as defined anywhere herein and a second antibody that specifically binds to VEGF.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one embodiment, the pharmaceutical composition further comprises two or more further therapeutic agents. In one embodiment, the two or more further therapeutic agents are two or more further antibodies.
In one embodiment, the pharmaceutical composition is formulated for intravenous, intramuscular or subcutaneous administration.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use as a medicament.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating HCMV-positive glioblastoma multiforme (GBM), said method comprising administering the antibody or composition to a patient.
In one embodiment, said method further comprises administration of chemotherapy or radiotherapy. The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient.
The antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, may be provided for use in a method of treating congenital HCMV infection.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV infection.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating HCMV -positive glioblastoma multiforme (GBM) in a patient.
In one embodiment, said method further comprises administration of chemotherapy or radiotherapy.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof.
Also provided is the use of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein, in the manufacture of a medicament for use in a method of treating congenital HCMV infection.
A method of treating HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
A method of reducing HCMV viral load in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
A method of reducing frequency of HCMV virus reactivation in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
A method of treating HCMV -positive glioblastoma multiforme (GBM) in a patient may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
In one embodiment, said method further comprises administration of chemotherapy or radiotherapy.
A method of preventing HCMV infection in a patient at risk of thereof may comprise administering to said human a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein. A method of treating congenital HCMV infection in a patient may comprise administering to said patient a therapeutically effective amount of an antibody that specifically binds to US28 as defined anywhere herein, or the composition comprising an antibody that specifically binds to US28 as defined anywhere herein or comprising an isolated nucleic acid encoding an antibody that specifically binds to US28 as defined anywhere herein.
In one embodiment, the patient shows one or more symptoms of HCMV infection.
In one embodiment, the patient is a transplant recipient.
In one embodiment, the patient is a transplant donor.
In one embodiment, the transplant is a solid organ transplant.
In one embodiment, the transplant is a stem cell transplant.
In one embodiment, the transplant is a haematopoietic stem cell transplant (HSCT).
In one embodiment, the patient is immunosuppressed.
In one embodiment, the patient is immunocompromised.
In one embodiment, the patient is HIV positive.
In one embodiment, the patient has previously been treated with an anti-viral agent.
In one embodiment, the patient has a HCMV infection which is refractory to at least one anti-viral agent.
In one embodiment, the patient is a pregnant woman.
In one embodiment, the HCMV infection is associated with an inflammatory disease.
In one embodiment, the patient has atherosclerosis.
In one embodiment, the patient has previously undergone balloon angioplasty. In one embodiment, the patient has glioblastoma multiforme (GBM).
In one embodiment, said method further comprises administration of a further therapeutic agent.
In one embodiment, said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
In one embodiment, the further therapeutic agent is a further antibody.
In one embodiment, the further antibody is an antibody that specifically binds to ULI 6 protein as described anywhere herein.
In one embodiment, the further antibody is an antibody that specifically binds to UL141 protein as described anywhere herein.
In one embodiment, the further antibody is a further antibody that specifically binds to US28 protein as described anywhere herein.
In one embodiment, the further antibody is an antibody that specifically binds to VEGF, for example bevacizumab.
In one embodiment, the further therapeutic agent is an anti-viral agent.
In one embodiment, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one embodiment, said method further comprises administration of two or more further therapeutic agents.
In one embodiment, said method further comprises administration of two or more further antibodies.
GENERAL (NUCLEIC ACID, VECTOR, HOST CELL, KIT, DIAGNOSTICS):
A nucleic acid may comprise a sequence that encodes a VH domain and/or an VL domain of an antibody as defined anywhere herein. The nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of an antibody as defined anywhere herein. The nucleic acid may comprise a sequence that encodes the VH domain of an antibody as defined anywhere herein. The nucleic acid may comprise a sequence that encodes the VL domain of an antibody as defined anywhere herein.
A vector may comprise the nucleic acid as defined anywhere herein; optionally wherein the vector is a CHO vector.
A host cell may comprise the nucleic acid as defined anywhere herein or the vector as defined anywhere herein.
A kit may comprise the pharmaceutical composition as defined anywhere herein. The kit may further comprise at least one further therapeutic agent. In one example, the further therapeutic agent is a further pharmaceutical composition comprising at least one, preferably one or two, further antibodies.
In one example, the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein as defined anywhere herein; b. an antibody that specifically binds to UL141 protein as defined anywhere herein; c. an antibody that specifically binds to US28 protein as defined anywhere herein; and d. an antibody that specifically binds to VEGF.
In one example, the further therapeutic agent is an anti-viral agent. In one example, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X . In one embodiment, the anti-viral agent is valganciclovir. In one embodiment, the anti-viral agent is letermovir.
In one example, the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds ULI 6 as defined anywhere herein and a pharmaceutical composition comprising a second antibody that specifically binds US28 as defined anywhere herein.
In one example, the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds UL141 as defined anywhere herein and a pharmaceutical composition comprising a second antibody that specifically binds US28 as defined anywhere herein. In one example, the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds ULI 6 as defined anywhere herein, a pharmaceutical composition comprising a second antibody that specifically binds UL141 as defined anywhere herein, and a pharmaceutical composition comprising a third antibody that specifically binds US28 as defined anywhere herein.
In one example, the kit comprises a pharmaceutical composition comprising a first antibody that specifically binds US28 as defined anywhere herein and a pharmaceutical composition comprising a second antibody that specifically binds to VEGF.
In one example, the kit further comprises a label or instructions for use to treat and/or prevent HCMV infection in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody or fragment.
Also provided is the use of an antibody as defined anywhere herein for determining the presence or absence of HCMV in a sample.
In one example, the use of an antibody that specifically binds ULI 6 as defined anywhere herein for determining the presence or absence of ULI 6 protein in a sample is provided.
In one example, the use of an antibody that specifically binds UL 141 as defined anywhere herein for determining the presence or absence of UL141 protein in a sample is provided.
In one example, the use of an antibody that specifically binds US28 as defined anywhere herein for determining the presence or absence of US28 protein in a sample is provided.
Also provided is a method of determining the presence or absence of HCMV in a sample, wherein the method comprises: contacting the sample with an antibody that specifically binds ULI 6 as defined anywhere herein; and testing for binding between the antibody and HCMV protein ULI 6 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
Also provided is a method of determining the presence or absence of HCMV in a sample, wherein the method comprises contacting the sample with an antibody that specifically binds UL141 as defined anywhere herein; and testing for binding between the antibody and HCMV protein UL141 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
Also provided is a method of determining the presence or absence of HCMV in a sample, the method comprising contacting the sample with an antibody that specifically binds US28 as defined anywhere herein; and testing for binding between the antibody and HCMV protein US28 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
In one example, the antibody comprises or is conjugated to a detectable label.
In one example, the sample has been obtained from a human who has been or is suspected of having been infected with HCMV.
In one example, the sample is a serum, plasma, or whole blood sample, or an oral or nasal swab, urine, faeces, or cerebrospinal fluid (CFS), or wherein the sample is from any suspected HCMV infected organ or tissue .
Also provided is a diagnostic kit for the use as defined anywhere herein, or the method as defined anywhere herein, comprising an antibody as defined anywhere herein, and optionally one or more buffering solutions. In one example, the antibody comprises or is conjugated to a detectable label. In one example, the diagnostic kit comprises a first reagent comprising the antibody as defined anywhere herein, and a second reagent comprising a detector molecule that binds to the first reagent. In one example, the detector molecule is an antibody that comprises or is conjugated to a detectable label. IV. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A: UL16 sequences
Multiple sequence alignment of three ULI 6 constructs. UL16_WT is the full-length untagged sequence. HA_UL16_His6_noER contains an HA tag (derived from influenza virus haemagglutinin (HA) protein) at the N-terminus, a 6xHistidine tag at the C-terminus (both boxed) and a truncation of 8 amino acids at the C-terminus which deletes the endoplasmic reticulum (ER) retention signal (underlined). UL16_noER contains the same 8 amino acid deletion and is untagged.
Figure IB: UL141 sequences
Multiple sequence alignment of three UL141 constructs. UL141_WT is the full-length untagged sequence. HA_UL141_His6_noER contains an HA tag (derived from influenza virus haemagglutinin (HA) protein) at the N-terminus, a 6xHistidine tag at the C-terminus (both boxed) and a truncation of 5 amino acids at the C-terminus which deletes the endoplasmic reticulum (ER) retention signal (underlined). UL141_noER contains the same 5 amino acid deletion and is untagged.
Figure 1C: US28 sequences
Multiple sequence alignment of four US28 constructs. US28_WT is the full-length untagged sequence. HA_US28_His6 contains an HA tag (derived from influenza virus haemagglutinin (HA) protein) at the N- terminus and a 6xHistidine tag at the C-terminus (boxed). US28_delta300 is untagged and truncated after amino acid 300. HA_US28_delta300 is also truncated after amino acid 300 and contains aN-terminal HA tag (boxed).
Figures 2A-2P: antibody VH and VL amino acid sequence alignments
Alignments of exemplary anti-UL16, UL141 and US28 antibody light and heavy chain amino acid sequences showing exemplary anti-UL16, UL141 and US28 antibodies and their siblings based on sequence homology. In summary, clusters were generated as follows: B cells were isolated from the immunised mice and their antibody-encoding sequences were recovered. By comparing sequences of the heavy and light chain variable domains, we identified clusters of sequences which correspond to families of B cells within a lineage. These clusters share the same v and j gene segments in their heavy and light chain variable domains and the same HCDR3 length. Given their inferred in vivo evolutionary relationship, all siblings within a cluster may be expected to share similar qualitative properties such as epitope binding and mode of action, especially where siblings were obtained from B cells which were recovered by antigen specific sorting, even if assay data for those siblings are not provided herein. Figure 3A: ADCC reporter assay for anti-UL16 antibodies
ADCC reporter assay showing strong Fc receptor engagement by ten anti-UL16 antibodies. Negative control is an isotype human IgGl and positive control is human immune globulin Cytotect. All of the antibodies tested showed activity significantly stronger than the control Cytotect.
Figure 3B: ADCC reporter assay for anti-UL141 antibodies
ADCC reporter assay showing the results from the 9 strongest binding anti-UL141 antibodies. Only one of these antibodies (ARAM-0601) shows ADCC activity in this assay. Negative control is an isotype human IgGl and positive control is human immune globulin Cytotect.
Figure 3C: ADCC reporter assay for anti-US28 antibodies
ADCC reporter assay showing the results from 7 anti-US28 antibodies. Two of these antibodies (PORT- 0601 and PORT-0501) shows ADCC activity in this assay. Negative control is an isotype human IgGl and positive control is a hybridoma anti-US28 antibody TUB-45.
Figure 4A: BATDA ADCC assay using UL16 antibody
BATDA ADCC assay showing NK mediated killing of ULI 6 expressing cells in the presence of antibody ATHO-0106. Human isotype IgGl is used as a negative control.
Figure 4B: BATDA ADCC assay using anti-US28 antibodies
Primary human NK cells showed significant killing of target cells expressing US28 in the presence of anti-US28 antibodies PORT-0601 and PORT-0501. Human isotype IgGl is used as a negative control and human immune globulin Cytotect is used as a positive control. Both antibodies showed greater NK mediated killing compared with Cytotect.
Figure 5A: ADCC activity of Fc modified and unmodified antibodies against UL16
Antibodies with a standard IgGl Fc region or that were mutated (S239D/I332E) in the Fc region were tested for activity using the reporter ADCC assay. Antibodies containing the Fc modifications (closed symbols) showed increased Fc receptor engagement compared to the unmodified antibodies (open symbols).
Figure 5B: ADCC activity of Fc modified clones and unmodified antibodies against UL141
Antibodies with a standard IgGl Fc region or that were mutated (S239D/I332E) in the Fc region were tested for activity using the reporter ADCC assay. Antibodies containing the Fc modifications (closed symbols) showed increased Fc receptor engagement compared to the unmodified antibodies (open symbols). Figure 6: Anti-UL16, anti-UL141 and anti-US28 antibodies bind to HCMV infected HFF cells
HFF cells were infected with HCMV and cell surface expression of ULI 6 detected using antibody ATHO-0601, UL141 expression detected by antibody ARAM-0203 and US28 expression detected by antibody PORT-0601 and Alexa647 secondary antibody. All targets were expressed on the cell surface by 48 hours after infection and the antibodies showed strong binding to these infected cells. Controls including isotype control, secondary antibody only and instainded cells did not detect staining, indicating specific staining for the targets in infected cells. All staining was also run using non-infected HFFs cells to determine non-specific binding.
Figure 7A: Degranulation assay for anti-US28 antibodies
HFFF cells were infected with either an adenovirus expressing full length US28 protein (RAdUS28), or a control adenovirus that does not express US28 (RAd-1253). Seven anti-US28 antibodies were incubated individually (1.5pg/ml) or as a mix (comprising 1.5pg/ml of each antibody), with human PBMCs and target cells expressing US28 or control (blue and red bars respectively). As a negative control each antibody was also incubated with PBMCs without the addition of target cells (black bars). Negative controls included wells with no antibody (RPMI, cell culture media only) and human serum from individuals seronegative for anti-HCMV antibodies (Neg IgG). Positive control was Cytotect (CT, 30pg/ml), a clinical-grade human polyclonal serum of anti-HCMV antibodies. NK cell degranulation was measured as CD107a positive cells by flow cytometry and expressed as a percentage of the total number of CD56+CD3-CD57+ NK cells. Results are means ± SD of triplicate samples.
Figure 7B: Degranulation assay for anti-UL16 antibodies
HFFF cells were infected with either an adenovirus expressing full length ULI 6 protein (RAdUL16), or a control adenovirus that does not express UL16 (RAd-1253). Ten anti-UL16 antibodies were incubated individually (1.5pg/ml) or as a mix (1.5pg/ml of each antibody), with human PBMCs and the target cells expressing ULI 6 or control (blue and red bars respectively). As a control each antibody was also incubated with PBMCs without the addition of target cells (black bars). Negative controls included wells with no antibody (RPMI, cell culture media only) and human serum from individuals seronegative for anti-HCMV antibodies (Neg IgG). Positive control was Cytotect (CT, 30pg/ml), a clinical-grade human polyclonal serum of anti- HCMV antibodies. NK cell degranulation was measured as CD107a positive cells by flow cytometry and expressed as a percentage of the total number of CD56+CD3-CD57+ NK cells. Results are means ± SD of triplicate samples. Figure 7C: Degranulation assay for anti-UL141 antibodies
HFFF cells were infected with either RAdUL141, an adenovirus expressing full length UL141 protein, or a control RAd-1253 that does not express UL141. Nine anti-UL141 antibodies were incubated individually (1.5 pg/ml) or as a mix (1.5 pg/ml of each antibody), with human PBMCs and the target cells expressing UL 141 or control (blue and red bars respectively). As a control each antibody was also incubated with PBMCs without the addition of target cells (black bars). Negative controls included wells with no antibody (RPMI, cell culture media only) and human serum from individuals seronegative for anti-HCMV antibodies (Neg IgG). Positive control was Cytotect (CT, 30pg/ml), a clinical-grade human polyclonal serum of anti-HCMV antibodies. NK cell degranulation was measured as CD 107a positive cells by flow cytometry and expressed as a percentage of the total number of CD56+CD3-CD57+ NK cells. Results are means ± SD of triplicate samples.
V. DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
Unless otherwise defined herein, scientific and technical terms shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthis disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."
In the specification and clauses, the term "about" is used to modify, for example, the quantity of an ingredient in a composition, concentration, volume, process temperature, process time, yield, flow rate, pressure, and like values, and ranges thereof, employed in describing the examples of the disclosure. The term "about" refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrates or use formulations; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of starting materials or ingredients used to carry out the methods, and like proximate considerations. The term "about" also encompasses amounts that differ due to aging of a formulation with a particular initial concentration or mixture and amounts that differ due to mixing or processing a formulation with a particular initial concentration or mixture. Where modified by the term "about" the clauses appended hereto include equivalents to these quantities.
As used herein, “administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an antibody that specifically binds UL16, an antibody that specifically binds UL141 or an antibody that specifically binds US28 provided herein, or its encoding nucleic acid e.g. in an expression vector) into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, inhalation e.g. nebulisation and/or any other method of physical delivery described herein or known in the art. When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease, or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof.
The term "antibody", “immunoglobulin” or “Ig” may be used interchangeably herein and means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies (including dual binding antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. The term "antibody" can also refer to a Y-shaped glycoprotein with a molecular weight of approximately 150 kDa that is made up of four polypeptide chains: two light (L) chains and two heavy (H) chains. There are five types of mammalian Ig heavy chain isotypes denoted by the Greek letters alpha (a), delta (5), epsilon (a), gamma (y), and mu (p). The type of heavy chain defines the class of antibody, i.e., IgA, IgD, IgE, IgG, and IgM, respectively. The y and a classes are further divided into subclasses on the basis of differences in the constant domain sequence and function, e.g., IgGl, hIgG2, mIgG2A, mIgG2B, IgG3, IgG4, IgAl and IgA2. In mammals, there are two types of immunoglobulin light chains, X and K. The "variable region" or "variable domain" of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as "VH" and "VL", respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites. An example of antibodies are heavy chain-only (i.e., H2) antibodies that comprise a dimer of a heavy chain (5'- VH-(optional Hinge)-CH2-CH3-3') and are devoid of a light chain.
The antibodies described herein may be oligoclonal, polyclonal, monoclonal (including full-length monoclonal antibodies), camelised, chimeric, CDR-grafted, multi-specific, bi-specific (including dual-binding antibodies), catalytic, chimeric, humanized, fully human, anti-idiotypic, including antibodies that can be labelled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques. An antibody may be from any species. Antibodies described herein can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.
The term “antigen binding domain,” “antigen binding region,” “antigen binding fragment,” and similar terms refer to that portion of an antibody which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g. the complementarity determining regions (CDRs)). The antigen binding region can be derived from any animal species, such as rodents (e.g. rabbit, rat or hamster) and humans. Preferably, the antigen binding region will be of human origin.
Antigen binding fragments described herein can include single-chain Fvs (scFv), single- chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (diabody), anti-idiotypic (anti-Id) antibodies (including, e.g. anti-Id antibodies to antibodies), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope -binding fragments of any of the above. In particular, antibodies and antibody fragments described herein can include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab" fragments, and a "Fc" fragment, having no antigen-binding activity but having the ability to crystallize. "Fab" when used herein refers to a fragment of an antibody that includes one constant and one variable domain of each of the heavy and light chains. The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native- sequence Fc regions and variant Fc regions. The "Fc fragment" refers to the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells. Digestion of antibodies with the enzyme, pepsin, results in a F(ab')2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites. The F(ab')2 fragment has the ability to crosslink antigen.
"Fv" when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g. isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, and are directed against a single antigenic determinant or epitope. In contrast, polyclonal antibody preparations typically include different antibodies directed against different antigenic determinants (or epitopes). The term "monoclonal antibody" as used herein encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, "monoclonal antibody" refers to such antibodies made in any number of ways including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.
The monoclonal antibodies herein can include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies that exhibit the desired biological activity.
The term "humanized antibody" refers to a subset of chimeric antibodies in which a "hypervariable region" from a non-human immunoglobulin (the donor antibody) replaces residues from a hypervariable region in a human immunoglobulin (recipient antibody). In general, a humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the framework regions are those of a human immunoglobulin sequence, although the framework regions may include one or more substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc.
The term “bispecific antibody” means an antibody which comprises specificity for two target molecules, and includes, but is not limited to, formats such as DVD-Ig (see DiGiammarino et al., “Design and generation of DVD-Ig™ molecules for dual-specific targeting”, Meth. Mo. Biol., 2012, 889, 145-156), mAb2 (see W02008/003103, the description of the mAb2 format is incorporated herein by reference), FIT-Ig (see W02015/103072, the description of the FIT-Ig scaffold is incorporated herein by reference), mAb-dAb, dock and lock, Fab-arm exchange, SEEDbody, Triomab, LUZ-Y, Fcab, K/.-body. orthogonal Fab, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, intrabody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, Triple body, Miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, scFv- CH-CL-scFv, F(ab’)2-scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCab, ImmTAC, knobs-in-holes, knobs-in- holes with common light chain, knobs-in-holes with common light chain and charge pairs, charge pairs, charge pairs with common light chain, DT-IgG, DutaMab, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig and zybody. For a review of bispecific formats, see Spiess, C., et al., Mol. Immunol. (2015). In another example, the bispecific molecule comprises an antibody which is fused to another non-Ig format, for example a T-cell receptor binding domain; an immunoglobulin superfamily domain; an agnathan variable lymphocyte receptor; a fibronectin domain (e.g. an Adnectin™); an antibody constant domain (e.g. a CH3 domain, e.g., a CH2 and/or CH3 of an Fcab™) wherein the constant domain is not a functional CHI domain; an scFv; an (scFv)2; an sc- diabody; an scFab; a centyrin and an epitope binding domain derived from a scaffold selected from CTLA-4 (Evibody™); a lipocalin domain; Protein A such as Z-domain of Protein A (e.g. an Affibody™ or SpA); an A- domain (e.g. an Avimer™ or Maxibody™); a heat shock protein (such as and epitope binding domain derived from GroEI and GroES); a transferrin domain (e.g. a trans-body); ankyrin repeat protein (e.g. a DARPin™); peptide aptamer; C-type lectin domain (e.g. Tetranectin™); human y- crystallin or human ubiquitin (an affilin); a PDZ domain; scorpion toxin; and a kunitz type domain of a human protease inhibitor.
In one example, the bispecific antibody is a mAb2. A mAb2 comprises a VH and VL domain from an intact antibody, fused to a modified constant region, which has been engineered to form an antigen-binding site, known as an “Fcab”. The technology behind the Fcab/mAb2 format is described in more detail in W02008/003103, and the description of the mAb2 format is incorporated herein by reference.
In one example, a “bispecific antibody” does not include a FIT-Ig format. In one example, a “bispecific antibody” does not include a mAb2 format. In one example, a “bispecific antibody” does not include either a FIT-Ig format or a mAb2 format.
In another example, the bispecific antibody is a “dual binding antibody”. As used herein, the term “dual binding antibody” is a bispecific antibody wherein both antigen-binding domains are formed by a VH/VL pair, and includes FIT-Ig (see W02015/103072, incorporated herein by reference), mAb-dAb, dock and lock, Fab-arm exchange, SEEDbody, Triomab, LUZ-Y, Fcab, K/.-body. orthogonal Fab, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, intrabody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, Triple body, Miniantibody, minibody, scFv-CH3 KIH, scFv-CH-CL-scFv, F(ab’)2-scFv, scFv- KIH, Fab-scFv-Fc, tetravalent HCab, ImmTAC, knobs-in-holes, knobs-in-holes with common light chain, knobs-in-holes with common light chain and charge pairs, charge pairs, charge pairs with common light chain, DT-IgG, DutaMab, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)- IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv and scFv4-Ig.
The term "hypervariable region", "CDR region" or "CDR" refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops. Generally, antigen binding sites of an antibody include six hypervariable regions: three in the VH (CDRH1, CDRH2, CDRH3), and three in the VL (CDRL1, CDRL2, CDRL3). These regions of the heavy and light chains of an antibody confer antigenbinding specificity to the antibody. CDRs may be defined according to the Kabat system (see Kabat, E. A.et al., 1991, “Sequences of Proteins of Immunological Interest”, 5th edit., NIH Publication no. 91-3242, U.S. Department of Health and Human Services). Other systems may be used to define CDRs, which as the system devised by Chothia et al (see Chothia, C. & Lesk, A. M., 1987, “Canonical structures for the hypervariable regions of immunoglobulins”, J. Mol. Biol., 196, 901-917) and the IMGT system (see Lefranc, M. P., 1997, “Unique database numbering system for immunogenetic analysis”, Immunol. Today, 18, 50). An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs. The term CDR or CDRs is used here to indicate one or several of these regions. A person skilled in the art is able to readily compare the different systems of nomenclature and determine whether a particular sequence may be defined as a CDR.
A "human antibody" is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies and specifically excludes a humanized antibody comprising non-human antigen-binding residues.
The term "specifically binds to" refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets. In one example, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g. by a radioimmunoassay (RIA).
An antibody that specifically binds to a UE16 protein antigen, an antibody that specifically binds to a UE141 protein antigen or an antibody that specifically binds to US28 protein antigen can be identified, for example, by immunoassays, BIAcore™, or other techniques known to those of skill in the art. An antibody binds specifically to a UE16 protein antigen when it binds to a UE16 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (EEISAs). Similarly, an antibody binds specifically to a UL141 protein antigen when it binds to a UL141 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISAs). Similarly, an antibody binds specifically to a US28 protein antigen when it binds to a US28 protein antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISAs). Typically, a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times (such as more than 15 times, more than 20 times, more than 50 times or more than 100 times) background. See, e.g. Paul, ed., 1989, Fundamental Immunology Second Edition, Raven Press, New York at pages 332-336 for a discussion regarding antibody specificity.
As used herein, “authorization number” or “marketing authorization number” refers to a number issued by a regulatory agency upon that agency determining that a particular medical product and/or composition may be marketed and/or offered for sale in the area under the agency’s jurisdiction. As used herein “regulatory agency” refers to one of the agencies responsible for evaluating, e.g. the safety and efficacy of a medical product and/or composition and controlling the sales/marketing of such products and/or compositions in a given area. The Food and Drug Administration (FDA) in the US and the European Medicines Agency (EP A) in Europe are but two examples of such regulatory agencies. Other non-limiting examples can include SDA, MPA, MHPRA, IMA, ANMAT, Hong Kong Department of Health-Drug Office, CDSCO, Medsafe, and KFDA.
As used herein, the term “carrier” refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
As used herein, the term “composition” is intended to encompass a product containing the specified ingredients (e.g. an antibody) in, optionally, the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in, optionally, the specified amounts.
As used herein the term "comprising" or "comprises" is used with reference to antibodies, uses, compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
The term "consisting of' refers to antibodies, uses, compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the example.
As used herein the term "consisting essentially of' refers to those elements required for a given example. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that example.
The term "effector function" as used herein is meant to refer to one or more of antibody dependant cell mediated cytotoxic activity (ADCC), complement-dependant cytotoxic activity (CDC) mediated responses, Fc-mediated phagocytosis or antibody dependant cellular phagocytosis (ADCP), and antibody recycling via the FcRn receptor.
An "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired effect, including a therapeutic or prophylactic result. A "therapeutically effective amount" refers to the minimum concentration required to effect a measurable improvement or prevention of a particular disorder. A therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount is also one in which toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at the dosages and for periods of time necessary, to achieve the desired prophylactic result. In some examples, the effective amount of an antibody is from about 0.1 mg/kg (mg of antibody per kg weight of the subject) to about 100 mg/kg. In certain examples, an effective amount of an antibody provided therein is about 0. 1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, 3 mg/kg, 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg about 90 mg/kg or about 100 mg/kg (or a range therein). In some examples, “effective amount” as used herein also refers to the amount of an antibody to achieve a specified result (e.g. killing a cell expressing the UL16, UL141 and/or US28 protein).
The term “epitope” as used herein refers to a localized region on the surface of an antigen, such as a ULI 6, UL141, or US28 protein, that is capable of being bound to one or more antigen binding regions of an antibody, and that has antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human, that is capable of eliciting an immune response. An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal. An epitope having antigenic activity is a portion of a polypeptide to which an antibody specifically binds as determined by any method well known in the art, for example, by the immunoassays described herein. Antigenic epitopes need not necessarily be immunogenic. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. A region of a polypeptide contributing to an epitope may be contiguous amino acids of the polypeptide or the epitope may come together from two or more non-contiguous regions of the polypeptide. The epitope may or may not be a three-dimensional surface feature of the antigen. In certain embodiments, a UL16, UL141, or US28 protein epitope is a three-dimensional surface feature of a UL16, UL141 or US28 protein polypeptide respectively. In other embodiments, a ULI 6, UL141 or US28 protein epitope is linear feature of aUL16, UL141, or US28 protein polypeptide respectively. In certain embodiments, antibodies provided herein may specifically bind to an epitope of the UL16, UL141 or US28 protein in part by using an interaction with an N-linked glycan or another post-translational modification of the protein. Binding to the respective epitope thus might involve moving the N-linked glycan or post-translational modification away thereby removing or reducing steric hindrance that would otherwise prevent or hinder antibody binding.. Antibodies may be provided which bind to the same epitope as an ATHO, ARAM or PORT antibody disclosed herein. This is optionally determined using X-ray crystallography or other fine mapping techniques such as electron microscopy to identify the contact points between antibody and antigen. An antibody may contact the UL16, UL141 or US28 protein with a footprint that fully or partly overlaps with that of an ATHO, ARAM or PORT antibody respectively. As described elsewhere herein, competition between antibodies may also be determined, for example using SPR, and antibodies of the present invention may compete for binding to the UL16, UL141 or US28 protein (compete for binding to their epitope) with an IgG antibody that is any ATHO, ARAM or PORT antibody described herein respectively.
The term “excipients” as used herein refers to inert substances which are commonly used as a diluent, vehicle, preservatives, binders, or stabilizing agent for drugs and includes, but not limited to, proteins (e.g. serum albumin, etc.), amino acids (e.g. aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g. alkyl sulfonates, caprylate, etc.), surfactants (e.g. SDS, polysorbate, non-ionic surfactant, etc.), saccharides (e.g. sucrose, maltose, trehalose, etc.) and polyols (e.g. mannitol, sorbitol, etc.). See, also, Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.
The term “fusion protein” as used herein refers to a polypeptide that comprises an amino acid sequence of an antibody and an amino acid sequence of a heterologous polypeptide or protein (i.e. a polypeptide or protein not normally a part of the antibody (e.g. a non-anti-UL16, UL141 or US28 protein antigen antibody)). The term “fusion” when used in relation to an antibody refers to the joining of a peptide or polypeptide, or fragment, variant and/or derivative thereof, with a heterologous peptide or polypeptide. Preferably, the fusion protein retains the biological activity of the antibody that specifically binds ULI 6 protein, the antibody that specifically binds UL141 protein, or the antibody that specifically binds US28 protein.
The term “heavy chain” when used with reference to an antibody refers to five distinct types, called alpha (a), delta (5), epsilon (a), gamma (y) and mu (p), based on the amino acid sequence of the heavy chain constant domain. These distinct types of heavy chains are well known and give rise to five classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including two subclasses of IgA, namely IgAl and IgA2 and four subclasses of IgG, namely IgGl, IgG2, IgG3 and IgG4. Preferably the heavy chain is a human heavy chain. In the human population, multiple heavy chain constant region alleles, of each immunoglobulin or immunoglobulin subclass, exist. The nucleotide and amino acid sequences of these allelic variants are accessible on publicly available databases such as IMGT, ENSEMBL Swiss-Prot and Uniprot. Allelic variants may also be identified in various genome sequencing projects. In one example, the antibodies disclosed herein comprise a heavy chain encoded by a IgGl constant region allele, which includes, but is not limited to, human IGHG1 *01, IGHG1*O2, IGHGl*03, IGHG1*O4 and IGHGl*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). In one example, the antibodies disclosed herein comprise a protein encoded by a IgG4 constant region allele, which includes but is not limited to human IGHG4*01, IGHG4*02, IGHG4*03 and IGHG4*04 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). In another example, the heavy chain is an IgA isotype, human IgAl or human IgA2, example amino acid sequences for which are shown in Table 2. In another example, the heavy chain is a disabled IgG isotype, e.g. a disabled IgG4. In certain examples, the antibodies comprise a human gamma 4 constant region. In another example, the heavy chain constant region does not bind Fc-y receptors, and e.g. comprises a Leu235Glu mutation. In another example, the heavy chain constant region comprises a Ser228Pro mutation to increase stability. In another example, the heavy chain constant region is IgG4-PE. In another example, the antibodies disclosed herein comprise a heavy chain constant region encoded by a murine IgGl constant region allele, which includes but is not limited to mouse IGHGl*01 or IGHG1*O2. Mutations in the Fc region have been shown in the literature to increase the Fc-mediated effector function of antibodies, including ADCC. The Fc-enhancing variants described by Lazar et al., 2006 include the single mutants S239D and I332E and the double and triple mutants S239D/I332E and S239D/I332E/A330L (Engineered antibody Fc variants with enhanced effector function” Greg A. Lazar, Wei Dang, Sher Karki, Omid Vafa, Judy S. Peng, Linus Hyun, Cheryl Chan, Helen S. Chung, Araz Eivazi, Sean C. Yoder, Jost Vielmetter, David F. Carmichael, Robert J. Hayes, Bassil I. Dahiyat. Proc Natl Acad Sci U S A. 2006 Mar 14; 103(11): 4005-4010). In some examples, the heavy chain constant region comprises a S239D mutation. In some examples, the heavy chain constant region comprises a I332E mutation. In some examples, the heavy chain constant region comprises the double mutation S239D/I332E. In some examples, the heavy chain constant region comprises the triple mutation S239D/I332E/A330L.
The term “host” as used herein refers to an animal, preferably a mammal, and most preferably a human.
The term “host cell” as used herein refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
The term “in combination” in the context of the administration of other therapies refers to the use of more than one therapy. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject with a disease. A first therapy can be administered before (e.g. 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently, or after (e.g. 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) the administration of a second therapy to a subject. Any additional therapy can be administered in any order with the other additional therapies. In certain examples, the antibodies can be administered in combination with one or more therapies. As used herein, "injection device" refers to a device that is designed for carrying out injections, an injection including the steps of temporarily fluidically coupling the injection device to a person's tissue, typically the subcutaneous tissue. An injection further includes administering an amount of liquid drug into the tissue and decoupling or removing the injection device from the tissue. In some examples, an injection device can be an intravenous device or IV device, which is a type of injection device used when the target tissue is the blood within the circulatory system, e.g. the blood in a vein. A common, but non-limiting example of an injection device is a needle and syringe.
As used herein, “instructions” refers to a display of written, printed or graphic matter on the immediate container of an article, for example the written material displayed on a vial containing a pharmaceutically active agent, or details on the composition and use of a product of interest included in a kit containing a composition of interest. Instructions set forth the method of the treatment as contemplated to be administered or performed.
An "isolated" or “purified” antibody or protein is one that has been identified, separated and/or recovered from a component of its production environment (e.g. natural or recombinant). For example, the antibody or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of an antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”). When the antibody is recombinantly produced, it is also preferably substantially free of culture medium, i.e. culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. When the antibody is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. In a preferred example, antibodies are isolated or purified.
The terms “Kabat numbering,” and like terms are recognized in the art and refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al., (1971) Ann. NY Acad. Sci., 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region typically ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. "Label" or "labelled" as used herein refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label, chemiluminescent label or a biotinyl group or gold. Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, 115In, 1251, 1311, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, P-galactosidase, luciferase, alkaline phosphatase. Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH"), alpha-D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes (e.g. cyanine dyes, e.g. Cy5TM, Cy5.5TM. or Cy7TM); additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein"), other fluorescent proteins (e.g. mCherry, mTomato), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g. Europium etc (Perkin Elmer and Cisbio Assays); chemoluminescent labels or chemiluminescers, such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5- bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, saporin or a cytotoxic fragment thereof, pokeweed antiviral toxin or a cytotoxic fragment thereof and bryodin 1 or a cytotoxic fragment thereof.
The term “light chain” when used in reference to an antibody refers to the immunoglobulin light chains, of which there are two types in mammals, lambda (X) and kappa (K). Preferably, the light chain is a human light chain. Preferably the light chain constant region is a human constant region. In the human population, multiple light chain constant region alleles exist. The nucleotide and amino acid sequences of these allelic variants are accessible on publicly available databases such as IMGT, ENSEMBL, Swiss-Prot and Uniprot. In one example, the antibodies disclosed herein comprise a protein encoded by a human K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*02, IGKC*03, IGKC*04 and IGKC*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). In one example, the antibodies disclosed herein comprise a protein encoded by a human X constant region allele, which includes but is not limited to IGLC1*OI, IGLC1*O2, IGLC2*01, IGLC2*02, IGLC2*03, IGLC3*01, IGLC3*02, IGLC3*03, IGLC3*04, IGLC6*01, IGLC7*01, IGLC7*02, and IGLC7*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). In another example, the antibodies disclosed herein comprise a light chain constant region encoded by a mouse K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*03 or IGKC*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). In another example, the antibodies disclosed herein comprise a light chain constant region encoded by a mouse X constant region allele, which includes, but is not limited to, IGLCl*01, IGLC2*01 or IGLC3*01 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
"Percent (%) amino acid sequence identity" with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEG ALIGN™ (DNASTAR) software. In one example, the % identity is about 70%. In one example, the % identity is about 75%. In one example, the % identity is about 80%. In one example, the % identity is about 85%. In one example, the % identity is about 90%. In one example, the % identity is about 92%. In one example, the % identity is about 95%. In one example, the % identity is about 97%. In one example, the % identity is about 98%. In one example, the % identity is about 99%. In one example, the % identity is 100%.
The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to those which are found in nature and not manipulated by a human being.
As used herein, “packaging” refers to how the components are organized and/or restrained into a unit fit for distribution and/or use. Packaging can include, e.g. boxes, bags, syringes, ampoules, vials, tubes, clamshell packaging, barriers and/or containers to maintain sterility, labelling, etc.
The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
As used herein, the term “polynucleotide,” “nucleotide,” nucleic acid” “nucleic acid molecule” and other similar terms are used interchangeable and include DNA, RNA, mRNA and the like.
As used herein, the terms “prevent”, “preventing”, and “prevention” refer to the total or partial inhibition of the development, recurrence, onset or spread of HCMV infection or a HCMV-related disease or condition, and/or symptom related thereto, resulting from the administration of a therapy or combination of therapies provided herein (e.g. a combination of prophylactic or therapeutic agents, such as an antibody). The term "soluble" refers to a polypeptide that is lacking one or more transmembrane or cytoplasmic domains found in the native or membrane-associated form. In one example, the "soluble" form of a polypeptide lacks both the transmembrane domain and the cytoplasmic domain.
The term "subject" or "patient" refers to any animal, including, but not limited to, mammals. As used herein, the term "mammal" refers to any vertebrate animal that suckle their young and either give birth to living young (eutharian or placental mammals) or are egg-laying (metatharian or nonplacental mammals). Examples of mammalian species include, but are not limited to, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats (including cotton rats) and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
As used herein “substantially all” refers to refers to at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.
The term “surfactant” as used herein refers to organic substances having amphipathic structures; namely, they are composed of groups of opposing solubility tendencies, typically an oil-soluble hydrocarbon chain and a water-soluble ionic group. Surfactants can be classified, depending on the charge of the surface -active moiety, into anionic, cationic, and non-ionic surfactants. Surfactants are often used as wetting, emulsifying, solubilizing, and dispersing agents for various pharmaceutical compositions and preparations of biological materials.
As used herein, the term “tag” refers to any type of moiety that is attached to, e.g. a polypeptide and/or a polynucleotide that encodes an antibody that specifically binds ULI 6 protein, an antibody that specifically binds UL141 protein or an antibody that specifically binds US28 protein. For example, a polynucleotide that encodes an antibody that specifically binds ULI 6 protein, an antibody that specifically binds UL141 protein or an antibody that specifically binds US28 protein can contain one or more additional tag-encoding nucleotide sequences that encode e.g. a detectable moiety or a moiety that aids in affinity purification. When translated, the tag and the antibody can be in the form of a fusion protein. The term “detectable” or “detection” with reference to a tag refers to any tag that is capable of being visualized or wherein the presence of the tag is otherwise able to be determined and/or measured (e.g. by quantitation). A non-limiting example of a detectable tag is a fluorescent tag.
As used herein, the term “therapeutic agent” refers to any agent that can be used in the treatment, management or amelioration of a HCMV infection or HMCV-related disease or condition, and/or a symptom related thereto. In certain examples, the term “therapeutic agent” refers to an antibody. In certain other examples, the term “therapeutic agent” refers to an agent other than an antibody. Preferably, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management or amelioration of a HCMV infection or HCMV-related disease or condition, and/or one or more symptoms related thereto. In specific examples, the therapeutic agent is an antibody that specifically binds ULI 6 protein, an antibody that specifically binds UL141 protein or an antibody that specifically binds US28 protein. In specific examples, the therapeutic agent is a fully human antibody that specifically binds ULI 6 protein, a fully human antibody that specifically binds UL141 protein or a fully human antibody that specifically binds US28 protein, such as a fully human monoclonal antibody that specifically binds ULI 6 protein, a fully human monoclonal antibody that specifically binds UL141 protein or a fully human monoclonal antibody that specifically binds US28 protein.
As used herein, the term “therapy” refers to any protocol, method and/or agent that can be used in the prevention, management, treatment and/or amelioration of a HCMV infection or HMCV-related disease or condition. In certain examples, the terms “therapies” and “therapy” refer to a biological therapy, supportive therapy, and/or other therapies useful in the prevention, management, treatment and/or amelioration of a HCMV infection or HMCV-related disease or condition, known to one of skill in the art such as medical personnel.
The terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of a HCMV infection or HMCV-related disease or condition resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody). In specific examples, such terms refer to the inhibition or reduction of one or more symptoms associated with a HCMV infection or HMCV-related disease or condition.
The term “variable region” or “variable domain” refers to a portion of the light and heavy chains, typically about the amino-terminal 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complimentarily determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). The CDRs are primarily responsible for the interaction of the antibody with antigen. Numbering of amino acid positions used herein is according to IMGT (Lefranc MP “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains”, Dev. Comp. Immunol. 27(l):55-77 (2003)). In preferred examples, the variable region is a human variable region.
Definitions of common terms in cell biology and molecular biology can be found in “The Merck Manual of Diagnosis and Therapy”, 19th Edition, published by Merck Research Laboratories, 2006 (ISBN 0-911910-19- 0); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); Benjamin Lewin, Genes X, published by Jones & Bartlett Publishing, 2009 (ISBN-10: 0763766321); Kendrew et al. (Eds.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8) and Current Protocols in Protein Sciences 2009, Wiley Intersciences, Coligan et al., eds.
Unless otherwise stated, the present disclosure was performed using standard procedures, as described, for example in Sambrook et al., Molecular Cloning: A Laboratory Manual (4 ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (1995); or Methods in Enzymology: Guide to Molecular Cloning Techniques Vol. 152, S. L. Berger and A. R. Kimmel Eds., Academic Press Inc., San Diego, USA (1987); Current Protocols in Protein Science (CPPS) (John E. Coligan, et al., ed., John Wiley and Sons, Inc.), Current Protocols in Cell Biology (CPCB) (Juan S. Bonifacino et al. ed., John Wiley and Sons, Inc.), and Culture of Animal Cells: A Manual of Basic Technique by R. Ian Freshney, Publisher: Wiley-Liss; 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, Jennie P. Mather and David Barnes editors, Academic Press, 1st edition, 1998) which are all incorporated by reference herein in their entireties.
Other terms are defined herein within the description of the various examples of the disclosure.
HCMV
HCMV prevalence and natural history lead to two predominant HCMV disease patterns. After a primary infection HCMV is not eliminated by the immune system and instead establishes latency and persistence. Like other members of the herpesvirus family, it remains dormant in cells throughout the body and asymptomatic reactivation can occur throughout life. During latency, the HCMV genome is maintained as a DNA episome with little or no major viral protein synthesis or virus production. Despite HCMV’s high species specificity productive infection can be established in nearly every tissue in humans.
When an adult undergoes immune suppressive therapy for organ transplantation, HCMV infection or reactivation causes significant morbidity, some mortality and can limit organ engraftment. In-utero or peri/post- natal infection can cause significant disease and permanent damage to a child.
During primary infection, the virus replicates in epithelial cells of the upper alimentary, respiratory and genitourinary tracts. Once HCMV infection is established, leukocyte and endothelial cell associated viremia appears to play an important role in disseminating the virus between the various tissues of the host. Productive HCMV replication can occur in diverse cell types including fibroblasts, epithelial cells, macrophages, smooth muscle and endothelial cells. Like all other herpesviruses, the primary infection is controlled by humoral and cell-mediated responses leading to a clearing of productive virus infected cells and the establishment of a latent reservoir of HCMV hematopoietic progenitor cells of the myeloid lineage. HCMV has a double stranded DNA genome of 235-kb encoding for -170 genes. Although many cytomegalovirus gene products are of importance in cytomegalovirus immunity, for example multiple virally encoded glycoproteins such as glycoprotein B (gB) and glycoprotein H (gH) are the targets of neutralizing antibodies, and cytotoxic T-cell (CTL) responses exist against various HCMV proteins, the immune response is insufficient to prevent reinfection (superinfection) as demonstrated by the presence of extensive HCMV genetic recombination and is inadequate in preventing trans-placental infection, which can occur even in women who are HCMV seropositive.
Flow cytometry assays based on the difference in cell surface expression of certain proteins in the latent phase as compared to the lytic phase have been developed to determine whether HCMV infected cells are in the latent or lytic phase. Such assays have been described, for example in WO2015/073788, the contents of which are hereby incorporated by reference. Certain proteins for which plasma membrane expression was upregulated following HCMV infection were identified by cell surface proteomics in WO2015/073788.
HCMV TARGETS
Here we identify HCMV-related proteins, specifically UL16, UL141 and US28 proteins, that are targets for the prevention of HCMV infection and HCMV-related diseases or conditions, and useful as markers for diagnostics. We have identified antibodies that specifically bind ULI 6 protein, antibodies that specifically bind UL141 protein and antibodies that specifically bind US28 protein. These antibodies may therefore be useful in the treatment and prevention of HCMV and HCMV-related diseases or conditions, and useful as diagnostics.
The antibodies of the invention bind to viral proteins produced by the cell in response to the HCMV invention and do not bind to the virus itself. It has been found that in mutant strains of HCMV, mutations are generally not found in the genes encoding the UL16, UL141 and US28 viral proteins. Thus, it is expected that the antibodies of the invention will have the advantage that they will be effective against multiple strains of HCMV. In other words, it is expected that mutation of the HCMV virus will not result in mutation of the epitope to which an antibody of the invention binds. Thus, the risk of so-called escape mutant versions of the virus i.e. strains of the virus against which the antibodies are not effective is greatly reduced.
The present inventors are the first to demonstrate that antibodies targeting UL16, UL141 or US28 proteins are effective in cell killing. Furthermore, the present inventors are the first to discover that antibodies binding to these targets may be Fc effector enabled. Such antibodies may be Fc effector enabled without additional Fc enhancing mutations being incorporated in the constant region. Antibodies of the invention may have their Fc effector function enhanced further by virtue of an Fc effector enhanced constant region as is known in the art. Alternatively, antibodies which may not display Fc effector enabled properties may be Fc effector enabled by virtue of an Fc effector enhanced constant region as is known in the art.
Exemplary antibodies described herein are set out in Table 1 and described further below.
UL16 PROTEIN
ULI 6 is a viral glycoprotein which plays a key role in NK cell evasion. The NK activating receptor NKG2D is ubiquitously expressed on all NK cells and is capable of recognising at least 8 ligands presented by target cells during stress and viral infection, including the major histocompatibility complex class I (MHC-I) chain-related molecules (MICA and MICB) and UL16-binding proteins (ULBP) 1-6 21. UL16 contributes to immune evasion by sequestration of NKG2D ligands MICB, ULBP1, ULBP2 and ULBP6 in the ER, thus reducing cell surface expression and evading NK killing 22-25. ULI 6 mimics a central binding motif of the structurally unrelated NKG2D protein to facilitate interaction with diverse NKG2D ligands 26. Table 4 shows the amino acid sequences for ligands of ULI 6.
(i) Anti-UL16 antibodies:
Antibodies that specifically bind UL16 protein are provided.
In some examples, the antibody is a human antibody. In one example, the antibody is a fully human antibody. In one example, the antibody is a fully human monoclonal antibody.
In some aspects the antibodies specifically bind the extracellular domain of the ULI 6 protein. Such antibodies binding the extracellular domain of ULI 6 may or may not compete with one or more of the respective ligands for binding to ULI 6 respectively and thus may or may not directly inhibit binding of ULI 6 to the ligand.
In particular, antibodies that specifically bind to ULI 6 protein which mediate killing of HCMV infected cells are provided. The antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region. An effector enabled antibody may recruit natural killer cells to infected cells to achieve ADCC.
In an example, the anti-UL16 antibody mediates killing of cells infected with HCMV. In an example, the anti- UL 16 antibody mediates killing of ULI 6 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody mediates killing of ULI 6 protein expressing cells lyrically infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of cells infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of UL16 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody mediates immune-mediated killing of ULI 6 protein expressing cells lytically infected with HCMV.
In an example, the anti-UL16 antibody mediates NK-cell killing of cells infected with HCMV. In an example, the anti-UL16 antibody mediates NK-cell killing of ULI 6 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody mediates NK-cell killing of ULI 6 protein expressing cells lytically infected with HCMV.
In an example, the anti-UL16 antibody reduces viral load of cells infected with HCMV. In an example, the anti- UL16 antibody reduces viral load of ULI 6 protein expressing cells infected with HCMV. In an example, the anti-UL16 antibody reduces viral load of ULI 6 protein expressing cells lytically infected with HCMV.
An antibody of the present invention may be one which competes for binding to the ULI 6 protein with any ATHO antibody described herein, such as ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-O 106, ATHO-O 107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-O 115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-080I.
Antibodies described herein may compete for binding to ULI 6 protein with one or more ligands of ULI 6 (e.g. MICB, ULBP1, ULBP2 and/or ULBP6). Antibodies described herein may compete for binding to UL16 protein with MICB, ULBP1, ULBP2 and/or ULBP6. Antibodies described herein may block UL16 protein binding to MICB, ULBP1, ULBP2 and/or ULBP6.
In one example, the antibody is selected from the group consisting of ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, and ATHO-0801. In one example, the antibody is selected from the group consisting of ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, and ATHO-0116 (lineage 1 in Figures 2A and 2B). In one example, the antibody is selected from the group consisting of ATHO-0301, ATHO-0302, and ATHO-0303 (lineage 2 in Figures 2C and 2D). In one example, the antibody is selected from the group consisting of ATHO-0201, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, and ATHO-0801 (singletons in Figures 2E and 2F). In one example the antibody is ATHO-0101. In one example the antibody is ATHO-0102. In one example the antibody is ATHO-0103. In one example the antibody is ATHO-0104. In one example the antibody is ATHO- 0105. In one example the antibody is ATHO-0106. In one example the antibody is ATHO-0107. In one example the antibody is ATHO-0108. In one example the antibody is ATHO-0109. In one example the antibody is ATHO-0110. In one example the antibody is ATHO-0111. In one example the antibody is ATHO-0112. In one example the antibody is ATHO-0113. In one example the antibody is ATHO-0114. In one example the antibody is ATHO-0115. In one example the antibody is ATHO-0116. In one example the antibody is ATHO-0201. In one example the antibody is ATHO-0301. In one example the antibody is ATHO-0302. In one example the antibody is ATHO-0303. In one example the antibody is ATHO-0401. In one example the antibody is ATHO- 0501. In one example the antibody is ATHO-0601. In one example the antibody is ATHO-0701. In one example the antibody is ATHO-0801.
Antibody ATHO-0101 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 111, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 110. Antibody ATHO-0101 has a light chain variable region (VL) amino acid sequence of Seq ID No: 116, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 115. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0102 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 121, comprising the CDRH1 amino acid sequence of Seq ID No: 122 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 123 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 120. Antibody ATHO-0102 has a light chain variable region (VL) amino acid sequence of Seq ID No: 125, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 124. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ATHO-0103 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 128, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 127. Antibody ATHO-0103 has a light chain variable region (VL) amino acid sequence of Seq ID No: 130, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 129. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0104 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 132, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 133 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 134 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 131. Antibody ATHO-0104 has a light chain variable region (VL) amino acid sequence of Seq ID No: 136, comprising the CDRL1 amino acid sequence of Seq ID No: 137 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 138 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 135. The VH domain may be combined with any ofthe heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0105 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 140, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 139. Antibody ATHO-0105 has a light chain variable region (VL) amino acid sequence of Seq ID No: 142, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 143 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 141. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ATHO-0106 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 145, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 146 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 144. Antibody ATHO-0106 has a light chain variable region (VL) amino acid sequence of Seq ID No: 148, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 147. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0107 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 150, comprising the CDRH1 amino acid sequence of Seq ID No: 151 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 152 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 149. Antibody ATHO-0107 has a light chain variable region (VL) amino acid sequence of Seq ID No: 154, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 153. The VH domain may be combined with any ofthe heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0108 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 156, comprising the CDRH1 amino acid sequence of Seq ID No: 157 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 123 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 158 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 155. Antibody ATHO-0108 has a light chain variable region (VL) amino acid sequence of Seq ID No: 160, comprising the CDRL1 amino acid sequence of Seq ID No: 161 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 159. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0109 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 163, comprising the CDRH1 amino acid sequence of Seq ID No: 164 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 165 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 166 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 162. Antibody ATHO-0109 has a light chain variable region (VL) amino acid sequence of Seq ID No: 168, comprising the CDRL1 amino acid sequence of Seq ID No: 169 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 167. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0110 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 171, comprising the CDRH1 amino acid sequence of Seq ID No: 172 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 170. Antibody ATHO-0110 has a light chain variable region (VL) amino acid sequence of Seq ID No: 174, comprising the CDRL1 amino acid sequence of Seq ID No: 175 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 173. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0111 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 177, comprising the CDRH1 amino acid sequence of Seq ID No: 178 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 179 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 180 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 176. Antibody ATHO-0111 has a light chain variable region (VL) amino acid sequence of Seq ID No: 182, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 143 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 181. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0112 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 184, comprising the CDRH1 amino acid sequence of Seq ID No: 185 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 186 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 183. Antibody ATHO-0112 has a light chain variable region (VL) amino acid sequence of Seq ID No: 188, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 143 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 187. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0113 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 190, comprising the CDRH1 amino acid sequence of Seq ID No: 191 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 158 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 189. Antibody ATHO-0113 has a light chain variable region (VL) amino acid sequence of Seq ID No: 193, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 192. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0114 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 195, comprising the CDRH1 amino acid sequence of Seq ID No: 164 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 165 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 166 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 194. Antibody ATHO-0114 has a light chain variable region (VL) amino acid sequence of Seq ID No: 197, comprising the CDRL1 amino acid sequence of Seq ID No: 169 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 198 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 196. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0115 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 200, comprising the CDRH1 amino acid sequence of Seq ID No: 112 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 201 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 199. Antibody ATHO-0115 has a light chain variable region (VL) amino acid sequence of Seq ID No: 203, comprising the CDRL1 amino acid sequence of Seq ID No: 126 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 138 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 202. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0116 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 205, comprising the CDRH1 amino acid sequence of Seq ID No: 206 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 113 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 114 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 204. Antibody ATHO-0116 has a light chain variable region (VL) amino acid sequence of Seq ID No: 208, comprising the CDRL1 amino acid sequence of Seq ID No: 117 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 119 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 207. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0201 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 210, comprising the CDRH1 amino acid sequence of Seq ID No: 211 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 212 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 213 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 209. Antibody ATHO-0201 has a light chain variable region (VL) amino acid sequence of Seq ID No: 215, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 217 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 218 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 214. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0301 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 220, comprising the CDRH1 amino acid sequence of Seq ID No: 221 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 222 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 223 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 219. Antibody ATHO-0301 has a light chain variable region (VL) amino acid sequence of Seq ID No: 225, comprising the CDRL1 amino acid sequence of Seq ID No: 226 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 227 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 228 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 224. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0302 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 230, comprising the CDRH1 amino acid sequence of Seq ID No: 231 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 232 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 233 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 229. Antibody ATHO-0302 has a light chain variable region (VL) amino acid sequence of Seq ID No: 235, comprising the CDRL1 amino acid sequence of Seq ID No: 226 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 227 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 236 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 234. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0303 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 238, comprising the CDRH1 amino acid sequence of Seq ID No: 239 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 240 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 241 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 237. Antibody ATHO-0303 has a light chain variable region (VL) amino acid sequence of Seq ID No: 243, comprising the CDRL1 amino acid sequence of Seq ID No: 244 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 227 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 245 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 242. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0401 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 247, comprising the CDRH1 amino acid sequence of Seq ID No: 248 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 249 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 250 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 246. Antibody ATHO-0401 has a light chain variable region (VL) amino acid sequence of Seq ID No: 252, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 253 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 218 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 251. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0501 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 255, comprising the CDRH1 amino acid sequence of Seq ID No: 256 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 257 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 258 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 254. Antibody ATHO-0501 has a light chain variable region (VL) amino acid sequence of Seq ID No: 260, comprising the CDRL1 amino acid sequence of Seq ID No: 261 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 262 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 263 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 259. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0601 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 265, comprising the CDRH1 amino acid sequence of Seq ID No: 266 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 267 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 268 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 264. Antibody ATHO-0601 has a light chain variable region (VL) amino acid sequence of Seq ID No: 270, comprising the CDRL1 amino acid sequence of Seq ID No: 271 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 272 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 269. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0701 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 274, comprising the CDRH1 amino acid sequence of Seq ID No: 275 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 276 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 277 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 273. Antibody ATHO-0701 has a light chain variable region (VL) amino acid sequence of Seq ID No: 279, comprising the CDRL1 amino acid sequence of Seq ID No: 280 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 118 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 281 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 278. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ATHO-0801 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 283, comprising the CDRH1 amino acid sequence of Seq ID No: 284 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 285 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 286 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 282. Antibody ATHO-0801 has a light chain variable region (VL) amino acid sequence of Seq ID No: 288, comprising the CDRL1 amino acid sequence of Seq ID No: 289 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 217 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 290 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 287. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
ATHO-0101-IgGl, ATHO-0102-IgGl, ATHO-0103-IgGl, ATHO-0104-IgGl, ATHO-0105-IgGl, ATHO- 0106-IgGl, ATHO-0107-IgGl, ATHO-0108-IgGl, ATHO-0109-IgGl, ATHO-0110-IgGl, ATHO-0111- IgGl, ATHO-0112-IgGl, ATHO-0113-IgGl, ATHO-0114-IgGl, ATHO-0115-IgGl, ATHO-0116-IgGl, ATHO-0201 -IgGl, ATHO-0301-IgGl, ATHO-0302-IgGl, ATHO-0303-IgGl, ATHO-0401 -IgGl, ATHO- 0501-IgGl, ATHO-0601-IgGl, ATHO-0701-IgGl, and ATHO-0801-IgGl are preferred antibodies according to the invention.
Particularly preferred heavy chain constant region sequnces for use with ATHO-0101, ATHO-0102, ATHO- 0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, and ATHO-0801 are as used in the Examples.
(ii) Competing anti-UL16 antibodies:
The present disclosure describes antibodies of the invention that specifically bind to a ULI 6 protein and which are defined by their function and/ or by their structure. The invention also provides antibodies that compete with those antibodies described herein for binding to the target ULI 6 protein. Such competition may be due, for example, to the antibody binding to an identical or overlapping epitope of the ULI 6 protein as the reference antibody. Such a ‘competing’ antibody may retain the same function as the reference antibody with which it competes. An antibody that binds to an identical (same) epitope can be expected to have the same function as the reference antibody with which it competes. The present inventors are the first to discover ‘active’ epitopes on ULI 6 protein which can be targeted with an antibody for cell killing.
An antibody of the present invention may be one which competes for binding to the ULI 6 protein with any antibody described herein, such as ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-O 106, ATHO-O 107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801 as defined herein. An antibody of the present invention may be one which binds to the same epitope on a ULI 6 protein as any antibody described herein, such as ATHO-0101, ATHO-0102, ATHO-O 103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801 as defined herein.
In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody competes for binding to a ULI 6 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a ULI 6 protein. In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody competes for binding to a ULI 6 protein with a reference antibody selected from antibody ATHO-0101, ATHO-0102, ATHO-O 103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol 10, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody binds to the same epitope on a ULI 6 protein as a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a ULI 6 protein. In one embodiment, an antibody that specifically binds to a ULI 6 protein is provided, wherein said antibody binds to the same epitope on a ULI 6 protein as a reference antibody selected from antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
(iii) Therapeutic anti-UL16 antibody uses:
Antibodies that specifically bind ULI 6 described herein are therefore useful as medicaments. In one example, antibodies that specifically bind ULI 6 described herein may be useful in treating HCMV infection. In one example, antibodies that specifically bind ULI 6 described herein may be useful in a method of reducing HCMV viral load in a patient. In one example, antibodies that specifically bind ULI 6 described herein may be useful in a method of reducing frequency of HCMV virus reactivation in a patient is also provided. In one example, antibodies that specifically bind ULI 6 described herein may be useful in a method of preventing HCMV infection in a patient at risk of thereof. In one example, antibodies that specifically bind ULI 6 described herein may be useful in a method of treating congenital HCMV infection is also provided.
In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
Therefore key therapeutic indications for the antibody are: prophylaxis to prevent HCMV disease associated with immune suppression following transplantation of kidney, lung, liver, pancreas, heart and allogeneic hematopoietic stem cell transplant (HSCT) o The antibody can be used alone, before or in combination with valganciclovir or letermovir (or other antiviral drugs). o Similar to the current label for Cytogam IGIV in the US, an IV human immune globulin product marketed by CSL Behring. treatment of primary HCMV infection in neonates (neonates defined as up to 28 days post birth) diagnosed as HCMV seropositive within the first 3 weeks post birth. prophylaxis against HCMV infection in HCMV seronegative pregnant women in the first trimester to prevent high risk transmission of HCMV to foetus. prophylaxis against HCMV infection in HCMV seropositive pregnant women in the first trimester to prevent transmission of HCMV to foetus leading to asymptomatic infection at birth.
An efficacious antibody that specifically binds ULI 6 should reduce the prevalence of HCMV disease providing an associated reduction in morbidity and improved allograft outcomes. The prevention of HCMV infection is a potential goal in seronegative recipients, but the key outcome would be reduction in disease.
UL141 PROTEIN
UL141 is a type 1 transmembrane glycoprotein involved in downregulation of NK targeting receptors and evasion of apoptosis. It functions to suppress cell surface expression of ligands for NK cell activating receptors via interaction with TNF-related apoptosis-inducing ligand (TRAIL) death receptors as well as CD155 (PVR) and CD 112 (PVRL2), which are both ligands for the ubiquitous NK activating receptor DNAM1 2-4. UL141 is capable of suppressing both CD155 and TRAIL-R2 cell surface expression by retaining proteins in the ER but requires co-operation with US2 for efficient downregulation of cell surface CD 112 2’3,5. Removal of NK activating ligands from the cell surface on infected cells markedly inhibits NK killing of those cells 2,3. Recent structural studies have shown high affinity dimeric binding to TRAIL-R2 and CD 155 (and low affinity binding to TRAIL-R1) forming a heterotetrameric complex 6,7. UL141 is located in the UL/b’ region of the HCMV genome that is frequently deleted in extensively passaged laboratory strains of HCMV 2,4,7. Table 4 shows the amino acid sequences for ligands of UL141. (i) Anti-UL141 antibodies:
Antibodies that specifically bind UL141 protein are provided.
In some examples, the antibody is a human antibody. In one example, the antibody is a fully human antibody. In one example, the antibody is a fully human monoclonal antibody.
In some aspects the antibodies specifically bind the extracellular domain of the UL141 protein. Such antibodies binding the extracellular domain of UL141 may or may not compete with the respective ligands for binding to UL141 respectively and thus may or may not directly inhibit binding of UL141 to its ligand.
In particular, antibodies that specifically bind to UL141 protein which mediate killing of HCMV infected cells are provided. The antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region. An effector enabled antibody may recruit natural killer cells to infected cells to achieve ADCC.
In an example, the anti-UL141 antibody mediates killing of cells infected with HCMV. In an example, the anti-UL141 antibody mediates killing of UL141 protein expressing cells infected with HCMV. In an example, the anti-UL141 antibody mediates killing of UL141 protein expressing cells lytically infected with HCMV.
In an example, the anti-UL141 antibody mediates immune -mediated killing of cells infected with HCMV. In an example, the anti-UL141 antibody mediates immune-mediated killing of UL141 protein expressing cells infected with HCMV. In an example, the anti-UL141 antibody mediates immune-mediated killing of UL141 protein expressing cells lytically infected with HCMV.
In an example, the anti-UL141 antibody mediates NK-cell killing of cells infected with HCMV. In an example, the anti-UL141 antibody mediates NK-cell killing of UL141 protein expressing cells infected with HCMV. In an example, the anti-UL141 antibody mediates NK-cell killing of UL141 protein expressing cells lytically infected with HCMV.
In an example, the anti -UL 141 antibody reduces viral load of cells infected with HCMV. In an example, the anti-UL141 antibody reduces viral load of UL141 protein expressing cells infected with HCMV. In an example, the anti-UL141 antibody reduces viral load of UL141 protein expressing cells lytically infected with HCMV.
An antibody of the present invention may be one which competes for binding to the UL141 protein with any ARAM antibody described herein, such as ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM- 0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801.
Antibodies described herein may compete for binding to UL141 protein with one or more ligands of UL141 (e.g. CD155, CD112 and/or TRAIL-R1/R2). Antibodies described herein may compete for binding to UL141 protein with CD155, CD112 and/or TRAIL-R1/R2. Antibodies described herein may block UL141 protein binding to CD155, CD112 and/or TRAIL-R1/R2.
In one example, the antibody is selected from the group consisting of ARAM-0101, ARAM-0102, ARAM- 0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, and ARAM-0801. In one example, the antibody is selected from the group consisting of ARAM-0101, ARAM-0102, ARAM-0103 (lineage 1 in Figures 2G and 2H). In one example, the antibody is selected from the group consisting of ARAM-0201, ARAM-0202, ARAM- 0203, and ARAM-0204, (lineage 2 in Figures 21 and 2J). In one example, the antibody is selected from the group consisting of ARAM-0301, ARAM-0302 and ARAM-0303 (lineage 3 in Figures 2K and 2L). In one example, the antibody is selected from the group consisting of ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, and ARAM-0801 (singletons in Figures 2M and 2N). In one example the antibody is ARAM- 0101. In one example the antibody is ARAM-0102. In one example the antibody is ARAM-0103. In one example the antibody is ARAM-0201. In one example the antibody is ARAM-0202. In one example the antibody is ARAM-0203. In one example the antibody is ARAM-0204. In one example the antibody is ARAM- 0301. In one example the antibody is ARAM-0302. In one example the antibody is ARAM-0303. In one example the antibody is ARAM-0401. In one example the antibody is ARAM-0501. In one example the antibody is ARAM-0601. In one example the antibody is ARAM-0701. In one example the antibody is ARAM- 0801.
Antibody ARAM-0101 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 2, comprising the CDRH1 amino acid sequence of Seq ID No: 3 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 4 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 5 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 1. Antibody ARAM-0101 has a light chain variable region (VL) amino acid sequence of Seq ID No: 7, comprising the CDRL1 amino acid sequence of Seq ID No: 8 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 9 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 10 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 6. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ARAM-0102 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 12, comprising the CDRH1 amino acid sequence of Seq ID No: 13 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 4 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 5 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 11. Antibody ARAM-0102 has a light chain variable region (VL) amino acid sequence of Seq ID No: 15, comprising the CDRL1 amino acid sequence of Seq ID No: 16 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 17 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 10 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 14. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0103 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 19, comprising the CDRH1 amino acid sequence of Seq ID No: 3 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 4 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 5 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 18. Antibody ARAM-0103 has a light chain variable region (VL) amino acid sequence of Seq ID No: 7, comprising the CDRL1 amino acid sequence of Seq ID No: 8 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 9 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 10 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 6. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0201 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 21, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 20. Antibody ARAM-0201 has a light chain variable region (VL) amino acid sequence of Seq ID No: 26, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 25. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ARAM-0202 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 31, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 30. Antibody ARAM-0202 has a light chain variable region (VL) amino acid sequence of Seq ID No: 33, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 32. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0203 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 35, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 34. Antibody ARAM-0203 has a light chain variable region (VL) amino acid sequence of Seq ID No: 37, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 38 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 36. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0204 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 40, comprising the CDRH1 amino acid sequence of Seq ID No: 22 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 23 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 24 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 39. Antibody ARAM-0204 has a light chain variable region (VL) amino acid sequence of Seq ID No: 42, comprising the CDRL1 amino acid sequence of Seq ID No: 27 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 28 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 29 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 41. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ARAM-0301 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 44, comprising the CDRH1 amino acid sequence of Seq ID No: 45 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 46 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 47 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 43. Antibody ARAM-0301 has a light chain variable region (VL) amino acid sequence of Seq ID No: 49, comprising the CDRL1 amino acid sequence of Seq ID No: 50 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 52 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 48. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0302 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 54, comprising the CDRH1 amino acid sequence of Seq ID No: 45 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 46 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 47 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 53. Antibody ARAM-0302 has a light chain variable region (VL) amino acid sequence of Seq ID No: 49, comprising the CDRL1 amino acid sequence of Seq ID No: 50 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 52 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 48. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0303 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 56, comprising the CDRH1 amino acid sequence of Seq ID No: 57 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 58 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 59 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 55. Antibody ARAM-0303 has a light chain variable region (VL) amino acid sequence of Seq ID No: 61, comprising the CDRL1 amino acid sequence of Seq ID No: 62 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 63 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 60. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ARAM-0401 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 65, comprising the CDRH1 amino acid sequence of Seq ID No: 66 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 67 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 68 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 64. Antibody ARAM-0401 has a light chain variable region (VL) amino acid sequence of Seq ID No: 70, comprising the CDRL1 amino acid sequence of Seq ID No: 71 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 72 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 73 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 69. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0501 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 75, comprising the CDRH1 amino acid sequence of Seq ID No: 76 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 77 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 78 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 74. Antibody ARAM-0501 has a light chain variable region (VL) amino acid sequence of Seq ID No: 80, comprising the CDRL1 amino acid sequence of Seq ID No: 81 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 9 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 82 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 79. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0601 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 84, comprising the CDRH1 amino acid sequence of Seq ID No: 85 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 86 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 87 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 83. Antibody ARAM-0601 has a light chain variable region (VL) amino acid sequence of Seq ID No: 89, comprising the CDRL1 amino acid sequence of Seq ID No: 90 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 91 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 92 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 88. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody ARAM-0701 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 94, comprising the CDRH1 amino acid sequence of Seq ID No: 95 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 4 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 96 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 93. Antibody ARAM-0701 has a light chain variable region (VL) amino acid sequence of Seq ID No: 98, comprising the CDRL1 amino acid sequence of Seq ID No: 99 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 17 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 100 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 97. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody ARAM-0801 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 102, comprising the CDRH1 amino acid sequence of Seq ID No: 103 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 104 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 105 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 101. Antibody ARAM-0801 has a light chain variable region (VL) amino acid sequence of Seq ID No: 107, comprising the CDRL1 amino acid sequence of Seq ID No: 108 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 51 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 109 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 106. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
ARAM-0101-IgGl, ARAM-0102-IgGl, ARAM-0103 -IgGl, ARAM-0201-IgGl, ARAM-0202-IgGl, ARAM- 0203-IgGl, ARAM-0204-IgGl, ARAM-0301 -IgGl, ARAM-0302-IgGl, ARAM-0303-IgGl, ARAM-0401- IgGl, ARAM-0501-IgGl, ARAM-0601 -IgGl, ARAM-0701 -IgGl, and ARAM-0801-IgGl are preferred antibodies according to the invention.
Particularly preferred heavy chain constant region sequnces for use with ARAM-0101, ARAM-0102, ARAM- 0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, and ARAM-0801 are as used in the Examples. (ii) Competing anti-UL141 antibodies:
The present disclosure describes antibodies of the invention that specifically bind to a UL141 protein and which are defined by their function and/ or by their structure. The invention also provides antibodies that compete with those antibodies described herein for binding to the target UL141 protein. Such competition may be due, for example, to the antibody binding to an identical or overlapping epitope of the UL141 protein as the reference antibody. Such a ‘competing’ antibody may retain the same function as the reference antibody with which it competes. An antibody that binds to an identical (same) epitope can be expected to have the same function as the reference antibody with which it competes. The present inventors are the first to discover ‘active’ epitopes on UL141 protein which can be targeted with an antibody for cell killing.
An antibody of the present invention may be one which competes for binding to the UL141 protein with any antibody described herein, such as ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM- 0601, ARAM-0701, or ARAM-0801 as defined herein. An antibody of the present invention may be one which binds to the same epitope on a UL141 protein as any antibody described herein, such as ARAM-0101, ARAM- 0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801 as defined herein.
In one embodiment, an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein. In one embodiment, an antibody that specifically binds to a UL141 protein is provided, wherein said antibody competes for binding to a UL141 protein with a reference antibody selected from antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
In one embodiment, an antibody that specifically binds to a UL141 protein is provided, wherein said antibody binds to the same epitope on a UL141 protein as a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a UL141 protein. In one embodiment, an antibody that specifically binds to a UL 141 protein is provided, wherein said antibody binds to the same epitope on a UL141 protein as a reference antibody selected from antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM- 0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
(iii) Therapeutic anti-UL141 antibody uses:
Antibodies that specifically bind UL141 described herein are therefore useful as medicaments. In one example, antibodies that specifically bind UL141 described herein may be useful in treating HCMV infection. In one example, antibodies that specifically bind UL141 described herein may be useful in a method of reducing HCMV viral load in a patient. In one example, antibodies that specifically bind UL141 described herein may be useful in a method of reducing frequency of HCMV virus reactivation in a patient is also provided. In one example, antibodies that specifically bind UL141 described herein may be useful in a method of preventing HCMV infection in a patient at risk of thereof. In one example, antibodies that specifically bind UL141 described herein may be useful in a method of treating congenital HCMV infection is also provided.
In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
Therefore key therapeutic indications for anti-UL141 antibodies described herein are: prophylaxis to prevent HCMV disease associated with immune suppression following transplantation of kidney, lung, liver, pancreas, heart and allogeneic hematopoietic stem cell transplant (HSCT) o The antibody can be used alone, before or in combination with valganciclovir or letermovir (or other antiviral drugs). o Similar to the current label for Cytogam IGIV in the US, an IV human immune globulin product marketed by CSL Behring. treatment of primary HCMV infection in neonates (neonates defined as up to 28 days post birth) diagnosed as HCMV seropositive within the first 3 weeks post birth. prophylaxis against HCMV infection in HCMV seronegative pregnant women in the first trimester to prevent high risk transmission of HCMV to foetus. prophylaxis against HCMV infection in HCMV seropositive pregnant women in the first trimester to prevent transmission of HCMV to foetus leading to asymptomatic infection at birth.
An efficacious antibody that specifically binds UL141 protein should reduce the prevalence of HCMV disease providing an associated reduction in morbidity and improved allograft outcomes. The prevention of HCMV infection is a potential goal in seronegative recipients, but the key outcome would be reduction in disease.
US28 PROTEIN
US28 is an early HCMV gene with mRNA detected as early as 2 hours post infection in human fibroblasts 8 and functions as an immune modulator to create a favourable environment for virus replication 9. It is also expressed in viral latency 10. US28 is a G-protein coupled chemokine receptor homologue with 38% homology with human CX3CR1 n. It also exhibits homology for other chemokine receptors including CCR1, CCR2 and CCR5 12 giving it a unique ability to bind multiple chemokine classes including the CC chemokines RANTES/CCL5, MCP-1/CCL2, MCP-3/CCL7, MIP-la/CCL3 and MIP-10/CCL4 as well as the CX3C chemokine, fractalkine/CX3CLl 12,13. Chemokine binding to US28 can induce an array of cellular responses including MAP kinase activation, calcium flux, cell migration and activation of transcription factors such as cyclic AMP responsive element binding protein (CREB) and NF-KB 12 14-16 US28 is an internalising receptor which displays agonist independent, constitutive signalling activity inducing phospholipase C activation leading to production of inositol triphosphate and diacyl glycerol, and as well as promoting NF-KB activation 17“19. Through such signalling pathways US28 can induce a wide variety of effects on host cell metabolism including promoting smooth muscle cell migration 14, which has been implicated in the association between HCMV infection and atherosclerosis 20. Table 4 shows the amino acid sequences for ligands of US28.
(i) Anti-US28 antibodies:
Antibodies that specifically bind US28 protein are provided.
In some examples, the antibody is a human antibody. In one example, the antibody is a fully human antibody. In one example, the antibody is a fully human monoclonal antibody.
In some aspects the antibodies specifically bind the extracellular domain of the US28 protein. Such antibodies binding the extracellular domain of US28 may or may not compete with one or more of the respective ligands for binding to US28 respectively and thus may or may not directly inhibit binding of US28 to the ligand. In particular, antibodies that specifically bind to US28 protein which mediate killing of HCMV infected cells are provided. The antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region. An effector enabled antibody may recruit natural killer cells to infected cells to achieve ADCC.
In an example, the anti-US28 antibody mediates killing of cells infected with HCMV. In an example, the anti- US28 antibody mediates killing of US28 protein expressing cells infected with HCMV. In an example, the anti-US28 antibody mediates killing of US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells.
In an example, the anti-US28 antibody mediates immune-mediated killing of cells infected with HCMV. In an example, the anti-US28 antibody mediates immune-mediated killing of US28 protein expressing cells infected with HCMV. In an example, the anti-US28 antibody mediates immune-mediated killing of US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells.
In an example, the anti-US28 antibody mediates NK-cell killing of cells infected with HCMV. In an example, the anti-US28 antibody mediates NK-cell killing of US28 protein expressing cells infected with HCMV. In an example, the anti-US28 antibody mediates NK-cell killing of US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells.
In an example, the anti-US28 antibody reduces viral load of cells infected with HCMV. In an example, the anti- US28 antibody reduces viral load of US28 protein expressing cells infected with HCMV. In an example, the anti-US28 antibody reduces viral load of US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells.
In an example, the anti-US28 antibody reduces frequency of viral reactivation in cells latently infected with HCMV. In an example, the anti-US28 antibody reduces frequency of viral reactivation in US28 protein expressing cells latently infected with HCMV
An antibody of the present invention may be one which competes for binding to the US28 protein with any PORT antibody described herein, such as PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801.
Antibodies described herein may compete for binding to US28 protein with one or more ligands of ULS28 (e.g. CX3CL1 and/or other chemokines). Antibodies described herein may compete for binding to US28 protein with CX3CL1 and/or other chemokines). Antibodies described herein may block US28 protein binding to CX3CL1 and/or other chemokines.
In one example, the antibody is selected from the group consisting of PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, and PORT-0801. In one example the antibody is PORT- 0101. In one example the antibody is PORT-0201. In one example the antibody is PORT-0301. In one example the antibody is PORT-0401. In one example the antibody is PORT-0501. In one example the antibody is PORT- 0601. In one example the antibody is PORT-0701. In one example the antibody is PORT-0801.
Antibody PORT-0101 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 292, comprising the CDRH1 amino acid sequence of Seq ID No: 293 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 294 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 295 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 291. Antibody PORT-0101 has a light chain variable region (VL) amino acid sequence of Seq ID No: 297, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 253 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 298 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 296. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0201 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 300, comprising the CDRH1 amino acid sequence of Seq ID No: 301 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 302 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 303 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 299. Antibody PORT-0201 has a light chain variable region (VL) amino acid sequence of Seq ID No: 305, comprising the CDRL1 amino acid sequence of Seq ID No: 306 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 307 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 308 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 304. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0301 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 310, comprising the CDRH1 amino acid sequence of Seq ID No: 311 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 312 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 313 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 309. Antibody PORT-0301 has a light chain variable region (VL) amino acid sequence of Seq ID No: 315, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 316 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 317 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 314. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0401 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 319, comprising the CDRH1 amino acid sequence of Seq ID No: 320 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 294 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 321 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 318. Antibody PORT-0401 has a light chain variable region (VL) amino acid sequence of Seq ID No: 323, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 324 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 325 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 322. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0501 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 327, comprising the CDRH1 amino acid sequence of Seq ID No: 328 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 329 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 330 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 326. Antibody PORT-0501 has a light chain variable region (VL) amino acid sequence of Seq ID No: 332, comprising the CDRL1 amino acid sequence of Seq ID No: 333 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 334 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 335 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 331. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). Antibody PORT-0601 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 337, comprising the CDRH1 amino acid sequence of Seq ID No: 338 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 339 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 340 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 336. Antibody PORT-0601 has a light chain variable region (VL) amino acid sequence of Seq ID No: 342, comprising the CDRL1 amino acid sequence of Seq ID No: 343 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 344 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 345 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 341. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0701 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 347, comprising the CDRH1 amino acid sequence of Seq ID No: 348 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 349 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 350 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 346. Antibody PORT-0701 has a light chain variable region (VL) amino acid sequence of Seq ID No: 352, comprising the CDRL1 amino acid sequence of Seq ID No: 353 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 354 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 355 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 351. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
Antibody PORT-0801 has a heavy chain variable region (VH) amino acid sequence of Seq ID No: 357, comprising the CDRH1 amino acid sequence of Seq ID No: 358 (IMGT), the CDRH2 amino acid sequence of Seq ID No: 359 (IMGT), and the CDRH3 amino acid sequence of Seq ID No: 360 (IMGT). The heavy chain nucleic acid sequence of the VH domain is Seq ID No: 356. Antibody PORT-0801 has a light chain variable region (VL) amino acid sequence of Seq ID No: 362, comprising the CDRL1 amino acid sequence of Seq ID No: 216 (IMGT), the CDRL2 amino acid sequence of Seq ID No: 253 (IMGT), and the CDRL3 amino acid sequence of Seq ID No: 298 (IMGT). The light chain nucleic acid sequence of the VL domain is Seq ID No: 361. The VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). The VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2). PORT-0101-IgGl, PORT-0201-IgGl, PORT-0301-IgGl, PORT-0401-IgGl, PORT-0501-IgGl, PORT-0601- IgGl, PORT-0701-IgGl, and PORT-0801-IgGl are preferred antibodies according to the invention.
Particularly preferred heavy chain constant region sequnces for use with PORT-0101, PORT-0201, PORT- 0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, and PORT-0801 are as used in the Examples.
(ii) Competing anti-US28 antibodies:
The present disclosure describes antibodies of the invention that specifically bind to a US28 protein and which are defined by their function and/ or by their structure. The invention also provides antibodies that compete with those antibodies described herein for binding to the target US28 protein. Such competition may be due, for example, to the antibody binding to an identical or overlapping epitope of the US28 protein as the reference antibody. Such a ‘competing’ antibody may retain the same function as the reference antibody with which it competes. An antibody that binds to an identical (same) epitope can be expected to have the same function as the reference antibody with which it competes. The present inventors are the first to discover ‘active’ epitopes on US28 protein which can be targeted with an antibody for cell killing.
An antibody of the present invention may be one which competes for binding to the US28 protein with any antibody described herein, such as PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT- 0601, PORT-0701, or PORT-0801 as defined herein. An antibody of the present invention may be one which binds to the same epitope on a US28 protein as any antibody described herein, such as PORT-0101, PORT- 0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801 as defined herein.
In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein. In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody competes for binding to a US28 protein with a reference antibody selected from antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody binds to the same epitope on a US28 protein as a reference antibody, where the reference antibody is an antibody as described anywhere herein that specifically binds to a US28 protein. In one embodiment, an antibody that specifically binds to a US28 protein is provided, wherein said antibody binds to the same epitope on a US28 protein as a reference antibody selected from antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801 as defined by the VH and VL sequences. In one embodiment, the reference antibody is in IgGl format. In one embodiment, the reference antibody is in ScFv format.
(iii) Therapeutic anti-US28 antibody uses:
Antibodies that specifically bind US28 described herein are therefore useful as medicaments. In one example, antibodies that specifically bind US28 described herein may be useful in treating HCMV infection. In one example, antibodies that specifically bind US28 described herein may be useful in a method of reducing HCMV viral load in a patient. In one example, antibodies that specifically bind US28 described herein may be useful in a method of reducing frequency of HCMV virus reactivation in a patient is also provided. In one example, antibodies that specifically bind US28 described herein may be useful in a method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient, preferably wherein said method further comprises administration of chemotherapy or radiotherapy. In one example, antibodies that specifically bind US28 described herein may be useful in a method of preventing HCMV infection in a patient at risk of thereof. In one example, antibodies that specifically bind US described herein may be useful in a method of treating congenital HCMV infection is also provided.
In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
Some key therapeutic indications for the antibody are: prophylaxis to prevent HCMV disease associated with immune suppression following transplantation of kidney, lung, liver, pancreas, heart and allogeneic hematopoietic stem cell transplant (HSCT) o The antibody can be used alone, before or in combination with valganciclovir or letermovir (or other antiviral drugs). o Similar to the current label for Cytogam IGIV in the US, an IV human immune globulin product marketed by CSL Behring. treatment of primary HCMV infection in neonates (neonates defined as up to 28 days post birth) diagnosed as HCMV seropositive within the first 3 weeks post birth. prophylaxis against HCMV infection in HCMV seronegative pregnant women in the first trimester to prevent high risk transmission of HCMV to foetus prophylaxis against HCMV infection in HCMV seropositive pregnant women in the first trimester to prevent transmission of HCMV to foetus leading to asymptomatic infection at birth.
An efficacious antibody that specifically binds US28 should reduce the prevalence of HCMV disease providing an associated reduction in morbidity and improved allograft outcomes. The prevention of HCMV infection is a potential goal in seronegative recipients, but the key outcome would be reduction in disease.
ANTI-UL 16 ANTIBODIES, ANTI-UL141 ANTIBODIES and ANTI-US28 ANTIBODIES
The antibodies described herein are described with respect to the following concepts, aspects, sentences, arrangements and embodiments. Unless otherwise stated, all concepts, embodiments, sentences, arrangements and aspects are to be read as being able to be combined with any other concept, aspect, sentence, arrangement or embodiment, unless such combination would not make technical sense or is explicitly stated otherwise.
(i) Binding Location and Measurement
As set out above, antibodies that specifically bind to a ULI 6 protein, antibodies that specifically bind to a UL141 protein and antibodies that specifically bind to a US28 protein are described herein.
The sequences of UL16, UL141 and US28 are shown in Figure 1A, IB, and 1C respectively.
Any suitable method may be used to determine whether an antibody binds to a UL16, UL141 or US28 protein. Such a method may comprise surface plasmon resonance (SPR), bio-layer interferometry, or an ELISA to determine specificity of antibodies. An antibody may be said to bind its antigen if the level of binding to antigen is at least 2.5 fold greater, e.g., at least 10 fold greater, than binding to a control antigen. Binding between an antibody and its cognate antigen is often referred to as specific binding. Precise identification of the residues bound by an antibody can usually be obtained using x-ray crystallography. This technique may be used to determine that an antibody described herein binds one or more residues of UL16, UL141 or US28 protein.
Ability of an antibody to bind its target antigen, and the specificity and affinity of that binding (KD, Kd and/or Ka) can be determined by any routine method in the art, e.g. using surface plasmon resonance (SPR), such as by BiacoreTM (Cytiva Life Sciences) or using the ProteOn XPR36TM (Bio-Rad®), using KinExA® (Sapidyne Instruments, Inc), or using ForteBio Octet (Pall ForteBio Corp.).
The term "KD", as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction. Affinity of antibody-antigen binding may be determined, e.g., by SPR. Affinity may also be determined by bio-layer interferometry. In some examples, an antibody may bind to a UL 16, UL 141 or US28 protein with an affinity (KD) of 1 mM or less, preferably less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, as determined by SPR. In other examples, the antibody may bind to a ULI 6, UL141 or US28 protein with a KD of less than 10 nM (e.g. less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM as determined by SPR. Preferably the KD may be less than 1 nM as determined by SPR. The KD may be 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, or 0.1 nM or less, as determined by SPR. In some examples, an antibody may bind to a UL16, UL141 or US28 protein with KD of O.lnM or less, as determined by SPR. In some examples, an antibody may bind to a UL16, UL141 or US28 protein with a KD of 50pM or less, as determined by SPR. Binding and binding affinity can be determined to various purified UL16, UL141 or US28 proteins and sub-domains, for example, the extracellular domain of UL16, UL141 or US28, or mutations to UL16, UL141 or US28 proteins observed in clinical isolates. If the antibody epitope is a linear continuous epitope, then binding and binding affinity can be determined using synthetic purified peptide sequences.
In one example, the antibody binds to UL16, UL141 or US28 protein with an affinity of less than 1 nM (e.g. from 1 nM to 0.01 pM or from 1 nM to 0. 1 pM, or from 1 nM to IpM), as determined by SPR. In one example, the antibody binds to UL16, UL141 or US28 protein with an affinity of less than 10 nM (e.g. from 10 nM to O.Ol pM or from lO nMto O. l pM, or from lO nM to IpM), as determined by SPR. In one example, the antibody binds to UL16, UL141 or US28 protein with an affinity of less than 0.1 nM (e.g. from 0.1 nM to 0.01 pM or from 0. 1 nM to 0.1 pM, or from 0. 1 nM to IpM), as determined by SPR. In one example, the antibody binds to UL16, UL141 or US28 protein with an affinity of less than 0.01 nM (e.g. from 0.011 nM to 0.01 pM or from 0.01 nM to 0. 1 pM), as determined by SPR. In another example, the KD is within a range of 0.01 to 1 nM, or a range of 0.05 to 2 nM, or a range of 0.05 to InM, as determined by SPR.
In one example, the SPR is carried out at 25°C. In brief, the affinity of the antibody can be determined using SPR by:
1. Coupling mouse anti -human (or other relevant human, rat or non-human vertebrate antibody constant region species-matched) IgG to a biosensor chip (e.g. dextran-coated gold chip) such as by primary amine coupling. Thus, an anti-Fc antibody may be covalently immobilised on the chip surface using amine coupling.
2. Exposing the mouse anti -human IgG (or other matched species antibody) to the test antibody (e.g., in human IgG format) to capture the test antibody on the chip; 3. Passing the test antigen over the chip’s capture surface at a series of concentrations up to a maximum of 100 nM, e.g., at 0.39, 1.56, 6.25, 25 and 100 nM, and a 0 nM (i.e. buffer alone) control run. The buffer may optionally be 0.01 M HEPES (4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid), 0.15 M NaCl and 0.05% v/v surfactant P20 in aqueous solution, buffered to pH 7.4; and
4. Determining the affinity of binding of test antibody to test antigen using surface plasmon resonance. KD, Ka and Kd may then be calculated.
SPR can be carried out using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®).
Regeneration of the capture surface can be carried out with 3 M magnesium chloride solution. This removes the captured test antibody and allows the surface to be used for another interaction. The binding data can be fitted to 1 : 1 model inherent using standard techniques, e.g. using analysis software such as Biacore Insight Evaluation Software.
(ii) Cross-reactivity
In some examples, an antibody that specifically binds to a UL16, UL141 or US28 protein antigen does not cross-react with other antigens
(iii) Cell Killing
Cells express ULI 6, UL141 and/or US28 as a consequence of infection with HCMV, thus the antibodies described herein may be useful in killing HCMV infected cells, specifically HCMV infected cells expressing ULI 6, UL141 and/or US28 proteins, thus being useful in therapy and prophylaxis to prevent infection with HCMV.
In some examples, the antibody mediates killing of cells infected with HCMV. In an example, the antibody mediates killing of UL16, UL141 or US28 protein expressing cells infected with HCMV. In an example, the antibody mediates killing of UL16, UL141 or US28 protein expressing cells lytically infected with HCMV. In one example, the killing of cells infected with HCMV is immune-mediated. In one example, the killing of cells infected with HCMV is mediated by NK cells.
In one example the antibody reduces the viral load of cells infected with HCMV. In an example, the antibody reduces viral load of UL16, UL141 or US28 protein expressing cells infected with HCMV. In an example, the antibody reduces viral load of UL16, UL141 or US28 protein expressing cells lytically infected with HCMV. In one example, the cells are latently infected cells. In an example, the antibody reduces frequency of viral reactivation in cells latently infected with HCMV. In an example, the antibody reduces frequency of viral reactivation in US28 protein expressing cells latently infected with HCMV.
Potency of cell killing:
The potency with which antibodies described herein are effective in cell killing may be measured using any suitable cell killing assay known in the art. For example, cell killing may be measured using an Fc effector assay (e.g. as described in the Examples herein). Alternatively, cell killing may be measured using an NK cell degranulation assay (e.g. as described in the Examples herein).
ADCC is a killing mechanism by which antibodies target specific cells for elimination. The classic protocol relies on the use of primary human Natural Killer (NK) cells isolated from blood donors that have, on their surface, FCyRIIIa receptors, which can bind the Fc portion of an antibody and activate the NK cell to kill the target cell to which the antibody is bound. The cells expressing the target of interest (E.g HEK cells expressing US28 or Uli 6 or UL141 on their surface, or possibly cells infected with HCMV in vitro) are co-incubated with effector NK cells which express FcyRIIIa, that in the presence of an ADCC-enabled antibody will induce cell killing. The ADCC activity is calculated as a fold induction by dividing the well sample signal by the control wells, where no antibody was added to the target and effector cells. Fluorescent (BADTA), colourimetric or radioactive (eg chromium-51 release) substrates can be used as the readout to measure cell killing in these assays.
In a degranulation assay, human NK cells (either as PBMCs or purified NK cells) are incubated with cells expressing the target of interest (e.g HEK cells expressing US28 or U116 or UL141 on their surface) and in the presence of an ADCC-enabled antibody NK cells are activated and express markers of degranulation which can be detected using fluorescent antibodies in flow cytometry. The ADCC activity can be expressed as the percent of NK cells that are positive for degranulation markers, such as CD 107a.
In some examples, the antibodies kill infected cells with an IC50 of lOnM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of InM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 500pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of lOOpM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 50pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 40pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 30pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 20pM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of lOpM or lower (e.g. as determined in an Fc effector reporter assay). In some examples, the antibodies kill infected cells with an IC50 of 5pM or lower (e.g. as determined in an Fc effector reporter assay).
In some examples, the antibodies kill infected cells with an IC50 of lOnM or lower (e.g. as determined in aNK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of InM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 500pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of lOOpM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 50pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 40pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 30pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 20pM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of lOpM or lower (e.g. as determined in a NK cell degranulation assay). In some examples, the antibodies kill infected cells with an IC50 of 5pM or lower (e.g. as determined in a NK cell degranulation assay).
In some examples, the antibodies may kill infected cells with an activity level which is greater than a reference antibody. In some examples, the reference antibody may be Cytotect. For example, the antibodies may kill infected cells with an activity level which is greater than the reference antibody expressed as fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 2-fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 25-fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 50-fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 100-fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 500-fold change relative to the reference antibody. In one example, the antibody may kill infected cells with an activity level greater than a 1000-fold change relative to the reference antibody.
The cell line to be used for measuring the activity level as compared to a reference antibody such as the polyclonal antibody Cytotect will vary depending on the antibody being tested and the target prtein to which it binds. This is due to differential protein expression of different cell lines. Recombinant, overexpressing cell lines such as HEK293 cells or HFF (human foreskin fibroblast) cells overexpressing the target viral protein suitably may be used. Cytotect is particularly suitable as a refemce antibody for anti-US28 antibodies due to high levels of anti-US28 antibodies in the polyclonal antibody. (iv) Fc Effector Function
Antibodies also act as a link between the antibody-mediated and cell-mediated immune responses through engagement of Fc receptors. Thus, antibody effector functions are an important part of the humoral immune response. Whereas the variable Fab domain mediates antigen specificity and binds its respective antigen, the Fc domain mediates diverse effector functions via recruitment of effector molecules such as complement and Fc receptors (FcRs). The Fc domain of immunoglobulin G (IgG) displays heterogeneity due to different subclasses with divergent amino acid sequences, as well as complex glycosylation patterns and this heterogeneity has been shown to modulate the effector function of IgG.
The interaction with Fc-receptors can lead to killing of virus-infected cells through a variety of immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Antibody-mediated complement activation may lead to complement-dependent cytotoxicity (CDC).
The antibodies of the invention may have ADCC, CDC or ADCP activity. In particular, the antibodies may have ADCC activity.
ADCC is an immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells expressing tumor- or pathogen-derived antigens on their surface. ADCC is largely mediated by NK cells through the CD 16 (FcyRIII) receptor that binds the Fc portion of IgG antibodies triggering the lysis of targeted cells. In humans, ADCC effector function generally is highest for IgGl.
CDC is triggered by binding of antibody - antigen complexes to the complement component Clq. In humans, antibodies of the IgG subclasses IgGl, IgG2 and IgG3 as well as IgM antibodies are generally capable of initiating the classical complement pathway.
An antibody described herein may have inherent effector function(s). Further, several novel technologies have evolved for the modification of antibodies to enhance their inherent effector functions ot to enable effector functions. These focus on the constant Fc domain and utilize either amino acid substitutions or glycoform perturbations to modulate their interaction with Fc receptors and the effector cells that bear them. Such modifications are discussed in more detail in relation to antibody heavy chain constant regions of the invention. a. ADCC Activity and Measurement: The antibodies described herein may have ADCC activity. ADCC activity may be measure in, for example, an Fc Effector Reporter Assay. In one example, the ADCC activity of the antibody is sufficient to achieve at least 50% inhibtion in an Fc effector reporter assay. In one example, the ADCC activity of the antibody is sufficient to achieve at least 50% killing of infected cells (e.g. as determined in an Fc effector reporter assay).
The classic ADCC protocol relies on the use of primary human Natural Killer (NK) cells isolated from blood donors that have, on their surface, FCyRIIIa receptors, which can bind the Fc portion of an antibody and activate the NK cell to kill the target cell to which the antibody is bound. Reporter assays provide a simpler and more cost effecive alternative to primary assays. In a reporter assay, the cells expressing the target of interest (E.g HEK cells expressing US28 or U116 or UL141 on their surface) are co-incubated with effector cells expressing human FcyRIIIa, that in the presence of an ADCC-enabled antibody produce luciferase in a concentration dependent manner. The soluble luciferase activity is then assessed by measuring the luminescence produced, with higher luminescence indicating higher ADCC activity of the antibody. The ADCC activity is calculated as a fold induction by dividing the well sample signal by the control wells, where no antibody was added to the target and effector cells. b. ADCP Activity and Measurement:
In some examples, the antibodies described herein may have ADCP activity. ADCP activity may be measure in, for example, an Fc Effector Reporter Assay.
ADCP is a potent mechanism of elimination of antibody-coated pathogens, infected cells or tumour cells. ADCP can be mediated by monocytes, macrophages, neutrophils, and dendritic cells, through FcyRIIa, FcyRI, and FcyRIIIa, of which FcyRIIa (CD32a) on macrophages represent the predominant pathway. Engagement of FcyRIIa and FcyRI expressed on macrophages triggers a signalling cascade leading to the engulfment of the IgG-opsonised pathogen or cell. In a typical assay target cells are incubated in the presence of a titration of mAb and an effector cell (such as primary human macrophages or a cell line such as monocytic cell line THP-1). Both effector and target cells are fluorescently labelled and cell engulfment is measured by flow cytometry. Phagocytosis can also be confirmed using microscopy or imaging cytometry. Reporter assays can also be used which include engineered cell lines stably expressing FcyRIIa (CD32a) as effector cells, rather than using primary cells. c. CDC Activity and Measurement:
In some examples, the antibodies described herein may have CDC activity. CDC activity may be measure in, for example, an Fc Effector Reporter Assay. CDC is the mechanism by which antibody-coated target cells recruit and activate components of the complement cascade, leading to the formation of a Membrane Attack Complex (MAC) on the cell surface and subsequent cell lysis. Similar to ADCC, antibodies, usually IgGl and IgG3, elicits CDC killing effects via binding its Fc region to serum complement components, particularly Clq.
In CDC assays, target-expressing cells are incubated with an antibody, in the presence of human serum containing either active or heat-inactivated complement. Dead-cell protease activity, which is released from cells that have lost membrane integrity, is measured as an indicator of cell lysis. Other readouts of cell lysis could include radioactive signal or flow cytometry. Assays can also be performed with recombinant complement proteins in place of primary human serum.
(v) Competing with ligand binding
ULI 6 and UL141 are NK activating proteins. Thus, preventing or inhibiting binding of ULI 6 and UL141 to one or more of their ligands can be expected to be advantageous. Without wishing to be bound by theory, it is thought that preventing or inhibiting binding of UL 16 and UL 141 to one or more of their ligands might lead to increased cell surface expression of these proteins, which in turn would enable further binding of antibodies of the invention and more potent cell killing. Table 4 shows the amino acid sequences for ligands of UL16 and ligands of UL141.
Further, preventing or inhibiting binding of US28 to CX3C chemokine, fractalkine/CX3CLl also can be expected to be advantageous. Chemokine binding to US28 can induce an array of cellular responses which may favour virus replication. Thus, without wishing to be bound by theory, it is thought that preventing or inhibiting binding of US28 to CX3CL1 and preventing such cellular responses may assist in preventing or slowing virus replication. Table 4 shows the amino acid sequences for ligands of US28.
The antibodies provided may inhibit the UL16, UL141 or US28 protein binding to one or more of their respective ligands. In some examples, an antibody specifically binds to the extracellular domain of the UL16, UL141 or US28 protein, wherein the antibody partially or completely inhibits the UL16, UL141 or US28 protein binding to one or more of the respective ligands for UL16, UL141 or US28. In another example, the antibody partially or completely inhibits binding of UL16, UL141 or US28 to soluble versions of one or more of the respective ligands. Various modes of inhibition may be envisaged. For instance, inhibition may be by competition for binding of UL16, UL141 or US28 protein to one or more of the respective ligands for UL16, UL141 or US28 (whether for the same epitope or by steric hindrance).
If the epitope to which the antibody binds completely blocks the binding site of the UL16, UL141 or US28 protein to its ligand, then ligand binding is completely prevented (which may be a physical blocking - in the case of overlapping epitopes - or steric blocking - where the antagonist is large such that it prevents the ligand binding to its distinct epitope). If the epitope to which the antibody binds partially blocks the binding site of the UL16, UL141 or US28 protein to its ligand, the ligand may be able to bind, but only weakly (in the case of partial inhibition), or in a different orientation to the natural binding interaction.
Whether an antibody competes with one or more of the respective ligands for UL 16, UL 141 or US28 for binding to UL16, UL141 or US28 protein may be measured using a competition assay. Competition may be determined by surface plasmon resonance (SPR), such techniques being readily apparent to the skilled person. SPR may be carried out using Biacore™, Proteon™ or another standard SPR technique. Such competition may be due, for example, to the antibodies or fragments binding to identical or overlapping epitopes of the ULI 6, UL141 or US28 protein to that which the one or more of the respective ligands for UL16, UL141 or US28 binds. In one example, competition is determined by ELISA, such techniques being readily apparent to the skilled person. In one example, competition is determined by homogenous time resolved fluorescence (HTRF), such techniques being readily apparent to the skilled person. In one example, competition is determined by fluorescence activated cell sorting (FACS), such techniques being readily apparent to the skilled person. In one example, competition is determined by ForteBio Octet® Bio-Layer Interferometry (BLI) such techniques being readily apparent to the skilled person.
In one example, the antibody competes (e.g. in a dose-dependent manner) with one or more of the respective ligands for UL16, UL141 or US28 (or a fusion protein thereof) for binding to UL16, UL141 or US28. The one or more respective ligands may be in a soluble form or may be expressed on the surface of cells.
(vi) Types of Antibody
In some examples, the antibody is a monoclonal antibody. Methods of making monoclonal antibodies are known and include, for example, fusing myeloma cells with the cells from an animal that was immunized with the desired antigen. In other examples, the monoclonal antibodies may be generated using recombinant DNA technology. In one example, the antibody is a monoclonal antibody that specifically binds UL16, UL141 or US28 protein. In one example, the antibody is a fully human monoclonal antibody.
In some examples, the antibody is a human antibody. In one example, the antibody is a fully human antibody.
In one example, the antibody is a fully human monoclonal antibody. (vii) Antibody Structure - CDRS, VL/VH:
In some examples the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of any one of the antibodies described herein and set out in Table 1.
In some examples, the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of any one of the antibodies described herein and set out in Table 1.
In some examples, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
In some examples, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% (preferably 95%, more preferably 98%) identity to the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, provided that the antibody has the CDRs of said antibody described herein and set out in Table 1.
In work underlying the present invention, antibody sequences were recovered from antigen-binding B cells or from plasma cells from immunised mice as described elsewhere herein, and grouped into the clusters shown in Figure 2 using bioinformatics analysis. It will be understood that antibodies in the same cluster (Figure 2) share a degree of sequence identity and/ or conserved sequences. As such, antibodies in the same cluster might be considered as ‘sibling antibodies’. Sibling antibodies are within the scope of the present invention. In one embodiment, the present invention provides an expanded group of antibodies consisting of any antibody disclosed herein together with its sibling antibodies. In one embodiment, the present invention provides an expanded group of antibodies consisting of any group of antibodies disclosed herein together with their sibling antibodies. The present invention also provides antibodies having at least 90% (preferably 95%, more preferably 98%) identity to the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, provided that any substitutions in the VH and VL domain sequences are to amino acid residues present in a sibling antibody in the same cluster disclosed herein. The present invention also provides antibodies comprising a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1, optionally with 1, 2, 3, 4 or 5 amino acid substitutions in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid substitutions in the variable light (VL) domain sequence, provided that any substitutions in the VH and VL domain sequences are to amino acid residues present in a sibling antibody in the same cluster disclosed herein.
One or more substitutions may be introduced in an antibody VH or VL domain at a position at which a different residue is present in a sibling antibody as shown in the clusters of Figure 2 herein. Thus, for example, an antibody may comprise the VH and VL domain of an ATHO, ARAM or PORT antibody disclosed herein, with one or more substitutions in framework regions, where those one or more substitutions are at positions shown to be variable in the cluster (optionally, at positions that vary between siblings obtained from antigen-binding B cells in the cluster and/or siblings for which assay data are presented herein). Optionally, the substituted residue is the amino acid residue present in the sibling sequence (preferably, the sequence of a sibling obtained from an antigen-binding B cell or a sibling for which assay data are presented herein). As noted, siblings which were recovered from plasma cells (i.e., not recovered via antigen-binding of their expressing B cell) and for which assay data are not shown herein may optionally be discounted for this analysis. The clusters are shown in Figure 2.
When one or more mutations (whether additions, insertions, substitutions or deletions of one or more amino acids) are made in the variable domain sequence of an antibody described herein, whether in a CDR or framework region, the resulting antibody may be tested (e.g., in one or more assays described herein) to confirm that affinity and/or potency are retained.
In some examples, the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of any one of the antibodies described herein and set out in Table 1.
Also provided herein is the variable heavy chain (VH) only of any antibody described herein.
Also provided herein is the variable light chain (VL) only of any antibody described herein. (viii) Sequence Identity
In some examples, the antibody comprises an amino acid sequence which has a high level of sequence identity to the amino acid sequence of one of the exemplary antibodies described herein and set out in Table 1.
In one example, the amino acid sequence is at least 70% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 75% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 95% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 96% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 97% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 98% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 99% identical to the specified SEQ ID No. In one example, the amino acid sequence is at least 99.5% identical to the specified SEQ ID No.
(ix) Amino Acid Substitutions
In some examples, the antibody comprises amino acid substitutions.
Amino acid substitutions include alterations in which an amino acid is replaced with a different naturally- occurring amino acid residue. Such substitutions may be classified as "conservative", in which case an amino acid residue contained in a polypeptide is replaced with another naturally occurring amino acid of similar character either in relation to polarity, side chain functionality or size. Such conservative substitutions are well known in the art. Substitutions encompassed by the present invention may also be "non-conservative", in which an amino acid residue which is present in a peptide is substituted with an amino acid having different properties, such as naturally-occurring amino acid from a different group (e .g . substituting a charged or hydrophobic amino; acid with alanine), or alternatively, in which a naturally-occurring amino acid is substituted with a non- conventional amino acid.
In one embodiment, the conservative amino acid substitutions are as described herein. For example, the substitution may be of Y with F, T with S or K, P with A, E with D or Q, N with D or G, R with K, G with N or A, T with S or K, D with N or E, I with L or V, F with Y, S with T or A, R with K, G with N or A, K with R, A with S, K or P. In another embodiment, the conservative amino acid substitutions may be wherein Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, S with A or T and A with S, G, T or V.
In one example, the amino acid substitutions are located outside the CDR sequences.
(x) Antibody Light Chain Constant Regions
In some examples, the antibody comprises a kappa light chain. Kappa light chain constant region amino acid and nucleotide sequences are set out in SEQ ID Nos: 395-404. In one example, the light chain may be a lambda light chain. Lambda light chain constant region amino acid and nucleotide sequences can be found in SEQ ID Nos: 405-428.
(xi) Antibody Heavy Chain Constant Regions
The antibodies described herein may comprise a constant region, such as a human constant region. An antibody of the invention may have any suitable constant region sequence. Table 2 shows exemplary constant region sequences either in terms of amino acid sequence or nucleic acid sequence encoding the constant region amino acid sequence.
In one embodiment, the constant region is wild-type human IgGl. In one embodiment, the constant region comprises an amino acid sequence as shown in SEQ ID No: 363.
In one embodiment, the antibody has natural effector function. In another embodiment, the constant region is engineered for enhanced effector function. In one embodiment, the constant region is engineered for enhanced ADCC and/or CDC and/or ADCP activity.
In one embodiment, the human IgG heavy chain constant region is a variant human IgGl heavy chain constant region comprising the S239D and I332E amino acid mutations (EU index numbering system). In one embodiment, the constant region comprises an amino acid sequence as shown in SEQ ID No: 364.
In some examples, the antibodies described herein facilitate the killing of an infected cell via antibody dependent cellular cytotoxicity (ADCC), where antibodies bind to infected cells and allow immune cells to kill them.
In some examples, the antibodies described herein facilitate the killing of an infected cell via antibodydependent cellular phagocytosis (ADCP).
In some examples, the antibodies described herein facilitate the killing of an infected cell via complementdependent cytotoxicity (CDC).
Selection of an appropriate format for the antibody (e.g., IgG4 or IgGl), can be used to enhance or achieve this outcome. Thus, the antibody can be formatted to target infected cells for killing by inclusion of a portion with Fc effector function, e.g., an IgGl constant region. An effector enhanced or enabled antibody may recruit natural killer cells to infected cells to achieve ADCC. In some embodiments, the antibody may comprise modifications that enhance the ability of the antibody to cluster and therefore be a better substrate for complement fixation. The Fc domain of IgGl may be mutated for example at E345 or E430 to reinforce inter-antibody Fc:Fc interactions, stimulating formation of hexamers, which enhances the induction of CDC and ADCC of target cells (de Jong et al., PloS Biol 14(1) e 1002344 2016). Hexamer formation is optionally combined with a bispecific antibody format.
The heavy chain constant region may be . an IgG4 constant region or an IgGl constant region, optionally wherein the constant region is IgG4-PE (SEQ ID Nos: 389-394 and 429-430), or a disabled IgGl as defined in SEQ ID Nos: 373-374.
The heavy chain constant region may be a wild-type human IgGl constant region (SEQ ID Nos: 363 or 365- 372).
The IgG4 constant region may be any of the IgG4 constant region amino acid sequences, or encoded by any of the nucleic acid sequences (SEQ ID Nos: 383-388). A heavy chain constant region may be an IgG4 comprising both the Leu235Glu mutation and the Ser228Pro mutation.
The heavy chain constant region may be an IgGl *01 allele comprising the L235A and/or G237A mutations (e.g. LAGA, SEQ ID Nos: 373-374). In one example, the antibodies or antibody fragments disclosed herein comprise an IgGl heavy chain constant region, wherein the sequence contains alanine at position 235 and/or 237 (EU index numbering). The antibody-dependent cell phagocytosis (ADCP) mechanism is discussed in Gul et al., “Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer”, Cancer Res., 75(23), December 1, 2015.
The potency of Fc-mediated effects may be enhanced by engineering the Fc domain by various established techniques. Such methods increase the affinity for certain Fc-receptors or decrease the affinity for inhibitory Fc-receptors, thus creating potential diverse profiles of activation enhancement. This can be achieved by modification of one or several amino acid residues (e.g. as described in Lazar et al., 2006, Proc. Natl. Acad. Sci. U.S.A., Mar 14; 103(11):4005-10; the modifications disclosed therein are incorporated herein by reference). Human IgGl constant regions containing specific mutations or altered glycosylation on residue Asn297 (e.g. N297Q, EU index numbering) have been shown to enhance binding to certain Fc receptors. In one example, such mutations are one or more of the residues selected from 239, 332 and 330 for human IgGl constant regions (or the equivalent positions in other IgG isotypes) . In one example, the antibody or fragment comprises a human IgGl constant region having one or more mutations independently selected from N297Q, S239D, I332E and A330L (EU index numbering). In one example, the antibody or fragment comprises a human IgGl constant region having an S239D mutation (EU index numbering). In one example, the antibody or fragment comprises a human IgGl constant region having an I332E mutation (EU index numbering). In one example, the antibody or fragment comprises a human IgGl constant region having S239D and I332E mutations (EU index numbering). In one example, the antibody or fragment comprises the human IgGl constant region sequence of SEQ ID NO: 364. As set out in Table 2, SEQ ID NO: 364 comprises the S239D and I332E mutations.
In another example, the increase in affinity for Fc-receptors is achieved by altering the natural glycosylation profile of the Fc domain by, for example, generating under fucosylated or de-fucosylated variants (as described in Natsume et al., 2009, Drug Des. Devel. Ther., 3:7-16 or by Zhou Q., Biotechnol. Bioeng., 2008, Feb 15, 99(3):652-65, the modifications described therein are incorporated herein by reference). Non-fucosylated antibodies harbour a tri-mannosyl core structure of complex-type N-glycans of Fc without fucose residue. These glycoengineered antibodies that lack core fucose residue from the Fc N-glycans may exhibit stronger ADCC than fucosylated equivalents due to enhancement of FcyRIIIa binding capacity. For example, to increase ADCC, residues in the hinge region can be altered to increase binding to Fc-yRIII (see, for example, Shields et al., 2001, J. Biol. Chem., Mar 2; 276(9):6591-604; the modifications described therein are incorporated herein by reference). Thus, in one example, the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild-type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human Fey receptors selected from the group consisting of FcyRIIB and FcyRIIA with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fey receptors. In one example, the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human FcyRIIB with higher affinity than the wild type human IgG heavy chain constant region binds to human FcyRIIB. In one example, the variant human IgG heavy chain constant region is a variant human IgGl, a variant human IgG2, or a variant human IgG4 heavy chain constant region. In one example, the variant human IgG heavy chain constant region comprises one or more amino acid mutations selected from G236D, P238D, S239D, S267E, L328F, and L328E (EU index numbering system). In another example the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S267E and L328F; P238D and L328E; P238D and one or more substitutions selected from the group consisting of E233D, G237D, H268D, P271G, and A330R; P238D, E233D, G237D, H268D, P271G, and A330R; G236D and S267E; S239D and S267E; V262E, S267E, and L328F; and V264E, S267E, and L328F (EU index numbering system). In another example, the variant human IgG heavy chain constant region further comprises one or more amino acid mutations that reduce the affinity of the IgG for human FcyRIIIA, human FcyRIIA, or human FcyRI. In one example, the FcyRIIB is expressed on a cell selected from the group consisting of macrophages, monocytes, B-cells, dendritic cells, endothelial cells, and activated T-cells. In one embodiment, the variant human IgG heavy chain constant region comprises one or more of the following amino acid mutations G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305I, A330L, I332E, E333A, K334A, A339T, and P396L (EU index numbering system). In one example, the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S239D; T256A; K290A; S298A; I332E; E333A; K334A; A339T; S239D and I332E; S239D, A330L, and I332E; S298A, E333A, and K334A; G236A, S239D, and I332E; and F243L, R292P, Y300L, V305I, and P396L (EU index numbering system). In one example, the variant human IgG heavy chain constant region comprises a S239D, A330L, or I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region comprises an S239D and I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region is a variant human IgGl heavy chain constant region comprising the S239D and I332E amino acid mutations (EU index numbering system). In one example, the antibody or fragment comprises the human IgGl constant region sequence of SEQ ID NO: 364. As set out in Table 2, SEQ ID NO: 364 comprises the S239D and I332E mutations. In one example, the antibody or fragment comprises an afiicosylated Fc region. In another example, the antibody or fragment thereof is defucosylated. In another example, the antibody or fragment is under fucosylated.
In another example, the antibodies and fragments disclosed herein may comprise a triple mutation (M252Y/S254T/T256E) which enhances binding to FcRn. See Dall’Aqua et al., Immunol 2002; 169:5171-5180 for a discussion of mutations affection FcRn binding in table 2, the mutations described therein are incorporated herein by reference.
Equally, the enhancement of CDC may be achieved by amino acid changes that increase affinity for Clq, the first component of the classic complement activation cascade (see Idusogie et al., J. Immunol., 2001, 166:2571— 2575; the modifications described are incorporated herein by reference). Another approach is to create a chimeric Fc domain created from human IgGl and human IgG3 segments that exploit the higher affinity if IgG3 for Clq (Natsume et al., 2008, Cancer Res., 68: 3863-3872; the modifications are incorporated herein by reference). In another example, the antibody or antibody fragments disclosed herein may comprise mutated amino acids at residues 329, 331 and/or 322 to alter the C Iq binding and/or reduced or abolished CDC activity. In another example, the antibodies or antibody fragments disclosed herein may contain Fc regions with modifications at residues 231 and 239, whereby the amino acids are replaced to alter the ability of the antibody to fix complement. In one example, the antibody or fragment has a constant region comprising one or more mutations selected from E345K, E430G, R344D and D356R, in particular a double mutation comprising R344D and D356R (EU index numbering system).
In another example, the antibodies disclosed herein are modified to increase or decrease serum half-life. In one embodiment, one or more of the following mutations: T252L, T254S or T256F are introduced to increase biological half-life of the antibody. Biological half-life can also be increased by altering the heavy chain constant region CHI domain or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Numbers. 5,869,046 and 6,121,022, the modifications described therein are incorporated herein by reference. In another example, the Fc hinge region of an antibody or antigen-binding fragment of the invention is mutated to decrease the biological half-life of the antibody or fragment. One or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody or fragment has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding. Other methods of increasing serum half-life are known to those skilled in the art. Thus, in one example, the antibody or fragment is PEGylated. In another example, the antibody or fragment is fused to an albumin-binding domain, e.g. an albumin binding single domain antibody (dAb). In another example, the antibody or fragment is PASylated (i.e. genetic fusion of polypeptide sequences composed of PAS (XL-Protein GmbH) which forms uncharged random coil structures with large hydrodynamic volume). In another example, the antibody or fragment is XTENylated®/rPEGylated (i.e. genetic fusion of non-exact repeat peptide sequence (Amunix, Versartis) to the therapeutic peptide). In another example, the antibody or fragment is ELPylated (i.e. genetic fusion to ELP repeat sequence (PhaseBio)). These various half-life extending fusions are described in more detail in Strohl, BioDrugs (2015) 29:215-239, which fusions are incorporated herein by reference.
The antibody may have a modified constant region which increases stability. Thus, in one example, the heavy chain constant region comprises a Ser228Pro mutation. In another example, the antibodies and fragments disclosed herein comprise a heavy chain hinge region that has been modified to alter the number of cysteine residues. This modification can be used to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
(xii) Gene Segments
In some aspects, the antibody comprises VH and/or VL domain and framework regions of human germline gene segment sequences. Gene segment sequences from which the exemplary antibodies described herein are derived are set out in Table 3.
In one example, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment.
In one example, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-34*01, IGHV4-31*03, IGHV3-ll*01, IGHVl-3*01, IGHV4- 59*01, or IGHV3-30* 18; and/or the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4- 34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one example, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4- 31*03, or IGHV3-48*02; and/or the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59* 01 , IGHV4-4* 02, IGHV5 -51*01, IGHV4-31 * 03 , or IGHV3 -48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4- 31*03, IGHV4-59*0I, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one example, the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-I*0I, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6- 1*01, or IGHV3-21*03with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one example, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment.
In one example, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*OI, IGLV3-I0*0I, IGLV2-8*0I, IGLVl-5I*0I, IGKV1D-39*OI, or IGKVl-9*dOI, and/or the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-I0*0I, IGLV2-8*0I, IGLV1-5I*OI, IGKV1D-39*OI, orIGKVl-9*dOI with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D- 39*01, or IGKVl-9*d01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGKJl*01, IGLJ2*01, or IGKJ3*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one example, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV2-23*dO2, IGLVl-51*01, IGKV3-l l*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01, and/or the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-I I*0I, IGLV3-I9*0I, IGKV2-24*0I, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-5I*0I, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGLV2-23*dO2, IGLV 1-51*01, IGKV3- 11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
In one example, the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01. In one example, the antibody comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV3-I0*0I, IGKV3-20*0I, , IGLV3-27*0I, IGLV3-9*0I, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGLV3- 10*01, IGKV3-20*01, , IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ4*01, or IGLJ2*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
ANTIBODIES THAT COMPETE FOR BINDING
Antibodies that compete with a reference antibody for binding to a target UL16, UL141 or US28 protein are described in this disclosure. Any suitable method may be used to determine whether an antibody competes with a reference antibody for binding to a target UL16, UL141 or US28 protein. Such methods are well known in the art.
Whether an antibody competes with a reference antibody for binding to UL16, UL141 or US28 protein may be measured using a competition assay. Competition may be determined by surface plasmon resonance (SPR), such techniques being readily apparent to the skilled person. SPR may be carried out using Biacore™, Proteon™ or another standard SPR technique. In one example, competition is determined by ELISA, such techniques being readily apparent to the skilled person. In one example, competition is determined by homogenous time resolved fluorescence (HTRF), such techniques being readily apparent to the skilled person. In one example, competition is determined by fluorescence activated cell sorting (FACS), such techniques being readily apparent to the skilled person. In one example, competition is determined by ForteBio Octet® Bio-Layer Interferometry (BLI) such techniques being readily apparent to the skilled person.
NUCLEIC ACIDS, VECTORS, HOST CELLS
Nucleic acids that encode a VH domain and/or a VL domain of any one of the antibodies described herein are also provided. The nucleic acid sequences encoding each of the VH and VL domains of each the exemplary antibodies described herein are set out in Table 1.
In one example, the nucleic acid sequence is at least 70% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 80% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 90% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 95% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 96% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 97% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 98% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 99% identical to the specified SEQ ID NO. In one example, the nucleic acid sequence is at least 99.5% identical to the specified SEQ ID NO.
In one example, the nucleic acid encodes a heavy chain of any one of the antibodies described herein. In another example, the nucleic acid encodes a light chain of any one of the antibodies described herein.
In one example, the nucleic acid is an isolated and purified nucleic acid.
Vectors comprising the nucleic acids described above are also provided. In one example, the vector may be a CHO vector. In one example, the vector may be a HEK293 vector.
Host cells comprising the nucleic acids described above are also provided. In some examples, the host cells are eukaryotic cells, e.g., mammalian cells, preferably CHO cells (e.g., CHO cells grown in suspension culture). PHARMACEUTICAL COMPOSITIONS
In one example, there is provided a pharmaceutical composition comprising an effective amount of an antibody as described herein and a pharmaceutically acceptable excipient. An effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. In one example, the composition includes other excipients or stabilizers.
Pharmaceutically acceptable excipients are known and include carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable excipient is an aqueous pH buffered solution. Examples of physiologically acceptable excipient include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as Ethylenediaminetetraacetic acid (EDTA); sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.
The antibodies can be administered intravenously or through the nose, lung, for example, as a liquid or powder aerosol (lyophilized) or by nebulisation of a liquid. The composition can also be administered parenterally or subcutaneously. When administered systemically, the composition should be sterile, pyrogen-free and in a physiologically acceptable solution having due regard for pH, isotonicity and stability. These conditions are known to those skilled in the art.
Methods of administering a prophylactic or therapeutic agent (e.g., an antibody as disclosed herein), or pharmaceutical composition include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g., intranasal and oral routes). In a specific example, a prophylactic or therapeutic agent (e.g., an antibody as disclosed herein), or a pharmaceutical composition is administered intranasally, intramuscularly, intravenously, or subcutaneously. The prophylactic or therapeutic agents, or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, intranasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. Each dose may or may not be administered by an identical route of administration. In one example, an anti-UL16, UL141 or US28 antibody as disclosed herein may be administered via multiple routes of administration simultaneously or subsequently to other doses of the same or a different anti-UL16, UL141 or US28 antibody as disclosed herein. Various delivery systems are known and can be used to administer a prophylactic or therapeutic agent (e.g., an antibody as disclosed herein), including, but not limited to, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. In addition, pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. See, e.g., U.S. Pat. Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos. WO92/19244, WO97/32572, WO97/44013, WO98/31346, and WO99/66903, each of which is incorporated herein by reference their entirety.
In a specific example, it may be desirable to administer a prophylactic or therapeutic agent, or a pharmaceutical composition as described herein locally to the area in need of treatment. This may be achieved by, for example, local infusion, by topical administration (e.g., by intranasal spray), by injection, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibres. When administering an anti-UL16, UL141 or US28 antibody, care must be taken to use materials to which the antibody does not absorb.
In the case of medicaments that are intended for local and/or topical administration, such as by absorption to epithelial or mucocutaneous linings, an antibody may be provided as an IgA isotype antibody. For human patients, human IgAl or human IgA2 antibodies are preferred. Medicaments formulated for inhalation and/or for delivery of antibody (or its encoding nucleic acid, e.g., in a DNA vector) to the upper and/or lower respiratory tract, including formulations for delivery of a nebulised medicament, may comprise an IgA (e.g., human IgAl or human IgA2) antibody. Inhalers, nebulisers and similar devices may thus be provided containing a medicament comprising an IgA antibody or its encoding nucleic acid, together with any buffers or other excipients suitable for stabilisation of the medicament and/or for promoting its delivery to the target tissue.
THERAPEUTIC USE
Antibodies described herein may be used to treat or prevent a HCMV infection or an HCMV-related disease or condition. One aspect includes use of an antibody or composition described herein as a medicament.
CMV in Transplantation. CMV is the most common and single most important viral infection in solid organ transplant recipients. CMV infection usually develops during the first few months after transplantation and is associated with clinical infectious disease (e.g., fever, pneumonia, GI ulcers, hepatitis) and acute and/or chronic graft injury and dysfunction. Sources of CMV infection in transplant recipients include reactivation of preexisting latent infections, donor-transmitted virus, and virus present in donor WBCs. 20% to 60% of all transplant recipients develop symptomatic CMV infection. The patients at highest risk for symptomatic disease are the CMV-seropositive donor/CMV-seronegative recipient (D+/R-) who often develop a primary infection after transplantation. Such patients are at particular risk for severe manifestations of CMV infection, including tissue-invasive CMV and CMV recurrence. Reactivation of infection can develop in the patient who is CMV- seropositive before transplantation due to immune suppression. CMV-seropositive recipients are also at risk of superinfection by CMV from a CMV-seropositive donor, again due to immunosuppression.
CMV infection presents a complex phenotype with a variety of direct and indirect effects in the organ transplant recipient. The symptomatology for clinical infectious disease (i.e., fever, pneumonia, GI ulcers, hepatitis) ranges from the mild, subclinical cases to life-threatening multi-organ disease. CMV infection can disseminate to the lungs, liver, pancreas, kidneys, stomach, intestine, brain, and parathyroid glands, and can cause death. CMV retinitis, manifested by decreased visual acuity and peripheral blindness, can occur and lead to retinal detachment and blindness. In addition to direct infectious syndromes produced by CMV, considerable attention has been given to indirect effects. The additional immunosuppression that results from CMV infection places the patient at an increased risk for fungal and other opportunistic infections. The type, duration, and intensity of exogenous immunosuppressive therapy influence and enhance CMV infection. HCMV infection also causes chronic allograft dysfunction, especially in the case of kidney and lung engraftment. CMV causes renal allograft injury that may be indistinguishable from injury caused by rejection or other factors, and it has been linked to acute rejection and chronic rejection in other lung transplant scenarios resulting in decreased allograft survival.
Antiviral therapy has improved the management of CMV infection and defined diagnostic and clinical criteria for two forms of interventions, prophylactic or pre-emptive. In prophylaxis, antiviral drugs are instituted solely on the basis of the CMV sero-status of donor and recipient regardless of clinical disease. In “pre-emptive treatment” antiviral therapy is not initiated until signs of CMV infection are observed often by the real time monitoring of changes in peripheral blood HCMV genome load (virus load). As a result, these centres may provide an opportunity to show the efficacy of an anti-CMV mAb in preventing CMV infection or disease as monotherapy. This means the diagnosis and treatment specify trigger points are available and data with existing or new antiviral drugs provides a standard of care setting for measuring efficacy.
An efficacious anti-CMV antibody should reduce the rate of CMV disease providing an associated reduction in morbidity and improved allograft outcomes. The antibody could be used prophylactically before organ donation in the donor and recipient to reduce virus load, and administered at the point of organ transplant to prevent de novo, reactivating or primary infection in the recipient. The prevention of CMV infection is a potential goal in seronegative recipients, but the key outcome would be reduction in disease incidence and/or a reduction in the use of antiviral salvage treatments. CMV Neonate - Congenital Infection. The prevalence of congenital CMV infection is between 0.4 - 2% of live births with 1% frequently quoted as the mean. Current estimates suggest that 30,000-40,000 infants are bom with congenital cytomegalovirus infection annually (1% of the 4 million child birth cohort) in the United States, making cytomegalovirus by far the most common and important of all congenital infections. Maternal seropositivity rate is strongly affected by socio economic factors, with middle and upper class adults being only 40-60% seropositive with lower income groups being 80% and above.
Of the congenital infections, 10% have immediate clinically apparent Cytomegalic Inclusion Disease (CID). CID almost always occurs in women who have primary cytomegalovirus infection during pregnancy and is characterized by intrauterine growth retardation, hepatosplenomegaly, haematological abnormalities (particularly thrombocytopenia), and various cutaneous manifestations. However, the most significant manifestations of CID involve the CNS; microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common. Most infants who survive symptomatic CID have significant long-term neurological and neurodevelopmental sequelae. It has been estimated that congenital cytomegalovirus may be second only to Down syndrome as an identifiable cause of mental retardation in children.
The remaining 90% of congenital infections are asymptomatic, bom to women who have pre-existing immunity to cytomegalovirus. These infants appear clinically healthy at birth; however, although infants with congenital cytomegalovirus infection appear well, they may have subtle growth retardation compared to uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae. The major consequence of unapparent congenital cytomegalovirus infection is sensorineural hearing loss. Approximately 15% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of cytomegalovirus-associated hearing loss because this deficit may develop months or even years after birth.
The gold standard method for congenial HCMV diagnosis is a positive ‘shell’ assay within the first three weeks of life to exclude perinatal infection post birth. The shell assay is a tissue culture assay usually with inoculation from saliva or urine. A positive shell vial culture is presumptive evidence of active cytomegalovirus infection. Rapid vims genome detection assays may soon supersede the Shell assay. At present there is little clinical trial evidence for the treatment of neonates with congenital infection with antiviral drugs but a Phase 2 US study ‘Congenital CMV and Hearing Uoss in Children up to 4 Years of Age: Treating With Valganciclovir Therapy’ (NCT01649869) will complete in 2017. Depending on the outcome therapeutic antibodies may be a safer alternative for treating congenital HCMV infection.
Thus, antibodies described herein or compositions described herein for use as a medicament are provided. Antibodies described herein or compositions described herein for use in a method of treating HCMV infection are provided, said method comprising administering the antibody or composition to a patient. Antibodies described herein or compositions described herein for use in a method of reducing HCMV viral load in a patient are also provided, said method comprising administering the antibody or composition to the patient. Antibodies described herein or compositions described herein for use in a method of reducing frequency of HCMV virus reactivation in the patient are also provided, said method comprising administering the antibody or composition to a patient. Antibodies described herein or compositions described herein for use in a method of treating HCMV -positive glioblastoma multiforme (GBM) are also provided, said method comprising administering the antibody or composition to a patient . in some examples, the method further comprises administration of chemotherapy or radiotherapy. Antibodies described herein or compositions described herein for use in a method of preventing HCMV infection in a patient at risk of thereof are also provided, said method comprising administering the antibody or composition to a patient. Antibodies described herein or compositions described herein for use in a method of treating congenital HCMV infection are also provided.
In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
In one example, said method further comprises administering at least one further therapeutic agent. In one example, the first antibody and further therapeutic agent are administered simultaneously, separately, or sequentially.
In one example, the further therapeutic agent is a further antibody. Accordingly, monoclonal antibodies of the invention might be administered as part of an antibody cocktail comprising multiple (e.g., 2, 3 or 4) different monoclonal antibodies.
The further antibody may be selected from: a. an antibody that specifically binds to ULI 6 protein as described herein; b. an antibody that specifically binds to UL141 protein as described herein; c. an antibody that specifically binds to US28 protein as described herein; and d. an antibody that specifically binds to VEGF, for example bevacizumab.
The further antibody might bind to the same or a different protein as the first antibody.
An antibody cocktail might comprise a first antibody and a second antibody and optionally one or more further antibodies.
In one example, where the first antibody specifically binds ULI 6 protein, the second antibody also specifically binds ULI 6 protein.
In one example, where the first antibody specifically binds ULI 6 protein, the second antibody specifically binds UL141 protein.
In one example, where the first antibody specifically binds ULI 6 protein, the second antibody specifically binds US28 protein.
In one example, where the first antibody specifically binds UL141 protein, the second antibody also specifically binds UL141 protein.
In one example, where the first antibody specifically binds UL141 protein, the second antibody specifically binds ULI 6 protein.
In one example, where the first antibody specifically binds UL141 protein, the second antibody specifically binds US28 protein.
In one example, where the first antibody specifically binds US28 protein, the second antibody also specifically binds US28 protein.
In one example, where the first antibody specifically binds US28 protein, the second antibody specifically binds ULI 6 protein.
In one example, where the first antibody specifically binds US28 protein, the second antibody specifically binds UL141 protein.
In one example, where the first antibody specifically binds US28 protein, the second antibody specifically binds UL141 protein.
In one example, where the first antibody specifically binds US28 protein, the second antibody specifically binds VEGF, for example bevacizumab.
Provided herein is the use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of treating HCMV infection. Use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient is also provided. Use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient is also provided. Use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient, preferably wherein said method further comprises administration of chemotherapy or radiotherapy. Use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. Use of an antibody described herein or a composition described herein in the manufacture of a medicament for use in a method of treating congenital HCMV infection is also provided.
In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
In one example, the use of an antibody or composition described herein further comprises administering at least one further therapeutic agent. In one example, the first antibody and further therapeutic agent are administered simultaneously, separately or sequentially. In one example, the further therapeutic agent is a further antibody as defined herein.
A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody described herein or a composition described herein is also provided. A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is also provided. A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is also provided. A method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is also provided, preferably wherein said method further comprises administration of chemotherapy or radiotherapy. A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is also provided. A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody described herein or a composition described herein is also provided. In one example the patient shows one or more symptoms of HCMV infection. In one example the patient is a transplant recipient. In one example the patient is a transplant donor. In one example the transplant is a solid organ transplant. In one example the transplant is a stem cell transplant. In one example the transplant is a haematopoietic stem cell transplant (HSCT). In one example the patient is immunosuppressed. In one example the patient is immunocompromised. In one example the patient is HIV positive. In one example the patient has previously been treated with an anti-viral agent. In one example the patient has a HCMV infection which is refractory to at least one anti-viral agent. In one example the patient is a pregnant woman. In one example the HCMV infection is associated with an inflammatory disease, for example wherein the patient has atherosclerosis and/or the patient has previously undergone balloon angioplasty. In one example the patient has glioblastoma multiforme (GBM).
In one example, said method further comprising administering at least one further therapeutic agent. In one example, the first antibody and further therapeutic agent are administered simultaneously, separately or sequentially. In one example, the further therapeutic agent is a further antibody as defined anywhere herein.
(i) Antibody-Drug Conjugates
UL16, UL141 and US28 are internalising receptors. As such, the antibodies described herein may also be used in antibody-drug conjugates to deliver e.g. a cytoxic drug inside the cell.
In one example, an antibody as described anywhere herein is administered as an antibody-drug conjugate in which the antibody is linked to a drug moiety. For example, the antibody may be linked to a drug moiety which may be a cytokine, chemokine, or small molecule antiviral. In some examples, the antibody is linked to a cytotoxic agent.
In some examples the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-I065, duocarmycins and anthracyclines. Alternatively, in some examples, the antibody is linked to an anti-viral agent. In some examples, the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. In one example, the anti-viral agent is valganciclovir. In one example, the anti-viral agent is letermovir.
(ii) Combination Therapy
In some examples, antibodies described anywhere herein or pharmaceutical compositions comprising the antibody as described herein may be used singly or in combination with other anti-UL16, UL141 or US28 antibodies or pharmaceutical compositions comprising other anti-UL16, UL141 or US28 antibodies. Combinations of two or more anti-UL16, UL141 or US28 antibodies may have additive or synergistic potency compared to the potency of a single antibody, e.g. as measured in a Fc effector reporter assay. In some examples, combinations of anti-UL16 and anti-US28 antibodies have additive potency over a single mAb. In some examples, combinations of anti-UL141 and anti-US28 antibodies have additive potency over a single mAb. In some examples, combinations of anti-UL16 and anti -UL 141 antibodies have additive potency over a single mAb. In some examples, combinations of anti-UL16 antibodies have additive potency over a single mAb. In some examples, combinations of anti-UL141 antibodies have additive potency over a single mAb. In some examples, combinations of anti-US28 antibodies have additive potency over a single mAb. In some examples, combinations of anti-UL16 and anti-US28 antibodies have synergistic potency over a single mAb. In some examples, combinations of anti-UL141 and anti-US28 antibodies have synergistic potency over a single mAb. In some examples, combinations of anti-UL16 and anti-UL141 antibodies have synergistic potency over a single mAb. In some examples, combinations of anti-UL16 antibodies have synergistic potency over a single mAb. In some examples, combinations of anti-UL141 antibodies have synergistic potency over a single mAb. In some examples, combinations of anti-US28 antibodies have synergistic potency over a single mAb. In some examples, triple combinations of UL16, UL141 and US28 antibodies have additive potency over a single mAb. In some examples, triple combinations of UL16, UL141 and US28 antibodies have synergistic potency over a single mAb.
In some examples, the antibody as described herein or pharmaceutical composition comprising the antibody as described herein is administered in combination with an anti-viral agent, such as a directly acting antiviral (DAA) drug. In some examples, the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 and GW275175X . In one example, the anti-viral agent is letermovir.
In some examples, the antibodies or compositions for use as described herein may be used in a method which further comprises administration of two or more further therapeutic agents. In some examples the two or more further therapeutic agents are two or more further antibodies (e.g. anti-UL16, UL141 or US28 antibodies as described herein).
(iii) Kits
In another example, a kit for treating a HCMV infection or a HCMV-related disease or condition is provided, wherein the kit includes an antibody as described herein or a pharmaceutical composition as described herein. In some examples, the kit further includes instructions to administer the antibody to a subject in need of treatment. There is also provided a pharmaceutical or diagnostic pack or kit comprising one or more containers fdled with one or more of the ingredients of the pharmaceutical compositions as disclosed herein, such as one or more anti-UL16, UL141 or US28 antibodies provided herein. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration, e.g., an authorisation number.
In another example, an article of manufacture that includes a container in which a composition containing an antibody as described herein and a packaging insert or label indicating that the composition can be used to treat a HCMV related disease is provided. In one example, there is provided a kit for treating and/or preventing a HCMV related disease, the kit comprising an antibody as disclosed herein in any example or combination of examples (and optionally one or more further therapeutic agents as described elsewhere herein, e.g. one or more further anti-UL-16, UL141 or US28 antibodies as described herein) optionally in combination with a label or instructions for use to treat and/or prevent said disease or condition in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody. In another example, the kit comprises an antibody contained within a container or an IV bag. In another example, the container or IV bag is a sterile container or a sterile IV bag. In another example, the antibody is formulated into a pharmaceutical composition contained within a (sterile) container or contained within a (sterile) IV bag. In a further example, the kit further comprises instructions for use.
In another example, a kit for treating a HCMV infection or a HCMV-related disease or condition is provided, wherein the kit includes an antibody as described herein or pharmaceutical composition as described herein and instructions to administer the antibody to a subject in need of treatment. The subject in need is specifically defined in the kit as someone of a specific higher risk group defined by epidemiological data, risk stratification data from the person’s health records, risk stratification by the genotype of certain genes of the individual or the presence of certain biomarkers in the person's blood or other tissue sample. Where the risk stratification involves another pharmaceutical or diagnostic pack or kit, the combined product will act as a linked diagnostic/prognostic and treatment kit.
PREVENTION OF INFECTION- PROPHYLATIC USE
Antibodies as described herein may be used prophylactically. Administration of antibodies may prevent infection or reduce the risk of infection by HCMV. Antibodies may for example be used to prevent infection in those at risk in high transmission environments.
Thus antibodies described herein may be used in a method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody as defined herein. DIAGNOSTICS
Antibodies as described herein can be used to detect the presence, absence and/or level of HCMV in a biological sample from a patient. Antibodies as described herein can be used to detect the presence, absence and/or level of UL16, UL141 or US28 in a biological sample from a patient as a marker of HCMV. In one example, the biological sample is a tissue sample (e.g., in pathology studies or biopsy samples of tissue used for diagnostics and prognostics). In other examples, the biological sample is blood, plasma, serum, urine, faeces, cerebrospinal fluid (CFS). In other examples, the biological sample is from a nasal or throat swab. In other examples, the biological sample is from any suspected HCMV infected organ or tissue. The sample may have been obtained from a human who has been or is suspected of having been infected with HCMV. Liquid samples are convenient for use in many types of diagnostic assays.
The antibodies described herein can be used to identify the presence, absence and/or level of HCMV at baseline, i.e., before treatment. The antibodies described herein can be used to identify the presence, absence and/or level of UL16, UL141 or US28 (as a marker of HCMV) at baseline, i.e., before treatment.
The antibodies described herein can be used to guide therapy, particularly to identify the presence, absence and/or level of HCMV during or after treatment. The antibodies described herein can be used to guide therapy, particularly to identify the presence, absence and/or level of UL16, UL141 or US28 (as a marker of HCMV) during or after treatment.
The antibodies described herein can be used for patient monitoring, to help evaluate whether a course of treatment is effective and whether or not treatment should be continued.
In one example, the antibodies described herein may be used in a method of determining the presence or absence of HCMV in a sample, the method comprising contacting the sample with an antibody that specifically binds ULI 6 protein; and testing for binding between the antibody and HCMV protein ULI 6 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
In another example, the antibodies described herein may be used in a method of determining the presence or absence of HCMV in a sample, the method comprising contacting the sample with an antibody that specifically binds UL141 protein; and testing for binding between the antibody and HCMV protein UL141 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample. In another example, the antibodies described herein may be used in a method of determining the presence or absence of HCMV in a sample, the method comprising contacting the sample with an antibody that specifically binds US28 protein; and testing for binding between the antibody and HCMV protein US28 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
In one example, the antibody described herein is labelled with a detectable moiety, for example, a radiolabel, fluorescent label, enzymatic label, chemiluminescent labelled or a biotinyl group. Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, 115In, 1251, 1311, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, P- galactosidase, luciferase, alkaline phosphatase. Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH"), alpha-D- galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes; additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein"), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o- phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g. Europium etc (Perkin Elmer and Cisbio Assays); chemoluminescent labels or chemiluminescers, such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5 -bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, saporin or a cytotoxic fragment thereof, pokeweed antiviral toxin or a cytotoxic fragment thereof and bryodin 1 or a cytotoxic fragment thereof.
In one example, the antibody can be administered to a patient, wherein the antibody is conjugated to a label. The presence of the label in the patient can be measured or observed, wherein a relatively high amount of the label may indicate a high risk of disease and a relatively low amount of the label may indicate a relatively low risk of the disease. In one example, the label is a contrast agent, isotopic tag, or fluorescent marker, such as green fluorescent protein.
For use in diagnostics, antibodies with high affinity, especially with fast on-rate and slow off-rate (e.g., as measured by SPR) are particularly valuable. In one example, a kit for detecting HCMV in a biological sample is provided. The kit can be used to screen for a HCMV infection or a HCMV-related disease or condition. In one example, the kit includes an antibody according to the invention as described anywhere herein and a means for determining whether the antibody is bound to UL16, UL141 or US28 in a sample as a marker of HCMV. In one example, the antibody is specific for UL16, UL141 or US28 protein. In one example, the antibody is labelled. In another example, the antibody is an unlabelled primary antibody and the kit includes means for detecting the primary antibody. In one example, the means for detecting includes a labelled secondary antibody that is an anti-immunoglobulin antibody. The antibody may be labelled with any suitable marker, including, for example, a fluorochrome, an enzyme, a radionuclide and a radiopaque material.
In one example, a kit for detecting HCMV is provided, wherein the kit includes an antibody as described herein. In one example, the kit may also include instructions and one or more reagents for detecting HCMV, particularly one or more reagents for detecting UL16, UL141 or US28 as a marker of HCMV.
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8. Zipeto, D., Bodaghi, B., Laurent, L., Virelizier, J. L. & Michelson, S. Kinetics of transcription of human cytomegalovirus chemokine receptor US28 in different cell types. J. Gen. Virol. 80, 543-547 (1999).
9. Boomker, J. M., Van Luyn, M. J. A., The, T. H., De Leij, L. F. M. H. & Harmsen, M. C. US28 actions in HCMV infection: Lessons from a versatile hijacker. Rev. Med. Virol. 15, 269-282 (2005).
10. Beisser, P. S., Laurent, L. & Virelizier, J. Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes. 75, 5949-5957 (2001). Chee, M. S., Satchwell, S. C., Preddie, E., Weston, K. M. & Barrell, B. G. Human cytomegalovirus encodes three G protein-coupled receptor homologues. Nature 344, 774-777 (1990). Gao, J. L. & Murphy, P. M. Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J. Biol. Chem. 269, 28539-42 (1994). Kledal, T. N., Rosenkilde, M. M. & Schwartz, T. W. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBSLett. 441, 209-214 (1998). Streblow, D. N. et al. Human Cytomegalovirus Chemokine Receptor US28-induced Smooth Muscle Cell Migration is Mediated by Focal Adhesion Kinase and Src. J. Biol. Chem. 278, 50456-50465 (2003). Stropes, M. P., Schneider, O. D., Zagorski, W. a, Miller, J. L. C. & Miller, W. E. The carboxy-terminal tail of human cytomegalovirus (HCMV) US28 regulates both chemokine -independent and chemokine- dependent signaling in HCMV-infected cells. J. Virol. 83, 10016-27 (2009). Billstrom, M. A., Johnson, G. L., Avdi, N. J. & Worthen, G. S. Intracellular Signaling by the Chemokine Receptor US28 during Human Cytomegalovirus Infection. 72, 5535-5544 (1998). Minisini, R. et al. Constitutive Inositol Phosphate Formation in Cytomegalovirus-Infected Human Fibroblasts Is due to Expression of the Chemokine Receptor Homologue pUS28. J. Virol. 77, 4489- 4501 (2003). Waldhoer, M., Kledal, T. N., Farrell, H. & Schwartz, T. W. Murine Cytomegalovirus (CMV) M33 and Human CMV US28 Receptors Exhibit Similar Constitutive Signaling Activities. J. Virol. 76, 8161-8168 (2002). Miller, W. E., Houtz, D. A., Nelson, C. D., Kolattukudy, P. E. & Lefkowitz, R. J. G-protein-coupled receptor (GPCR) kinase phosphorylation and -arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR. J. Biol. Chem. 278, 21663-21671 (2003). Caposio, P., Orloff, S. L. & Streblow, D. N. The Role of Cytomegalovirus in Angiogenesis. 157, 204- 211 (2011). Lanier, L. L. NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunol. Res. 3, 575-582 (2015). Dunn, C. et al. Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration ofNKG2D ligands, protecting against natural killer cell cytotoxicity. J. Exp. Med. 197, 1427-1439 (2003). Wu, J. et al. Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human cytomegalovirus UL16 glycoprotein. J. Immunol. 170, 4196-4200 (2003). Cosman, D. et al. ULBPs, Novel MHC Class I-Related Molecules, Bind to CMV Glycoprotein UL16 and Stimulate NK Cytotoxicity through the NKG2D Receptor. Immunity 14, 123-133 (2001). Sutherland, C. L. et al. UL16-Binding Proteins, Novel MHC Class I-Related Proteins, Bind to NKG2D and Activate Multiple Signaling Pathways in Primary NK Cells. J. Immunol. 168, 671-679 (2002). Muller, S., Zocher, G., Steinle, A. & Stehle, T. Structure of the HCMV UL16-MICB complex elucidates select binding of a viral immunoevasin to diverse NKG2D ligands. PLoS Pathog. 6, (2010).
VI. EXAMPLES
Here we describe antibodies binding to UL16, UL141 or US28 proteins which are suitable for use in treating HCMV infection and HCMV-related disease or condition. Through immunising transgenic mice which generate fully human antibodies and testing a wide diversity of antibodies in a series of biologically relevant assays, we were able to obtain UL16, UL141 or US28-binding monoclonal antibodies which mediate killing of infected cells. These antibodies can be used alone or in combination as a therapeutic or prophylactic against HCMV infection or HCMV-related disease or condition (e.g., for administration to human patients) or as a diagnostic for detecting HCMV infection or HCMV-related disease or condition (e.g., in in vitro diagnostic test assays and kits).
Example 1: Generation of HCMV antigens and anti-US28, anti-UL16 and anti-UL141 antibodies
Kymab transgenic mice (Kymouse HKL v2.1), which produce chimeric antibodies with mouse constant region and human variable regions, were immunised with HCMV antigens in a variety of immunisation regimens and immunogenic formats, and antigen-specific B cells were isolated from the immunised mice. Single B cells from spleen and lymph node samples from UL16 or UL141 immunised mice were sorted using UL16 or UL141 soluble extracellular domain protein as antigen specific probes.
US28 is a G-protein coupled receptor (GPCR) with a seven-pass transmembrane structure typical of these receptors. To maintain the correct conformation GPCRs need to be expressed within a membrane, therefore it is not possible to generate soluble US28 protein. To identify US28 binding antibodies green fluorescent protein (GFP) virus like particles (VLPs) were used for sorting US28 immunised mice, in combination with antigenindependent plasma cell sorting.
1312 antigen specific B-cells were sorted from UL16 immunised mice, 574 antigen specific B-cells from UL141 immunised mice and 3095 B-cells from US28 immunised mice and paired heavy and light chain sequences generated. 295 anti-UL16 antibodies, 102 anti-UL141 antibodies and 237 anti-US28 antibodies were selected for synthesis based on in silico clustering and antibody lineage analysis. All antibodies were synthesized as fully human IgGl with either kappa or lambda light chains and taken forward for screening.
Materials and methods
DNA constructs and purified protein production
DNA constructs were generated for HCMV genes US28, UL16 and UL141 to use for DNA immunisations. For each protein all available strain sequences were obtained from the NCBI Genbank database and a multiple sequence alignment used to generate a consensus sequence. Both ULI 6 and UL141 contain an endoplasmic reticulum (ER) retention signal at the C-terminal end of the gene. In order to reduce ER retention of the protein and increase cell surface expression these signals were deleted (see sequence alignments in Figure 1A and IB). All DNA constructs were codon optimised for mammalian expression. The consensus DNA sequence was cloned into an expression vector (PB-CAG) under the control of the CAGGS promotor flanked by 3 ’ and 5 ’ piggyBac specific terminal repeat sequences, which facilitated stable integration into the cell genome. DNA plasmids were prepared using standard E-coli bacterial expression and Maxiprep (Qiagen) purification. The sequence of all plasmids was confirmed by capillary sequencing. 50ug DNA was administered to mice via hydrodynamic tail vein injection using HyperPBase to ensure integration of the PiggyBac transposon in the cell genome for stable expression.
Purified ULI 6 and UL141 proteins used as immunogens and for sorting of B cells were a gift from Dr Richard Stanton at University of Cardiff. These proteins consisted of the extracellular domain (ECD) of the protein and were codon optimised for mammalian expression and expressed in HEK cells. UL141 protein used for screening was synthesized in house. The UL141 coding sequence was fused with a C-terminal His tag, codon optimised for mammalian expression and expressed in CHO cells. Protein was sequentially purified by a HisTrap HP column and a HiPrep 16/60 Sephacryl S-300 HR size exclusion chromatography (SEC) column (both from GE Healthcare). Purified protein was first analysed by Native-PAGE and Western blot, and then filtered through a 0.22 pm membrane, aliquoted and stored at -80 °C.
Stable cell line generation and VLP production
To generate table cell lines the DNA sequences for UL16 and UL141 were cloned into the R184N expression vector under the control of the EFl alpha promotor flanked by 3’ and 5’ piggyBac specific terminal repeat sequences, which facilitated stable integration into the cell genome. This expression vector also contained ampicillin and neomycin antibiotic resistance genes to allow selection of stable cell lines. The UL16 and UL141 ER retention signals were removed to increase cell surface expression (see previous section and Figures 1 A and IB). The proteins were cloned both as untagged proteins and with the addition of an N-terminally fused HA- tag (YPYDVPDYA), derived from influenza virus haemagglutinin (HA) protein and a C-terminally fused six histidine tag (6xHis).
Untagged and tagged (C-terminal His/N-terminal HA) constructs were transfected into the human embryonic kidney cell line (HEK293) using Lipofectamine 2000 (ThermoFisher) transfection and stable cell lines selected using G418 (Geneticin, Thermo Fisher) antibiotic resistance. Surface expression of the target proteins was confirmed by flow cytometry using antibodies to the tags (anti-Penta His mouse IgGl, Qiagen #34660 and mouse IgGl anti-HA tag, Biolegend #901503) and cell lines were sorted based on high expression of the targets to have a more uniform cell population.
For US28, untagged constructs encoding either the full-length protein or a truncated version were also transfected into the mouse dendritic cell line DC2.4. The truncated version of US28, US28A300, was constructed by inserting a STOP-codon after residue Gln-300, resulting in a 54 amino acid deletion from the C- terminal end of the protein. This truncation was shown in the literature to increase cell surface expression of this antigen (Waldoer et al., 2003). Transfection of both the full-length protein and the delta300 mutant into DC2.4 cells was performed using Lipofectamine 2000 (ThermoFisher) transfection and stable cell lines were selected using G418 (Geneticin, Thermo Fisher) antibiotic resistance.
US28 expressing stable cell lines were also generated in HEK293 cells using 4 different US28 constructs, wild type US28 tagged (N-terminal HA tag) and untagged and US28A300 tagged (N-terminal HA tag) and untagged. See Figure 1C for construct sequences.
Virus like particles (VLPs) were generated from HEK293 cells encoding US28A300 to be used as a sorting probe. The DNA sequence was cloned into an expression vector under the control of the CMV promoter flanked by 3’ and 5’ piggyBac specific terminal repeat sequences, which facilitated stable integration into the cell genome. The expression vector contained a neomycin selection cassette to facilitate stable cell line generation. Constructs were transfected into HEK293 cell line, cultured under G418 (Geneticin, Thermo Fisher) selection for 2 weeks and cell surface expression of UL16, UL141 or US28 was validated by using flow cytometry to check for antigen surface expression using antibodies supplied by Dr Richard Stanton, Cardiff University.
Example 2: Primary screening of UL141 and UL16 antibodies by HTRF
All antibodies taken forward for screening were expressed in human embryonic kidney (HEK) cells and antibody supernatants were screened for binding to ULI 6 or UL141. A homogeneous time resolved FRET (HTRF) assay was used for primary screening to establish binding of the recovered antibodies to soluble purified ULI 6 and UL141 proteins. Antibody supernatants (unquantified) from HEK cell expression were screened undiluted and at 1: 10, 1: 100 and 1: 1000 in an initial screen for binding to the soluble target protein. HTRF assays have a known “hook effect” whereby very high concentrations of antibody can give a lower signal in this assay so screening at multiple dilutions was undertaken to capture all possible binders. Antibodies that showed binding activity greater than 10% of effect relative to a control antibody at any of the dilutions tested were taken forward to secondary screening. For UL16, 295 antibodies were screened, and 207 antibodies identified as binders. For UL141, 102 antibodies were screened, and 77 UL141 binding antibodies were identified.
After identifying antibodies that bind to the target proteins the antibody supernatants were purified using Phynexus purification, quantified and then taken forward for screening in further functional assays. Materials and methods
Antibodies were expressed in 2ml cultures of Expi293 HEK cells and supernatants collected for screening. For initial screening, the supernatants were not quantified, and several dilutions were needed to cover the range of expected concentrations. Supernatants were screened undiluted or at 1: 10, 1: 100 and 1: 1000 dilutions in Expi293 Expression Medium (Gibco, #A1435101).
Control antibodies used were anti-penta His msIgGl (Qiagen, #34660), anti-UL141 mAb550.2 HuIgGl (made in house), mouse IgGl isotype CM7, (Sigma #M9269), human IgGl isotype control (Sigma #1-5154). Each control antibody was diluted in Expi293 Expression Medium at 4x final assay concentration (120nM). Final assay concentration for all control antibodies started at 30nM and each antibody was diluted 1 in 3 for a total of 11 -point dilution series to generate a titration curve.
Soluble extracellular domain of ULI 6 (gift from Richard Stanton, Cardiff University) and UL141 (see Example 1) were labelled with AlexaFluor647 using the AlexaFluor647 Conjugation Kit (Fast) - Lightning-Link (Abeam, #ab269823). 5pl of AlexaFluor647-labelled UL16 or UL141 was diluted in HTRF buffer (PBS + 0.53M potassium fluoride + 0.1%BSA) and added to each well of the assay plates (384-well white low volume nonbinding surface polystyrene plates Greiner #784904). The final concentration of the protein was lOnM for UL16 and 15nM for UL141.
5pl/well of each diluted control or test antibody supernatant was added to assay plate. Then lOpl/well of antimouse Europium cryptate (CisBio #61PAMKLA, final concentration 1:4000) or anti-human Europium cryptate (CisBio #61HFCKLA, final concentration 1:200) diluted in HTRF buffer was added and plates incubated overnight at room temperature in the dark.
HTRF assay plates are read on a barcoded HTRF protocol on the Envision plate reader (Ex: 340nm EME620 nm EM2: 665 nm). The data analysis was performed in Excel, GraphPad Prism and Genedata Biologies. Each well is read at two different wavelengths (620 and 665nm): a ratio of these two readings is calculated for each well.
Figure imgf000141_0001
To assess the binding, the results are then expressed as Delta F values, where Non-Specific Binding (NSB) refers to the average HTRF ratio of wells with isotype control antibody.
Figure imgf000141_0002
Data are then expressed as a percentage of Effect, relative to a control antibody. Total binding (TB) refers to average HTRF ratio of wells with the control anti-His antibody for UL16 and mAb550.2 antibody for UL141. 100
Figure imgf000142_0001
Example 3: Primary screening of US28 antibodies by flow cytometry
Unpurified supernatants from US28 antibodies (unquantified) were screened for binding by flow cytometry. As US28 is a GPCR and needs to be expressed in a cell membrane to maintain the correct conformation, HTRF using soluble protein is not a suitable assay for US28. Flow cytometry was performed using a stable cell line expressing truncated (A300) US28 to increase cell surface expression. This truncation was shown in the literature to increase cell surface expression of this antigen (Waldoer et al., 2003). The truncation is at the C- terminal intracellular end of the protein, therefore the protein that is visible on the extracellular surface of the cells is identical to the wild-type protein. Antibody supernatants were tested at two concentrations, 1: 10 and 1: 100.
237 antibodies were screened, and 21 antibodies were identified as binding to the US28 expressing cells. Antibodies were considered positive binders if the binding was greater than threefold over background (binding to wildtype HEK293 cells not expressing US28). The binding values for a subset of antibodies is shown in Table 3-1. The number of antibodies that passed screening was lower for US28 compared to UL16 and UL141 as expected, due to the sorting strategy that was a combination of VLP positive cells and antigen independent sorting. All antibodies that were binders at any concentration were purifed using Phynexus purification, quantified and taken forward to screening in further functional assays.
Figure imgf000143_0001
Table 3-1: Anti-US28 antibody binding to US28 expressing cells by flow cytometry
Materials and methods
Antibodies were expressed in 2ml cultures of Expi293 HEK cells and supernatants collected for screening. Supernatants were tested for binding to HEK cells overexpressing US28delta300 N’HA tag by flow cytometry. lOOul of US28delta300 N’HA tag cell suspension (~lxl0A5 cells) was seeded in 96well plate (Greiner, cat#651901-012) and cells incubated with 50ul of antibody supernatant (pre diluted 1: 100 in Expi293 Expression Medium (Gibco, #A1435101)) or with control antibodies (mouse IgGl anti-HA tag, Biolegend cat#901503; mouse IgGl isotype control, in house or anti-US28 antibody TUB-45, made in house) at a final concentration of 30nM. Wild type (untransfected) HEK293 cells were used as control cells. Cells are incubated for 45minutes at 4degrees, washed 3x with PBS and incubated with 50ul of detection antibody (anti-mouse AlexaFluor647 antibody, Jackson Immunoresearch, #115-605-071 or anti-Human AlexaFluor647, Jackson Immunoresearch, #709-605-098) for 30minutes at 4degrees. Cells are washed 3x with PBS, fixed with 4%PFA in PBS for 10 minutes and washed again 3 times with PBS. Cells were resuspended in lOOul PBS and fluorescence emission is read on CytoFlex Flow Cytometer. Data were analysed using FlowJo, Microsoft Excel, GraphPad Prism and Genedata Biologies. The GeoMean at 647nm obtained for the gated HEK cells of each well is calculated and then exported in an Excel table. The GeoMean values for the positive controls (TUB45 and anti-HA tag antibodies), together with the isotype controls are then plotted using GraphPad Prism to draw titration curves. They are proportional to the binding of antibodies to US28. GeoMean values from binding to HEK wildtype were only taken into consideration for positive clones. Non-Specific Binding (NSB), being the averaged GeoMean value of wells with isotype control (either human or mouse) per plate is subtracted from each well (divided) first to show the fold over background of the binding. Fold
Figure imgf000144_0001
Example 4: ADCC Promega Reporter assay
All antibodies that passed through primary screening for binding to the target protein by either HTRF or flow cytometry were screened using a high throughput reporter assay for Antibody dependent cellular cytotoxicity (ADCC). The objective of this assay is to evaluate the capacity of the antibodies to engage the Fc receptor as a surrogate reporter assay for ADCC. If the antibody can bind the Fc receptor on the effector cells, then it should be able to have ADCC activity in a primary NK killing assay.
The Fc Effector Reporter Bioassay (Promega) uses as a readout the FcyR and NFAT-mediated activation of luciferase activity in the effector cells . Effector cells are Jurkat cell line stably expressing human FcyRIIIa V 158 and NFAT-induced luciferase. Following engagement with the Fc region of a relevant antibody bound to a target cell, ADCC bioassay effector cells expressing FcyRIIIa (V-variant) will transduce intracellular signals resulting in NFAT-mediated luciferase activity that can be easily quantified using a plate reader.
For ULI 6, 207 antibodies were tested in this assay and 25 antibodies showed significant activity. Figure 3 A shows titration curves for ten of these antibodies. Cytotect, which is a concentrated human immune serum and an existing HCMV therapeutic, was used as a control. All of the antibodies that were active in this assay showed stronger activity compared to Cytotect. Table 4-1 shows the IC50 values for the UL16 antibodies. ATHO-0601 was the most potent antibody in this assay.
Figure imgf000145_0001
Table 4-1: IC50 values for anti-UL16 antibodies in ADCC reporter assay For UL141, 77 antibodies were tested for ADCC activity in this reporter assay. Only one of these antibodies (ARAM-0601) showed ADCC activity in this assay (Figure 3B). The IC50 value for this antibody is shown in Table 4-2.
Figure imgf000146_0001
Table 4-2: IC50 values for anti-UL141 antibody in ADCC reporter assay
For US28, 21 antibodies were tested for ADCC activity in this reporter assay. Two antibodies (ARAM-0601) showed ADCC activity in this assay (Figure 3C). The IC50 values for these antibodies are shown in Table 4-3. PORT-0601 had significantly greater binding to US28 by flow cytometry compared to all other antibodies tested in primary screening and was the most potent antibody in this assay.
Figure imgf000146_0002
Table 4-3: IC50 values for anti-US28 antibodies in ADCC reporter assay
Materials and methods
HEK293 cells overexpressing one ofUL141, UL16 or US28 were as described in Example 1. In addition human foreskin fibroblast cell lines overexpressing one of UL141, UL16 or US28 were also used for this assay. These cell lines were generated by Richard Stanton, Cardiff University. The HEK293 cell lines express ULI 6 and UL141 proteins with the ER retention signals deleted to increase expression and US28A300, truncated to increase expression. The HFF cell lines express native sequences and therefore the cell surface expression is lower compared to the HEK cell lines and is likely to be more representative of the expression on a infected cell.
Target cells (HEK or HFF) were resuspended at 3 xlOA6 cells/ml in 3% Ultra LowIgG FBS (Gibco, #16250078, batch#1939770). lOpl/well (30,000 cells/well) of cell suspension was added to a 384 white plate (Greiner, cat#781098). Antibodies were pre-diluted in a low binding 96well plate (Greiner, #651901) at a concentration 3 times higher than the final working concentration. The highest concentration tested was 5ug/ml, with a 1:3 serial dilution performed. 1 Opil of pre-diluted antibodies were added to the 384well on top of the previously plated cells. Antibodies are not added to the background control wells, which consisted of only effector and target cells. Effector cells from the Reporter ADCC assay Kit V-variant (Promega, #G7010) were defrosted on the day of experiment from LN2 and diluted at 1.5 x 10A6 cells/ml in 3% Ultra LowIgG FBS(Gibco, cat#16250078, batch#1939770). lOul/well (so 15.000 cells/well) of cell suspension was added to a 384 well white plate (Greiner, cat#781098). The ratio between Effector and Target cells used was 1:2 with 15,000 effector cells and 30,000 target cells. The assay plate was then incubated 24hours at 37°C, 5% CO2.
After 24hours incubation, the detection reagent (Bio-Gio™ Luciferase Assay Buffer & Substrate) was equilibrated to ambient temperature, protected from light and 30ul/well Bio-Gio™ Reagent added to all wells. The plate was sealed using optical clear plate seal (Starlab, cat#E2796-9795), incubated in the dark at ambient temperature for 5 minutes, then luciferase emission was detected on an Envision plate reader.
The data were analysed using Microsoft Excel and GraphPad Prism. Data analysis is based on the calculation of Fold Induction of each well in the plate.
Raw well signal value (RLU)
Fold Induction =
Average Assay Background (No mAb)
The fold Induction was ploted in GraphPad Prism using the analysis “Nonlinear regression (curve fit)/ log inhibition vs response - variable slope (four parameters)” and IC50 values calculated for each antibody.
Example 5: BATDA ADCC assay on primary cells
The most potent antibodies in the reporter ADCC assay were further screened using a BATDA ADCC assay on primary natural killer (NK) cells. This assay uses primary NK cells freshly isolated from donor blood and is therefore a more authentic assay compared to using a reporter cell line as a readout.
The BATDA ADCC assay is based on loading target cells with a fluorescent BATDA ligand and co-culturing withNK cells freshly isolated from a human blood leukocyte cone. The hydrophobic BATDA reagent penetrates the target cell membrane quickly and once in the cell forms a hydrophilic ligand which can no longer pass through the membrane. The ligand is released into the supernatant after NK cell mediated cytolysis. The supernatant is then removed and added to the DELFIA Eu solution which results in the formation of a highly fluorescent and stable chelate which is measurable on a plate reader. Fluorescence correlates with dye release into the supernatant and measures NK mediated cell killing in the presence of antibody.
Figure 4A shows an example graph for an anti-UL16 antibody ATHO-0106 that showed a high percentage of specific NK mediated killing in this assay.
The same assay was used to determine NK mediated killling in the presence of anti-US28 antibodies. Figure 4B shows activity of two anti-US28 antibodies PORT-0601 and PORT-0501 that showed a high percentage of specific NK mediated killing in this assay. Both antibodies had activity greater than the currently available therapeutic polyclonal serum Cytotect.
Materials and methods
Primary NK cells were freshly isolated from a leucocyte cone following the method described in EasySep™ Human NK Cell Isolation Kit (StemCell Kit #17955). At the end of the isolation protocol, NK cells are counted using Trypan Blue method and resuspended at a final concentration of 2 x 106/ml in RPMI +10% Ultra LowIgG FBS.
Antibodies were pre-diluted (3x times more concentrated than the final working concentration) in a low binding 96 well plate. 50ul of each antibody or isotype control (HuIgGl, Sigma) are added to a 96 well plate while media only is added to the “Spontaneous Release”, “Background” and “Max Release” wells. In the “Max Release” wells, 50ul of Lysis Buffer supplied in the DELFIA EuTDA kit is added to establish 100% killing.
Target cells overexpressing the target (HFF or HEK293, expressing UL16, UL141 or US28, see Example 4) were counted and resuspended at a final concentration of lxl06cells/ml in pre-warmed assay media. 20ul of DELFIA BATDA reagent (5ul/million of cells) was added to the target cells and incubated for 30min in the dark at 37degrees. Target cells were then washed 3x with 50ml of PBS and resuspended at 400,000 cells/ml (20,000 cells/well).
50ul of each of target cells, effector cells and antibody dilutions were added to 96 well plate and incubated for 4hours at 37 degrees. After incubation, 50ul of the supernatant was transferred to a 96-well black plate and 200ul of Europium solution added to the plate. Plates were incubated at RT for 15minutes and then read on an Envision plate reader using DELFIA filter.
Data are plotted in GraphPad Prism software after calculation of %Specific release and %Spontaneous release.
Formulas for calculating
Experimental release (counts) - Spontaneous release (counts)
% Specific release = Maximum release (counts) - Spontaneous release (counts)
Figure imgf000148_0001
Spontaneous release (counts) - background (counts) „
% Spontaneous release Maximum release (counts) - background (counts)
Figure imgf000148_0002
Example 6: Generation of Fc modified antibodies and ADCC activity Mutations in the Fc region have been shown in the literature to increase the Fc-mediated effector function of antibodies, including ADCC. The Fc-enhancing variants described by Lazar et al., 2006 include the single mutants S239D and I332E and the double and triple mutants S239D/I332E and S239D/I332E/A330L.
In order to test whether the ADCC activity of the HCMV antibodies could be increased, a subset of antibodies were modified in the Fc region using the S239D/I332E mutations (thus each of the modified antibodies comprised the IgGl constant region sequence of SEQ ID NO: 364 as set out in Table 2) and the activity of these antibodies in the ADCC reporter assay were measured compared to the wild type unmutated version of the same antibodies (the wild type unmutated versions comprising the IgGl constant region sequence of SEQ ID NO: 363 as set out in Table 2).
Four Fc modified (S239D/I332E) anti-UL16 antibodies were tested using the reporter ADCC assay compared to the unmodified antibodies with the standard IgGl Fc region. For all four of the UL16 antibodies tested, the antibodies containing the Fc modifications showed significantly increased ADCC activities compared to the unmodified antibodies with the same variable regions (Figure 5A).
Four Fc modified UL141 antibodies were tested using the reporter ADCC assay and all of these antibodies showed significant ADCC activity. Three of these clones had previously not shown activity in this assay, indicating a significant increase in potency in the modified clones (Figure 5B). Antibody ARAM-0601 previously showed some activity but this was markedly increased after the Fc modification.
One US28 antibody (PORT-0501) was modified in the Fc region and the activity of this mutated antibody compared with the unmutated antibody in the ADCC reporter assay. In this case the Fc modification did not increase the activity of the antibody.
Materials and methods
DNA strings containing the required S239D/I332E mutations in the Fc region were ordered from Geneart and cloned into an expression vector using Aarl golden gate cloning. DNA plasmids were prepared using standard E-coli bacterial expression and Miniprep (Qiagen) purification. The sequence of all plasmids was confirmed by capillary sequencing.
Antibodies with the Fc modification were expressed in CHO cells and purified by a HisTrap HP column and a HiPrep 16/60 Sephacryl S-300 HR size exclusion chromatography (SEC) column (both from GE Healthcare).
ADCC reporter assays were run using the Fc modified clones and the unmodified clones as described in Example 4 using HFF cells expressing UL16 and UL141 and HEK cells expressing US28A300. Example 7: Binding of anti-HCMV antibodies to virus infected cells
To establish if the antibodies are able to bind to HCMV infected cells, human fibroblast (HFF) cell lines were infected in vitro with wild type HCMV (Merlin strain) and cells analysed by flow cytometry for expression of the targets and binding of the described antibodies.
Using one representative antibody for each target, each of the three targets were detected on the cell surface by flow cytometry at 48 hours post infection (Figure 6). The expression level of these targets is expected to be much lower on the surface of virus infected cells compared to cell lines overexpressing individual proteins. Controls including isotype control, secondary antibody only and unstained cells did not show significant staining. All staining was also run using non-infected HFFs cells to determine non-specific binding. The staining in infected cells is higher compared to uninfected cells and all controls, indicating specific binding of the antibodies to the targets expressed on infeccted cells.
This experiment is more representative of the expression level that would be seen in vivo and suggests that these antibodies would be able to bind to infected cells in vivo and have a therapeutic function.
Materials and methods
For this experiment a subset of the best binding antibodies to each target were re-expressed using the same variable regions but replacing the human Fc with mouse Fc (IgG2a) regions to ensure no background staining from the human cells and Fc decoys expressed by the HCMV virus.
HF-Test (HFFF cells immortalized with htert, from Richard Stanton at Cardiff University) were trypsinized, counted and resuspended in media lacking FBS at a final concentration of 1.5xl0A5 cells/ml. 1ml of the cells suspension is seeded in each well of a 12 well plate (CellBIND Coming, #CUS3336). The absence of FBS in the assay media is necessary for CMV infection (the HF -test cells can be infected only if they have been growth arrested before to infection).
24 hours after seeding the target cells, media is removed and cells are infected with HCMV 2582 (7xlOA7 PFU/ml stock, from Cardiff University) at MOI (multiplicity of infection) of three in 300ul. Plates were incubated for 2 hours at 37 degrees, and gently rocked every 30 minutes to ensure good infectivity. After 2 hours, the inoculum is removed and replaced with 500ul of fresh 1%FBS DMEM medium. Plates are then incubated at 37 degrees for 24, 48 or 72 hours.
At each time point, cells were harvested and blocked with Human IgGl isotype control (Human IgGl, made in house) for 10 minutes at 4 degrees. After incubation, each well was stained with anti -UU 141 msIgG2a antibody (ARAM-0601); anti-UU16 msIgG2a antibody (ATHO-0601); anti-US28 msIgG2a antibody (PORT-0601) and msIgG2a isotype control (made in house). The cells were incubated for 45 min at 4 degrees, washed 3x with PBS and incubated with secondary detection antibody (anti -Mouse IgG AF647 1: 1000) for 30 minutes at 4 degrees. Cells were washed with 3x PBS and fixed with 4% paraformaldehyde in PBS for 30minutes. Then cells were washed 3x with PBS, resuspended in lOOul of PBS and fluorescence read on a CytoFlex flow cytometer.
Example 8: NK cell degranulation assay
To examine the ability of anti-HCMV antibodies to mediate ADCC of target cells using primary human NK cells, the lead antibodies were tested in vitro in an NK degranulation assay as a measure of ADCC activity.
Peripheral blood mononuclear cells (PBMCs) were isolated from human donors and incubated for 48hours with antibodies and target cells that were infected with recombinant adenovirus to express either UL16 or US28 or UL141. The cells were then examined by flow cytometry with gating on CD3-/CD56+/CD57+ NK cells. The percentage of CD3-/CD56+/CD57+ cells that were positive for the NK cell degranulation marker CD107a indicates the level of NK cell degranulation and therefore ADCC activity. Cytotect (human immune serum) was included in each assay to allow comparison across different assays as there is some variability between different blood donors in the NK cell response.
Seven anti-US28 antibodies were tested in the degranulation assay, both individually and in combination. Two antibodies (PORT-0501 and PORT-0601) showed highly potent NK degranulation, significantly higher than Cytotect (CT), despite the concentration of Cytotect being 20 times higher than the individual antibodies. Pooling all seven antibodies together into one mix did not increase the potency and resulted in similar levels of degranulation to each of the two antibodies alone (Figure 7A).
Ten anti-UL16 antibodies were tested in the degranulation assay, both individually and in combination. All ten of the antibodies tested showed NK degranulation in this assay. ATHO-0105, ATHO-0106 and ATHO-0601 had the most potent activity, giving a higher effect than Cytotect (CT). Pooling all ten antibodies together into one mix resulted in significantly higher levels of degranulation compared to the response to each antibody alone (Figure 7B). The increased activity when multiple antibodies were combined suggests that there is an additive effect or possibly synergistic, possibly due to the antibodies targeting different epitopes.
Ten anti -UL 141 antibodies were tested in the degranulation assay and nine antibodies showed NK degranulation activity. ARAM-0102 and ARAM-0801 had the most potent activity, higher than Cytotect (CT). Pooling all nine antibodies together into one mix resulted in significantly higher levels of degranulation compared to the response to each antibody alone (Figure 7C). The increased activity when multiple antibodies were combined suggests that there is an additive effect or possibly synergistic, possibly due to the antibodies targeting different epitopes. Materials and methods
Cell lines
Human fetal foreskin fibroblasts (HFFFs) immortalized with human telomerase (HF-TERTs) (McSharry et al., 2001), TERT-immortalized healthy donor skin fibroblasts (SFis) and 293 TREXs were maintained in a humidified incubator at 37 °C with 5% CO2 and grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% FCS, penicillin (lOOunit/ml) and streptomycin (lOOpg/ml).
Recombinant adenovirus
Recombinant adenovirus (Rad) vectors were generated as described in Stanton et al., 2008. The RAd vectors used were RAd-Ctrl (RAd- 1253, containing no exogenous ORF), RAd-UL141 AER (UL141 carrying a deletion of the ER retention signal in the cytoplasmic tail, and an exogenous signal peptide containing a HA tag after the cleavage site), RAd-UL16AER (ULI 6 carrying a deletion of the ER retention signal in the cytoplasmic tail, and an exogenous signal peptide containing a HA tag after the cleavage site), RAd-UL141 (expressing the native form of UL141 (Tomasec et al., 2005) and RAd-UL16 (expressing the native form of UL16). Recombinant adenoviruses all contained a C-terminal V5 epitope tag and were propagated by transfection of the relative plasmids in 293 TREX cells as described previously (Stanton et al., 2008).
CD 107a NK degranulation assays
Functional NK assays were based on previously described assays (Prod’homme et al., 2007). Effector cells (PBMCs) were rested overnight in RPMI media (supplemented with 10% FCS, penicillin (lOOunit/ml), streptomycin (lOOpg/ml) and 2mM L-Glutamine). For target cells either HF-TERTs for allogeneic assays or SFis for autologous assays were used. Cells were plated in DMEM without FCS the day before infection and the following day they were infected with recombinant adenovirus at MOI 5. At 24h media was exchanged for DMEM containing 10% FCS and the assay performed at 48h post infection. On the day of the assay the cells were detached with TrypLE Express (Gibco) and counted. The E:T ratios were adjusted to 10: 1, and the target cells were pre-incubated for 30 minutes with the antibody preparations. Antibodies were used at 1.5pg/ml final concentration when used individually or 1.5pg/ml of each antibody when used as a mix. The effector cells (PBMCs) were then added in the reaction along with golgi-stop (eBioscience™), and anti-human CD 107a antibody. All reactions were performed in triplicate, in U-bottom 96-well plates, at 200pl final volume. The reactions were incubated for 5 hours, then cells were thoroughly washed with cold PBS and stained with fixable Live/Dead Aqua and anti-human CD3, CD56, CD57 and NKG2C. Flow cytometric analysis was performed with a 14-color AttuneNxT flow cytometer (Thermo Fisher) and analysed using the Attune NxT or FlowJo V10 software. The whole sample was analysed for each reaction. Samples without targets were used to determine background activation. Cytotect clinical grade polyclonal anti-HCMV serum (Biotest) and human serum from individuals seronegative for anti-HCMV were used as positive and negative controls, respectively. VII. SEQUENCES
Table 1:
Table 1 below shows amino acid sequences of antibodies and encoding nucleic acids described in this specification. All ATHO, ARAM or PORT VH domains, ATHO, ARAM or PORT VL domains, ATHO, ARAM or PORT CDRs, ATHO, ARAM or PORT heavy chains and ATHO, ARAM or PORT light chains, antibodies comprising them, as well as their encoding nucleic acids, represent examples of the present invention. CDRs are determined according to IMGT method.
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Table 2:
Table 2 shows constant region sequences relevant to the UL16, UL141 and US28 antibodies of the invention.
Figure imgf000185_0002
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Table 3:
Table 3 below shows the heavy and light chain v and j gene segments corresponding to each of the antibodies set out in Table 1 above.
Figure imgf000201_0002
Figure imgf000202_0001
Table 4:
Table 4 below shows the amino acid sequences of UL16 ligands, UL141 ligands and US28 ligands.
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
CLAUSES
Aspects of the invention are disclosed in the following lettered and numbered clauses:
CLAUSE SET A -UL16 ANTIBODIES
1. An antibody that specifically binds to a UL 16 viral protein.
2. An antibody that specifically binds to the extracellular domain of a UL16 viral protein.
3. An antibody according to clause Al or A2, wherein the antibody is a monoclonal antibody.
4. An antibody according to any one of clauses Al to A3, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
5. An antibody according to any one of clauses Al to A4, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
6. An antibody according to any one of clauses Al to A5, wherein the antibody mediates killing of cells infected with HCMV.
7. An antibody according to any one of clauses Al to A6, wherein the antibody mediates immune- mediated killing of cells infected with HCMV.
8. An antibody according to any one of clauses Al to A7, wherein the antibody mediates NK-cell killing of cells infected with HCMV.
9. An antibody according to any one of clauses Al to A8, wherein the antibody reduces viral load of cells infected with HCMV.
10. An antibody according to any one of clauses Al to A9, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
11. An antibody according to any one of clauses Al to A 10, wherein the antibody has CDC activity.
12. An antibody according to any one of clauses Al to Al 1, wherein the antibody has ADCP activity. An antibody according to any one of clauses Al to A12, wherein the antibody competes for binding to UL16 protein with MICB, ULBP1, ULBP2 and/or ULBP6. An antibody according to any one of clauses Al to A13, wherein the antibody blocks UL16 protein binding to MICB, ULBP1, ULBP2 and/or ULBP6. An antibody according to any one of clauses Al to A14, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO- 0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO- 0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO- 0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO- 0801. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0101. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0102. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0103. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0104. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0105. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0106. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0107. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0108. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0109. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0110. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0111. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0112. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0113. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0114. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0115. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0116. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0201. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0301. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0302. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0303. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0401. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0501. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0601. The antibody according to clause A 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0701. The antibody according to clause A15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0801. An anti-UL 16 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. An antibody according to any one of clauses Al to A41, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0101. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0102. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0103. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0104. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0105. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0106. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0107. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0108. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0109. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-Ol lO. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0111. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0112. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0113. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0114. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0115. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0116. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0201. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0301. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0302. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0303. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0401. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0501. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0601. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody
ATHO-0701. An antibody according to clause A41 or clause A42, wherein the antibody has the CDRs of antibody ATHO-0801. An antibody according to any one of clauses Al to A67, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO- 0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO- 0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO- 0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence. An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)., An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 11, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-Ol 12, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 12, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-Ol 13, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 13, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-Ol 14, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 14, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-Ol 15, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 15, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-Ol 16, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-Ol 16, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause A68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to any one of clauses Al to A94, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-O 112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201 , ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-O 111, ATHO-O 112, ATHO-O 113, ATHO-O 114, ATHO-O 115, ATHO-O 116, ATHO-0201 , ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0101, provided that the antibody has the CDRs of antibody ATHO-0101. The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0102, provided that the antibody has the CDRs of antibody ATHO-0102. The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0103, provided that the antibody has the CDRs of antibody ATHO-0103. The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0104 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0104, provided that the antibody has the CDRs of antibody ATHO-0104. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0105 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0105, provided that the antibody has the CDRs of antibody ATHO-0105. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0106 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0106, provided that the antibody has the CDRs of antibody ATHO-0106. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0107 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0107, provided that the antibody has the CDRs of antibody ATHO-0107. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0108 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0108, provided that the antibody has the CDRs of antibody ATHO-0108. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0109 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0109, provided that the antibody has the CDRs of antibody ATHO-0109. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0110 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0110, provided that the antibody has the CDRs of antibody ATHO-0110. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0111 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0111, provided that the antibody has the CDRs of antibody ATHO-0111. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0112 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0112, provided that the antibody has the CDRs of antibody ATHO-0112. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0113 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0113, provided that the antibody has the CDRs of antibody ATHO-0113. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0114 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0114, provided that the antibody has the CDRs of antibody ATHO-0114. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0115 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0115, provided that the antibody has the CDRs of antibody ATHO-0115. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0116 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0116, provided that the antibody has the CDRs of antibody ATHO-0116. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0201, provided that the antibody has the CDRs of antibody ATHO-0201. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0301, provided that the antibody has the CDRs of antibody ATHO-0301. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0302, provided that the antibody has the CDRs of antibody ATHO-0302. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0303, provided that the antibody has the CDRs of antibody ATHO-0303. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0401, provided that the antibody has the CDRs of antibody ATHO-0401. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0501, provided that the antibody has the CDRs of antibody ATHO-0501. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0601, provided that the antibody has the CDRs of antibody ATHO-0601. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0701, provided that the antibody has the CDRs of antibody ATHO-0701. . The antibody according to clause A95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0801. . An antibody according to any one of clauses Al to A120, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0101. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0102. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0103. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0104. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0105. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0106. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0107. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0108. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0109. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0110. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-O 111. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0112. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0113. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0114. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0115. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0116. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0201. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0301. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0302. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0303. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0401. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0501. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0601. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0701. . The antibody according to clause A121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0801. . The antibody according to any one of clauses Al to A146, wherein the antibody is a human IgGl. . The antibody according to clause A147, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. . The antibody according to clause A 147, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. . The antibody according to clause A149, wherein the antibody is a human IgGl having S239D and I332E mutations. . The antibody according to clause A 150, wherein the antibody is a human IgG 1 comprising a constant region sequence of SEQ ID NO: 364. . The antibody according to any one of clauses Al to A151 wherein the antibody comprises kappa (K) light chain constant regions. . An antibody that specifically binds to a ULI 6 protein, wherein said antibody competes for binding to a ULI 6 protein with a reference antibody, where the reference antibody is an antibody according to any one of clauses Al to A152. . An antibody that specifically binds to the same epitope on a ULI 6 protein as the epitope on a ULI 6 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of clauses Al to A152. . The antibody according to any one of clauses Al to A154, comprising VH and/or VL domain framework regions of human germline gene segment sequences. . The antibody according to any one of clauses Al to A 155, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18; and/or the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of clauses Al to A 156, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV4-34*01, IGHV4- 31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18, a human heavy chain D gene segment and a human heavy chain J gene segment, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations. 158. The antibody according to any one of clauses Al to A157, wherein the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with 1, 2, 3, 4 or 5 amino acid alterations.
159. The antibody according to any one of clauses Al to A158, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01, and/or the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGKJl*01, IGLJ2*01, or IGKJ3*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
160. The antibody according to any one of clauses Al to A 159, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01, and optionally the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01.
161. The antibody according to any one of clauses Al to A 160, wherein the antibody is linked to a cytotoxic agent.
162. The antibody according to clause A161, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-1065, duocarmycins and anthracy clines. . The antibody according to any one of clauses Al to A 160, wherein the antibody is linked to an anti-viral agent. . The antibody according to clause A 163, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A pharmaceutical composition comprising an antibody according to any one of clauses Al to A 164 and a pharmaceutically acceptable excipient. . A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of clauses Al to A 164 and a pharmaceutically acceptable excipient. . The pharmaceutical composition according to clauses A 165 or A 166, further comprising at least one further therapeutic agent. . The pharmaceutical composition of clause A 167, wherein the further therapeutic agent is a further antibody. . The pharmaceutical composition of clause A168, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein; b. an antibody that specifically binds to UL141 protein; and c. an antibody that specifically binds to US28 protein. . The pharmaceutical composition of clause A168, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. . The pharmaceutical composition of clause A 168, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein according to any of clauses Al to A 164; b. an antibody that specifically binds to UL141 protein according to any of clauses Bl to Bl 13; and c. an antibody that specifically binds to US28 protein according to any of clauses Cl to C80. . A pharmaceutical composition comprising a first antibody according to any one of clauses Al to A164 and a second antibody according to any one of clauses Cl to C80. . A pharmaceutical composition comprising a first antibody according to any one of clauses Al to A164, a second antibody according to any one of clauses Bl to Bl 13, and a third antibody according to any one of clauses Cl to C80. . The pharmaceutical composition of clause A167, wherein the further therapeutic agent is an anti-viral agent. . The pharmaceutical composition of clause A174, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The pharmaceutical composition according to any one of clauses A165 to A175, further comprising two or more further therapeutic agents. . The pharmaceutical composition according to clause A176, wherein the two or more further therapeutic agents are two or more further antibodies. . The pharmaceutical composition according to any one of clauses A165 to A177, formulated for intravenous, intramuscular or subcutaneous administration. . The antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A 165 to A 178, for use as a medicament. . The antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses A 1 to A 164, or the composition according to any one of clauses A165 to A178, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. . The antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Al to A 164, or the composition according to any one of clauses A165 to A178, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, for use in a method of treating congenital HCMV infection. . Use of an antibody according to any one of clauses Al to A 164, or the composition according to any one of clauses A165 to A178, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178, in the manufacture of a medicament for use in a method of treating congenital HCMV infection. . A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Al to A 164, or the composition according to any one of clauses A165 to A178. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Al to A 164, or the composition according to any one of clauses A165 to A178. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178. . A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178. . A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Al to A164, or the composition according to any one of clauses A165 to A178. . The antibody for use according to any one of clauses A 180 to A 184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the patient is a transplant recipient. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the patient is a transplant donor. . The antibody for use according to any one of clauses A 180 to A 184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of clauses A 180 to A 184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein the patient is immunosuppressed. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein the patient is immunocompromised. . The antibody for use according to any one of clauses A 180 to A 184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein the patient is HIV positive. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the patient has previously been treated with an anti-viral agent. . The antibody for use according to any one of clauses A 180 to A 184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A189, or a method according to any one of clauses A190 to A194, wherein the patient is a pregnant woman. . The antibody for use according to any one of clauses A180 to A184, or the composition for use according to any one of clauses A 180 to A 184, or use according to any one of clauses A 185 to A 189, or a method according to any one of clauses A 190 to A 194, wherein HCMV infection is associated with an inflammatory disease.
208. The antibody for use according to clause A207, or the composition for use according to clause A207, or use according to clause A207, or a method according to clause A207, wherein the patient has atherosclerosis.
209. The antibody for use according to clause A207 or clause A208, or the composition for use according to clause A207 or clause A208, or use according to clause A207 or clause A208, or a method according to clause A207 or clause A208, wherein the patient has previously undergone balloon angioplasty.
210. The antibody for use according to any one of clauses A180 to A184 or A195 to A209, or the composition for use according to any one of clauses A 180 to A 184 or A 195 to A209, the use according to any one of clauses A 185 to A 189 or A 195 to A209, or the method according to any one of clauses A 190 to A210, wherein said method further comprises administration of a further therapeutic agent.
211. The antibody for use according to any one of clauses A 180 to A 184 or A 195 to A209, or the composition for use according to any one of clauses A 180 to A 184 or A 195 to A209, the use according to any one of clauses A 185 to A 189 or A 195 to A209, or the method according to any one of clauses A 190 to A210, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
212. The antibody for use according to clauses A210 or A211, or the composition for use according to clauses A210 or A211, or use according to clauses A210 or A211, or a method according to clauses A210 or A211, wherein the further therapeutic agent is a further antibody.
213. The antibody for use according to clause A212, or the composition for use according to clause A212, or use according to clause A212, or a method according to clause A212, wherein the further antibody is a further antibody that specifically binds to ULI 6 protein, for example an antibody according to any of clauses Al to A 164.
214. The antibody for use according to clause A212, or the composition for use according to clause A212, or use according to clause A212, or a method according to clause A212, wherein the further antibody is an antibody that specifically binds to UL141 protein, for example an antibody according to any of clauses B 1 to B 113.
215. The antibody for use according to clause A212, or the composition for use according to clause A212, or use according to clause A212, or a method according to clause A212, wherein the further antibody is an antibody that specifically binds to US28 protein, for example an antibody according to any of clauses Cl to C80.
216. The antibody for use according to clauses A210 or A211 , or the composition for use according to clauses A210 or A211, or use according to clauses A210 or A211, or a method according to clauses A210 or A211, wherein the further therapeutic agent is an anti-viral agent.
217. The antibody for use according to clause A216, or the composition for use according to clause A216, or use according to clause A216, or a method according to clause A216, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X.
218. The antibody for use according to any one of clauses A 180 to A 184 or A 195 to A209, or the composition for use according to any one of clauses A 180 to A 184 or A 195 to A209, the use according to any one of clauses A 185 to A 189 or A 195 to A209, or the method according to any one of clauses A 190 to A210, wherein said method further comprises administration of two or more further therapeutic agents.
219. The antibody for use according to any one of clauses A180 to A184 or A195 to A209, or the composition for use according to any one of clauses A 180 to A 184 or A 195 to A209, the use according to any one of clauses A 185 to A 189 or A 195 to A209, or the method according to any one of clauses A 190 to A210, wherein said method further comprises administration of two or more further antibodies.
CLAUSES SET B - UL141 ANTIBODIES
1. An antibody that specifically binds to a UL 141 viral protein.
2. An antibody that specifically binds to the extracellular domain of a UL141 viral protein. An antibody according to claim B 1 or B2, wherein the antibody is a monoclonal antibody. An antibody according to any one of clauses Bl to B3, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain. An antibody according to any one of clauses Bl to B4, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains. An antibody according to any one of clauses Bl to B5, wherein the antibody mediates killing of cells infected with HCMV. An antibody according to any one of clauses Bl to B6, wherein the antibody mediates immune- mediated killing of cells infected with HCMV. An antibody according to any one of clauses Bl to B7, wherein the antibody mediates NK-cell killing of cells infected with HCMV. An antibody according to any one of clauses Bl to B8, wherein the antibody reduces viral load of cells infected with HCMV. An antibody according to any one of clauses Bl to B9, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay. An antibody according to any one of clauses B 1 to B 10, wherein the antibody has CDC activity. An antibody according to any one of clauses Bl to Bl 1, wherein the antibody has ADCP activity. An antibody according to any one of clauses Bl to B12, wherein the antibody competes for binding to
UL141 protein with CD155, CD112 and/or TRAIL-R1/R2. An antibody according to any one of clauses Bl to B13, wherein the antibody blocks UL141 protein binding to CD155, CD112 and/or TRAIL-R1/R2. An antibody according to any one of clauses Bl to Bl 4, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM- 0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0102. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0103. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0201. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0202. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0203. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0204. The antibody according to clause Bl 5, wherein the HCDR3 is the HCDR3 of antibody ARAM-0301. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0302. The antibody according to clause Bl 5, wherein the HCDR3 is the HCDR3 of antibody ARAM-0303. The antibody according to clause Bl 5, wherein the HCDR3 is the HCDR3 of antibody ARAM-0401. The antibody according to clause Bl 5, wherein the HCDR3 is the HCDR3 of antibody ARAM-0501. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0601. The antibody according to clause Bl 5, wherein the HCDR3 is the HCDR3 of antibody ARAM-0701. The antibody according to clause B15, wherein the HCDR3 is the HCDR3 of antibody ARAM-0801. An anti-UL141 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. An antibody according to any one of clauses B 1 to B31, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0101. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0102. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0103. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0201. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0202. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0203. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0204. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0301. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0302. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0303. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0401. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0501. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0601. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0701. An antibody according to clause B31 or clause B32, wherein the antibody has the CDRs of antibody ARAM-0801. An antibody according to any one of clauses Bl to B47, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence. An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause B48, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to any one of clauses Bl to B63, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0101, provided that the antibody has the CDRs of antibody ARAM-0101. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0102, provided that the antibody has the CDRs of antibody ARAM-0102. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0103, provided that the antibody has the CDRs of antibody ARAM-0103. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0201, provided that the antibody has the CDRs of antibody ARAM-0201. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0202 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0202, provided that the antibody has the CDRs of antibody ARAM-0202. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0203 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0203, provided that the antibody has the CDRs of antibody ARAM-0203. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0204 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0204, provided that the antibody has the CDRs of antibody ARAM-0204. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0301, provided that the antibody has the CDRs of antibody ARAM-0301. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0302, provided that the antibody has the CDRs of antibody ARAM-0302. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0303, provided that the antibody has the CDRs of antibody ARAM-0303. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0401, provided that the antibody has the CDRs of antibody ARAM-0401. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0501, provided that the antibody has the CDRs of antibody ARAM-0501. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0601, provided that the antibody has the CDRs of antibody ARAM-0601. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0701, provided that the antibody has the CDRs of antibody ARAM-0701. The antibody according to clause B64, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0801. An antibody according to any one of clauses Bl to B 79, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0101. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0102. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0103. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0201. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0202. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0203. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0204. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0301. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0302. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0303. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0401. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0501. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0601. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0701. The antibody according to clause B80, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0801. The antibody according to any one of clauses Bl to B95, wherein the antibody is a human IgGl. The antibody according to clause B96, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. The antibody according to clause B96, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. The antibody according to clause B98, wherein the antibody is a human IgGl having S239D and I332E mutations. . The antibody according to clause B99, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364. . The antibody according to any one of clauses B 1 to B 100 wherein the antibody comprises kappa (K) light chain constant regions. . An antibody that specifically binds to a UL141 protein, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody according to any one of clauses Bl to B101. . An antibody that specifically binds to the same epitope on a UL141 protein as the epitope on a UL141 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of clauses Bl to B101. . The antibody according to any one of clauses B 1 to B 103, comprising VH and/or VL domain framework regions of human germline gene segment sequences. . The antibody according to any one of clauses Bl to Bl 04, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02; and/or the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of clauses Bl to Bl 05, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV4-31*03, IGHV4- 59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02, a human heavy chain D gene segment and a human heavy chain J gene segment, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
107. The antibody according to any one of clauses Bl to B106, wherein the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
108. The antibody according to any one of clauses B 1 to B 107, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV2-23*dO2, IGLV 1-51*01, IGKV3-l l*01, IGLV3- 19*01, IGKV2-24*01, or IGKV3-15*01, and/or the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
109. The antibody according to any one of clauses B 1 to B 108, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV2-23*dO2, IGLV 1-51*01, IGKV3-l l*01, IGLV3- 19*01, IGKV2-24*01, or IGKV3-15*01, and optionally the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01. . The antibody according to any one of clauses B 1 to B 109, wherein the antibody is linked to a cytotoxic agent. . The antibody according to clause B 110, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC-1065, duocarmycins and anthracy clines. . The antibody according to any one of clauses B 1 to B 109, wherein the antibody is linked to an anti-viral agent. . The antibody according to clause Bl 12, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A pharmaceutical composition comprising an antibody according to any one of clauses B 1 to B 113 and a pharmaceutically acceptable excipient. . A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of clauses B 1 to B 113 and a pharmaceutically acceptable excipient. . The pharmaceutical composition according to clauses B114 or B115, further comprising at least one further therapeutic agent. . The pharmaceutical composition of clause Bl 16, wherein the further therapeutic agent is a further antibody. . The pharmaceutical composition of clause B 117, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein; b. an antibody that specifically binds to UL141 protein; and c. an antibody that specifically binds to US28 protein. . The pharmaceutical composition of clause B 117, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. . The pharmaceutical composition of clause B 117, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein according to any of clauses Al to A 164; b. an antibody that specifically binds to UL141 protein according to any of clauses Bl to Bl 13; and c. an antibody that specifically binds to US28 protein according to any of clauses Cl to C80. . A pharmaceutical composition comprising a first antibody according to any one of clauses B 1 to Bl 13 and a second antibody according to any one of clauses Cl to C80. . The pharmaceutical composition of clause Bl 16, wherein the further therapeutic agent is an anti-viral agent. . The pharmaceutical composition of clause B122, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The pharmaceutical composition according to any one of clauses Bl 14 to B 123, further comprising two or more further therapeutic agents. . The pharmaceutical composition according to clause B124, wherein the two or more further therapeutic agents are two or more further antibodies. . The pharmaceutical composition according to any one of clauses B 114 to B 125, formulated for intravenous, intramuscular or subcutaneous administration. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses B 114 to B 126, for use as a medicament. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to Bl 26, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B 126, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B126, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses B 114 to B 126, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B126, for use in a method of treating congenital HCMV infection. . Use of an antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B 126, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of an antibody according to any one of clauses B 1 to B 113, or the composition according to any one of clauses Bl 14 to B 126, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of an antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B 126, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of an antibody according to any one of clauses B 1 to B 113, or the composition according to any one of clauses Bl 14 to B 126, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of an antibody according to any one of clauses B 1 to B 113, or the composition according to any one of clauses Bl 14 to B 126, in the manufacture of a medicament for use in a method of treating congenital HCMV infection. . A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B126. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses B 1 to B 113 , or the composition according to any one of clauses Bl 14 to B126. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B126. . A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Bl to Bl 13, or the composition according to any one of clauses Bl 14 to B126. . A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Bl to B 113, or the composition according to any one of clauses B 114 to B 126. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B137, or a method according to any one of clauses B 138 to Bl 42, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to
B 137, or a method according to any one of clauses B 138 to B 142, wherein the patient is a transplant recipient. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to
B 137, or a method according to any one of clauses B 138 to B 142, wherein the patient is a transplant donor. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to Bl 42, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B137, or a method according to any one of clauses B138 to B142, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to
B 137, or a method according to any one of clauses B 138 to Bl 42, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to Bl 42, wherein the patient is immunosuppressed. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to Bl 42, wherein the patient is immunocompromised. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to
B 137, or a method according to any one of clauses B 138 to Bl 42, wherein the patient is HIV positive. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to
B 137, or a method according to any one of clauses B 138 to B 142, wherein the patient has previously been treated with an anti-viral agent. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to B 142, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to B 142, wherein the patient is a pregnant woman. . The antibody for use according to any one of clauses B128 to B132, or the composition for use according to any one of clauses B128 to B132, or use according to any one of clauses B133 to B 137, or a method according to any one of clauses B 138 to Bl 42, wherein HCMV infection is associated with an inflammatory disease.
156. The antibody for use according to clause Bl 55 or the composition for use according to clause B 155, or use according to clause B 155, or a method according to clause Bl 55, wherein the patient has atherosclerosis.
157. The antibody for use according to clause B 155 or clause B 156 or the composition for use according to clause B155 or clause B156, or use according to clause B 155 or clause Bl 56, or a method according to clause Bl 55 or clause Bl 56, wherein the patient has previously undergone balloon angioplasty.
158. The antibody for use according to any one of clauses B128 to B 132 or B 143 to B157, or the composition for use according to any one of clauses B128 to B 132 or B 143 to B157, or use according to any one of clauses B 133 to Bl 37 or B 143 to Bl 57, or a method according to any one of clauses B138 to B157, wherein said method further comprises administration of a further therapeutic agent.
159. The antibody for use according to any one of clauses B128 to B 132 or B 143 to B157, or the composition for use according to any one of clauses B128 to B 132 or B 143 to B157, or use according to any one of clauses B 133 to Bl 37 or B 143 to Bl 57, or a method according to any one of clauses B138 to B157, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
160. The antibody for use according to clauses B158 or B 159, or the composition for use according to clauses B158 or B159, or use according to clauses B158 or B159, or a method according to clauses B158 or B159, wherein the further therapeutic agent is a further antibody.
161. The antibody for use according to clause B 160, or the composition for use according to clause B160, or use according to clause Bl 60, or a method according to clause Bl 60, wherein the further antibody is an antibody that specifically binds to ULI 6 protein, for example an antibody according to any of clauses Al to A 164.
162. The antibody for use according to clause B 160, or the composition for use according to clause B160, or use according to clause Bl 60, or a method according to clause Bl 60, wherein the further antibody is an further antibody that specifically binds to UL141 protein, for example an antibody according to any of clauses Bl to Bl 13.
163. The antibody for use according to clause B 160, or the composition for use according to clause B160, or use according to clause Bl 60, or a method according to clause Bl 60, wherein the further antibody is an antibody that specifically binds to US28 protein, for example an antibody according to any of clauses Cl to C80.
164. The antibody for use according to clauses B 158 or B 159, or the composition for use according to clauses B 158 or B 159, or use according to clauses B 158 or B 159, or a method according to clauses B 158 or B 159, wherein the further therapeutic agent is an anti-viral agent.
165. The antibody for use according to clause Bl 64, or the composition for use according to clause B164, or use according to clause Bl 64, or a method according to clause Bl 64, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X.
166. The antibody for use according to any one of clauses B128 to B132 or B 143 to B157, or the composition for use according to any one of clauses B128 to B 132 or B 143 to B157, or use according to any one of clauses B 133 to Bl 37 or B 143 to Bl 57, or a method according to any one of clauses B138 to B157, wherein said method further comprises administration of two or more further therapeutic agents.
167. The antibody for use according to any one of clauses B128 to B132 or B 143 to B157, or the composition for use according to any one of clauses B128 to B 132 or B 143 to B157, or use according to any one of clauses B 133 to Bl 37 or B 143 to Bl 57, or a method according to any one of clauses B138 to B157, wherein said method further comprises administration of two or more further antibodies.
CLAUSE SET C - US28 ANTIBODIES
1. An antibody that specifically binds to a US28 viral protein.
2. An antibody that specifically binds to the extracellular domain of a US28 viral protein. An antibody according to clause Cl or C2, wherein the antibody is a monoclonal antibody. An antibody according to any one of clauses Cl to C3, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain. An antibody according to any one of clauses Cl to C4, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains. An antibody according to any one of clauses Cl to C5, wherein the antibody mediates killing of cells infected with HCMV. An antibody according to any one of clauses Cl to C6, wherein the antibody mediates immune- mediated killing of cells infected with HCMV. An antibody according to any one of clauses Cl to C7, wherein the antibody reduces viral load of cells infected with HCMV. An antibody according to clause C8, wherein the cells are lytically infected cells. An antibody according to clause C8, wherein the cells are latently infected cells. An antibody according to any one of clauses Cl to CIO, wherein the antibody reduces frequency of viral reactivation in cells latently infected with HCMV. An antibody according to any one of clauses Cl to Cl 1, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay. An antibody according to any one of clauses Cl to C12, wherein the antibody has CDC activity. An antibody according to any one of clauses Cl to C13, wherein the antibody has ADCP activity. An antibody according to any one of clauses Cl to C14, wherein the antibody competes for binding to
US28 protein with CX3CL1 and/or other chemokines. An antibody according to any one of clauses Cl to C15, wherein the antibody blocks US28 protein binding to CX3CL1 and/or other chemokines. An antibody according to any one of clauses Cl to Cl 6, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801. The antibody according to clause Cl 7, wherein the HCDR3 is the HCDR3 of antibody PORT-0101. The antibody according to clause C17, wherein the HCDR3 is the HCDR3 of antibody PORT-0201. The antibody according to clause C17, wherein the HCDR3 is the HCDR3 of antibody PORT-0301. The antibody according to clause Cl 7, wherein the HCDR3 is the HCDR3 of antibody PORT-0401. The antibody according to clause C17, wherein the HCDR3 is the HCDR3 of antibody PORT-0501. The antibody according to clause Cl 7, wherein the HCDR3 is the HCDR3 of antibody PORT-0601. The antibody according to clause C17, wherein the HCDR3 is the HCDR3 of antibody PORT-0701. The antibody according to clause Cl 7, wherein the HCDR3 is the HCDR3 of antibody PORT-0801. An anti-US28 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801. An antibody according to any one of clauses Cl to C26, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0101. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0201. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0301. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0401. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0501. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0601. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0701. An antibody according to clause C26 or clause C27, wherein the antibody has the CDRs of antibody PORT-0801. An antibody according to any one of clauses Cl to C35, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT- 0601, PORT-0701, or PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence. An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to clause C36, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to any one of clauses Cl to C44, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801, provided that the antibody has the CDRs of antibody PORT-0101, PORT-0201, PORT-0301, PORT- 0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0101, provided that the antibody has the CDRs of antibody PORT-0101. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0201, provided that the antibody has the CDRs of antibody PORT-0201. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0301, provided that the antibody has the CDRs of antibody PORT-0301. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0401, provided that the antibody has the CDRs of antibody PORT-0401. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0501, provided that the antibody has the CDRs of antibody PORT-0501. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0601, provided that the antibody has the CDRs of antibody PORT-0601. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0701, provided that the antibody has the CDRs of antibody PORT-0701. The antibody according to clause C45, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0801, provided that the antibody has the CDRs of antibody PORT-0801. An antibody according to any one of clauses Cl to C53, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT- 0701, or PORT-0801. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0101. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0201. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0301. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0401. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0501. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0601. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0701. The antibody according to clause C54, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0801. The antibody according to any one of clauses Cl to C62, wherein the antibody is a human IgGl. The antibody according to clause C63, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. The antibody according to clause C63, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. The antibody according to clause C65, wherein the antibody is a human IgGl having S239D and I332E mutations. The antibody according to clause C66, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364. The antibody according to any one of clauses Cl to C67 wherein the antibody comprises kappa (K) light chain constant regions. An antibody that specifically binds to a US28 protein, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody according to any one of clauses Cl to C68. An antibody that specifically binds to the same epitope on a US28 protein as the epitope on a US28 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of clauses Cl to C68. The antibody according to any one of clauses Cl to C70, comprising VH and/or VL domain framework regions of human germline gene segment sequences. The antibody according to any one of clauses Cl to C71, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR2 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR3 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
73. The antibody according to any one of clauses Cl to C72, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV2-5* 10, IGHV4- 39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03, a human heavy chain D gene segment and a human heavy chain J gene segment, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations.
74. The antibody according to any one of clauses Cl to C73, wherein the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
75. The antibody according to any one of clauses Cl to C74, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR2 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations
FR3 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ4*01, or IGLJ2*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
76. The antibody according to any one of clauses Cl to C75, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and optionally the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01. The antibody according to any one of clauses Cl to C76, wherein the antibody is linked to a cytotoxic agent. The antibody according to clause C77, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC- 1065, duocarmycins and anthracyclines. The antibody according to any one of clauses Cl to C76, wherein the antibody is linked to an antiviral agent. The antibody according to clause C79, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. A pharmaceutical composition comprising an antibody according to any one of clauses Cl to C80 and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of clauses Cl to C80 and a pharmaceutically acceptable excipient. The pharmaceutical composition according to clauses C81 or C82, further comprising at least one further therapeutic agent. The pharmaceutical composition of clause C83, wherein the further therapeutic agent is a further antibody. The pharmaceutical composition of clause C84, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein; b. an antibody that specifically binds to UL141 protein; c. an antibody that specifically binds to US28 protein; and d. an antibody that specifically binds to VEGF, for example bevacizumab. The pharmaceutical composition of clause C84, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. The pharmaceutical composition of clause C84, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein according to any of clauses Al to A 164; b. an antibody that specifically binds to UL141 protein according to any of clauses Bl to Bl 13; c. an antibody that specifically binds to US28 protein according to any of clauses Cl to C80; and d. an antibody that specifically binds to VEGF. A pharmaceutical composition comprising a first antibody according to any one of clauses Cl to C80 and a second antibody that specifically binds to VEGF. The pharmaceutical composition of clause C83, wherein the further therapeutic agent is an anti-viral agent. The pharmaceutical composition of clause C89, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. The pharmaceutical composition according to any one of clauses C81 to C90, further comprising two or more further therapeutic agents. The pharmaceutical composition according to clause C91, wherein the two or more further therapeutic agents are two or more further antibodies. The pharmaceutical composition according to any one of clauses C81 to C92, formulated for intravenous, intramuscular or subcutaneous administration. The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use as a medicament. The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of treating HCMV-positive glioblastoma multiforme (GBM), said method comprising administering the antibody or composition to a patient. The antibody for use according to clause C98, or the composition for use according to clause C98, wherein said method further comprises administration of chemotherapy or radiotherapy. . The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, for use in a method of treating congenital HCMV infection. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient. . The use of an antibody according to clause Cl 05, or the use of a composition according to clause C105, wherein said method further comprises administration of chemotherapy or radiotherapy. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93, in the manufacture of a medicament for use in a method of treating congenital HCMV infection. . A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . A method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . The method of clause Cl 12, wherein said method further comprises administration of chemotherapy or radiotherapy. . A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses Cl to C80, or the composition according to any one of clauses C81 to C93. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C101, or use according to any one of clauses C102 to C108, or a method according to any one of clauses C109 to Cl 15, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is a transplant recipient. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is a transplant donor. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of clauses C95 to CIO 1, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is immunosuppressed. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is immunocompromised. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is HIV positive. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient has previously been treated with an anti-viral agent. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient is a pregnant woman. . The antibody for use according to any one of clauses C95 to C101, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein HCMV infection is associated with an inflammatory disease. . The antibody for use according to clause C128 or the composition for use according to clause C128, or use according to clause C128, or a method according to clause C128, wherein the patient has atherosclerosis. . The antibody for use according to clause C128 or clause C129 or the composition for use according to clause C128 or clause C129, or use according to clause C128 or clause C129, or a method according to clause C128 or clause C129, wherein the patient has previously undergone balloon angioplasty. . The antibody for use according to any one of clauses C95 to CIO 1, or the composition for use according to any one of clauses C95 to C 101, or use according to any one of clauses Cl 02 to Cl 08, or a method according to any one of clauses C109 to Cl 15, wherein the patient has glioblastoma multiforme (GBM). . The antibody for use according to any one of clauses C95 to CIO 1 or Cl 16 to C 131, or the composition for use according to any one of clauses C95 to C101 or C116 to C131, or use according to any one of clauses C102 to C108 or Cl 16 to C131, or a method according to any one of clauses C109 to C131, wherein said method further comprises administration of a further therapeutic agent.
133. The antibody for use according to any one of clauses C95 to CIO 1 or Cl 16 to C 131, or the composition for use according to any one of clauses C95 to C101 or C116 to C131, or use according to any one of clauses C102 to C108 or Cl 16 to C131, or a method according to any one of clauses C109 to C131, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
134. The antibody for use according to clauses C 132 or C133, or the composition for use according to clauses C132 or C133, or use according to clauses C132 or C133, or a method according to clauses C132 or C133, wherein the further therapeutic agent is a further antibody.
135. The antibody for use according to clause C134, or the composition for use according to clause C134, or use according to clause C134, or a method according to clause C134, wherein the further antibody is an antibody that specifically binds to ULI 6 protein, for example an antibody according to any of clauses Al to A 164.
136. The antibody for use according to clause C134, or the composition for use according to clause C134, or use according to clause C134, or a method according to clause C134, wherein the further antibody is an antibody that specifically binds to UL141 protein, for example an antibody according to any of clauses B 1 to B 113.
137. The antibody for use according to clause C134, or the composition for use according to clause C134, or use according to clause C134, or a method according to clause C134, wherein the further antibody is a further antibody that specifically binds to US28 protein, for example an antibody according to any of clauses Cl to C80.
138. The antibody for use according to clause Cl 34, or the composition for use according to clause C134, or use according to clause C134, or a method according to clause C134, wherein the further antibody is an antibody that specifically binds to VEGF, for example bevacizumab. 139. The antibody for use according to clauses C132 or C133, or the composition for use according to clauses C132 or C133, or use according to clauses C132 or C133, or a method according to clauses C132 or C133, wherein the further therapeutic agent is an anti-viral agent.
140. The antibody for use according to clause Cl 39, or the composition for use according to clause C 139, or use according to clause Cl 39, or a method according to clause Cl 39, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X.
141. The antibody for use according to any one of clauses C95 to CIO 1 or Cl 16 to C 131, or the composition for use according to any one of clauses C95 to C101 or C116 to C131, or use according to any one of clauses C102 to C108 or Cl 16 to C131, or a method according to any one of clauses C109 to C131, wherein said method further comprises administration of two or more further therapeutic agents.
142. The antibody for use according to any one of clauses C95 to CIO 1 or Cl 16 to C 131, or the composition for use according to any one of clauses C95 to C101 or C116 to C131, or use according to any one of clauses C102 to C108 or Cl 16 to C131, or a method according to any one of clauses C109 to C131, wherein said method further comprises administration of two or more further antibodies.
CLAUSE SET D - COMMON CLAUSES FOR ALL ABS
1. A nucleic acid comprising a sequence that encodes a VH domain and/or an VL domain of an antibody as defined in any preceding clause.
2. A nucleic acid comprising a sequence that encodes the VH domain of an antibody as defined in any preceding clause.
3. A nucleic acid comprising a sequence that encodes the VL domain of an antibody as defined in any preceding clause.
4. A vector comprising the nucleic acid of any one of clauses DI to D3; optionally wherein the vector is a CHO vector.
5. A host cell comprising the nucleic acid of any one of clauses DI to D3 or the vector of clause D4. A kit comprising the pharmaceutical composition of any one of clauses A165 to A178, Bl 14 to B126, or C81 to C93. The kit according to clause D6 further comprising at least one further therapeutic agent. The kit according to clause D7, wherein the further therapeutic agent is a further pharmaceutical composition comprising at least one, preferably one or two, further antibodies. The kit according to clause D8, wherein the further antibody is selected from: a. an antibody that specifically binds to ULI 6 protein; b. an antibody that specifically binds to UL141 protein; c. an antibody that specifically binds to US28 protein; and d. an antibody that specifically binds to VEGF. The kit according to clause D8, wherein the further antibody is selected from: a. an antibody that specifically binds to UL16 protein according to any of clauses Al to A164; b. an antibody that specifically binds to UL141 protein according to any of clauses Bl to Bl 13; c. an antibody that specifically binds to US28 protein according to any of clauses Cl to C80; and d. an antibody that specifically binds to VEGF. The kit of clause D7, wherein the further therapeutic agent is an anti-viral agent. The kit of clause Dl l, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. A kit comprising a pharmaceutical composition comprising a first antibody according to any one of clauses Al to A 164 and a pharmaceutical composition comprising a second antibody according to any one of clauses Cl to C80. A kit comprising a pharmaceutical composition comprising a first antibody according to any one of clauses Bl to Bl 13 and a pharmaceutical composition comprising a second antibody according to any one of clauses Cl to C80. A kit comprising a pharmaceutical composition comprising a first antibody Al to A 164, a pharmaceutical composition comprising a second antibody according to any one of clauses B 1 to B 113, and a pharmaceutical composition comprising a third antibody according to any one of clauses Cl to C80.
16. A kit comprising a pharmaceutical composition comprising a first antibody according to any one of clauses Cl to C80 and a pharmaceutical composition comprising a second antibody that specifically binds to VEGF.
17. The kit according to any of clauses D6 and DI 6, further comprising a label or instructions for use to treat and/or prevent HCMV infection in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody or fragment.
18. Use of an antibody according to any of clauses Al to A164, Bl to Bl 13, or Cl to C80, determining the presence or absence of HCMV in a sample.
19. Use of an antibody according to any of clauses Al to A164 for determining the presence or absence of ULI 6 protein in a sample.
20. Use of an antibody according to any of clauses Bl to Bl 13 for determining the presence or absence of UL141 protein in a sample.
21. Use of an antibody according to any of clauses Cl to C80 for determining the presence or absence of US28 protein in a sample.
22. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of clauses Al to A 164; and testing for binding between the antibody and HCMV protein ULI 6 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
23. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of clauses Bl to Bl 13; and testing for binding between the antibody and HCMV protein UL141 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
24. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of clauses Cl to C80; and testing for binding between the antibody and HCMV protein US28 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
25. Use according to any one of clauses D18 to D21 or a method according to any one of clauses D22 to D24, wherein the antibody comprises or is conjugated to a detectable label.
26. Use according to any one of clauses D18 to D21 or D25, or a method according to any one of clauses D22 to D25, wherein the sample has been obtained from a human who has been or is suspected of having been infected with HCMV.
27. Use according to any one of clauses D18 to D21 or D25 to D26, or a method according to any one of clauses D22 to D26, wherein the sample is a serum, plasma, or whole blood sample, or an oral or nasal swab, urine, faeces, or cerebrospinal fluid (CFS), or wherein the sample is from any suspected HCMV infected organ or tissue.
28. A diagnostic kit for the use according to any one of clauses D18 to D21 or D25 to D27, or the method according to any one of clauses D22 to D27, comprising an antibody according to any of clauses Al to A164, Bl to Bl 13, or Cl to C80, and optionally one or more buffering solutions.
29. A diagnostic kit according to clause D28, wherein the antibody comprises or is conjugated to a detectable label.
30. A diagnostic kit according to clause D28, comprising a first reagent comprising the antibody according to any of clauses Al to A164, Bl to Bl 13, or Cl to C80, and a second reagent comprising a detector molecule that binds to the first reagent.
31.A diagnostic kit according to clause D30, wherein the detector molecule is an antibody that comprises or is conjugated to a detectable label.

Claims

1. An antibody that specifically binds to a UL 16 viral protein.
2. An antibody that specifically binds to the extracellular domain of a UL16 viral protein.
3. An antibody according to claim 1 or 2, wherein the antibody is a monoclonal antibody.
4. An antibody according to any one of claims 1 to 3, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain.
5. An antibody according to any one of claims 1 to 4, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains.
6. An antibody according to any one of claims 1 to 5, wherein the antibody mediates killing of cells infected with HCMV.
7. An antibody according to any one of claims 1 to 6, wherein the antibody mediates immune-mediated killing of cells infected with HCMV.
8. An antibody according to any one of claims 1 to 7, wherein the antibody mediates NK-cell killing of cells infected with HCMV.
9. An antibody according to any one of claims 1 to 8, wherein the antibody reduces viral load of cells infected with HCMV.
10. An antibody according to any one of claims 1 to 9, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
11. An antibody according to any one of claims 1 to 10, wherein the antibody has CDC activity.
12. An antibody according to any one of claims 1 to 11, wherein the antibody has ADCP activity.
13. An antibody according to any one of claims 1 to 12, wherein the antibody competes for inding to
UL16 protein with MICB, ULBP1, ULBP2 and/or ULBP6.
265 An antibody according to any one of claims 1 to 13, wherein the antibody blocks ULI 6 protein binding to MICB, ULBP1, ULBP2 and/or ULBP6. An antibody according to any one of claims 1 to 14, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO- 0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO- 0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO- 0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or THO- 0801. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0101. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0102. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0103. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0104. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0105. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0106. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0107. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0108. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0109. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0110. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0111. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0112. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0113. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0114. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0115. The antibody according to claim 15 , wherein the HCDR3 is the HCDR3 of antibody ATHO-0116. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0201. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0301. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0302. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0303. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0401. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0501. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0601. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0701. The antibody according to claim 15, wherein the HCDR3 is the HCDR3 of antibody ATHO-0801. An anti-UL16 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or THO-0801. An antibody according to any one of claims 1 to 41, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or THO-0801. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0101. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0102. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0103. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0104. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0105. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0106. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0107. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0108. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0109. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-Ol lO. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0111. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0112. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0113. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0114. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0115. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0116. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0201. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0301. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0302. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0303. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0401. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0501. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0601. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0701. An antibody according to claim 41 or claim 42, wherein the antibody has the CDRs of antibody ATHO-0801. An antibody according to any one of claims 1 to 67,
268 wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO- 0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO- 0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO- 0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or THO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence. An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)., An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0104, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
269 An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0105, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0106, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0107, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0108, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0109, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0110, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0111, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0112, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the
270 complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0112, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0113, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0113, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0114, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0115, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0115, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0116, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to claim 68, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ATHO-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). An antibody according to any one of claims 1 to 94, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-O 111, ATHO-O 112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201 , ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-Ol lO, ATHO-O 111, ATHO-O 112, ATHO-O 113, ATHO-O 114, ATHO-O 115, ATHO-O 116, ATHO-0201 , ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801. The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0101, provided that the antibody has the CDRs of antibody ATHO-0101. The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0102, provided that the antibody has the CDRs of antibody ATHO-0102. The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0103, provided that the antibody has the CDRs of antibody ATHO-0103. The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-0104 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0104, provided that the antibody has the CDRs of antibody ATHO-0104. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0105 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0105, provided that the antibody has the CDRs of antibody ATHO-O 105.
273
. The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0106 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0106, provided that the antibody has the CDRs of antibody ATHO-0106. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0107 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0107, provided that the antibody has the CDRs of antibody ATHO-0107. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0108 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0108, provided that the antibody has the CDRs of antibody ATHO-0108. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0109 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0109, provided that the antibody has the CDRs of antibody ATHO-0109. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0110 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0110, provided that the antibody has the CDRs of antibody ATHO-0110. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0111 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0111, provided that the antibody has the CDRs of antibody ATHO-O 111. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0112 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0112, provided that the antibody has the CDRs of antibody ATHO-0112. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO-
274 0113 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0113, provided that the antibody has the CDRs of antibody ATHO-0113. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0114 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0114, provided that the antibody has the CDRs of antibody ATHO-0114. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0115 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0115, provided that the antibody has the CDRs of antibody ATHO-0115. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0116 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0116, provided that the antibody has the CDRs of antibody ATHO-0116. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0201, provided that the antibody has the CDRs of antibody ATHO-0201. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0301, provided that the antibody has the CDRs of antibody ATHO-0301. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0302, provided that the antibody has the CDRs of antibody ATHO-0302. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity
275 to the VL domain sequence of antibody ATHO-0303, provided that the antibody has the CDRs of antibody ATHO-0303. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0401, provided that the antibody has the CDRs of antibody ATHO-0401. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0501, provided that the antibody has the CDRs of antibody ATHO-0501. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0601, provided that the antibody has the CDRs of antibody ATHO-0601. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0701, provided that the antibody has the CDRs of antibody ATHO-0701. . The antibody according to claim 95, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ATHO- 0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ATHO-0801, provided that the antibody has the CDRs of antibody ATHO-0801. . An antibody according to any one of claims 1 to 120, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ATHO-0101, ATHO-0102, ATHO-0103, ATHO-0104, ATHO-0105, ATHO-0106, ATHO-0107, ATHO-0108, ATHO-0109, ATHO-0110, ATHO-0111, ATHO-0112, ATHO-0113, ATHO-0114, ATHO-0115, ATHO-0116, ATHO-0201, ATHO-0301, ATHO-0302, ATHO-0303, ATHO-0401, ATHO-0501, ATHO-0601, ATHO-0701, or ATHO-0801.
276
. The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0101. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0102. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0103. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0104. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0105. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0106. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0107. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0108. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0109. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0110. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-O 111. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0112. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0113. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0114. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0115. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0116. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0201. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0301.
277
. The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0302. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0303. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0401. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0501. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0601. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0701. . The antibody according to claim 121, wherein the antibody comprises the VH domain and VL domain sequences of antibody ATHO-0801. . The antibody according to any one of claims 1 to 146, wherein the antibody is a human IgGl. . The antibody according to claim 147, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. . The antibody according to claim 147, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. . The antibody according to claim 149, wherein the antibody is a human IgGl having S239D and I332E mutations. . The antibody according to claim 150, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364. . The antibody according to any one of claims 1 to 151 wherein the antibody comprises kappa (K) light chain constant regions. . An antibody that specifically binds to a ULI 6 protein, wherein said antibody competes for inding to a ULI 6 protein with a reference antibody, where the reference antibody is an antibody according to any one of claims 1 to 152.
278
. An antibody that specifically binds to the same epitope on a ULI 6 protein as the epitope on a ULI 6 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of claims 1 to 152. . The antibody according to any one of claims 1 to 154, comprising VH and/or VL domain framework regions of human germline gene segment sequences. . The antibody according to any one of claims 1 to 155, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18; and/or the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-34*01, IGHV4-31*03, IGHV3-11*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of claims 1 to 156, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV4-34*01, IGHV4- 31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18, a human heavy chain D gene segment and a human heavy chain J gene segment, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-34*01, IGHV4-31*03, IGHV3-l l*01, IGHVl-3*01, IGHV4-59*01, or IGHV3-30* 18 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of claims 1 to 157, wherein the J gene segment is IGHJ6*02, IGHJ4*02, or IGHJ3*02, or wherein the VH domain framework region FR4 aligns with
279 human germline J gene segment IGHJ6*02, IGHJ4*02, or IGHJ3*02 with 1, 2, 3, 4 or 5 amino acid alterations.
159. The antibody according to any one of claims 1 to 158, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01, and/or the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGKJl*01, IGLJ2*01, or IGKJ3*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
160. The antibody according to any one of claims 1 to 159, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGKV1-12*O1, IGLV3-10*01, IGLV2-8*01, IGLVl-51*01, IGKV1D-39*O1, or IGKVl-9*d01, and optionally the J gene segment is IGKJl*01, IGLJ2*01, or IGKJ3*01.
161. The antibody according to any one of claims 1 to 160, wherein the antibody is linked to a cytotoxic agent.
162. The antibody according to claim 161, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC- 1065, duocarmycins and anthracyclines.
163. The antibody according to any one of claims 1 to 160, wherein the antibody is linked to an anti-viral agent.
280
. The antibody according to claim 163, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A pharmaceutical composition comprising an antibody according to any one of claims 1 to 164 and a pharmaceutically acceptable excipient. . A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of claims 1 to 164 and a pharmaceutically acceptable excipient. . The pharmaceutical composition according to claims 165 or 166, further comprising at least one further therapeutic agent. . The pharmaceutical composition of claim 167, wherein the further therapeutic agent is a further antibody. . The pharmaceutical composition of claim 168, wherein the further antibody is selected from: d. an antibody that specifically binds to UL16 protein; e. an antibody that specifically binds to UL141 protein; and f. an antibody that specifically binds to US28 protein. . The pharmaceutical composition of claim 168, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. . The pharmaceutical composition of claim 168, wherein the further antibody is selected from: d. an antibody that specifically binds to ULI 6 protein according to any of claims 1 to 164; e. an antibody that specifically binds to UL141 protein according to any of claims 220 to 332; and f. an antibody that specifically binds to US28 protein according to any of claims 387 to 466. . A pharmaceutical composition comprising a first antibody according to any one of claims 1 to 164 and a second antibody according to any one of claims 387 to 466. . A pharmaceutical composition comprising a first antibody according to any one of claims 1 to 164, a second antibody according to any one of claims 220 to 332, and a third antibody according to any one of claims 387 to 466.
281
. The pharmaceutical composition of claim 167, wherein the further therapeutic agent is an antiviral agent. . The pharmaceutical composition of claim 174, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The pharmaceutical composition according to any one of claims 165 to 175, further comprising two or more further therapeutic agents. . The pharmaceutical composition according to claim 176, wherein the two or more further therapeutic agents are two or more further antibodies. . The pharmaceutical composition according to any one of claims 165 to 177, formulated for intravenous, intramuscular or subcutaneous administration. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use as a medicament. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, for use in a method of treating congenital HCMV infection.
282
. Use of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178, in the manufacture of a medicament for use in a method of treating congenital HCMV infection. . A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178. . A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178.
283
. A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 1 to 164, or the composition according to any one of claims 165 to 178. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is a transplant recipient. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is a transplant donor. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to A 194, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or method according to any one of claims 190 to 194, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is immunosuppressed. . The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is immunocompromised.
284
203. The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is HIV positive.
204. The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient has previously been treated with an anti-viral agent.
205. The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent.
206. The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein the patient is a pregnant woman.
207. The antibody for use according to any one of claims 180 to 184, or the composition for use according to any one of claims 180 to 184, or use according to any one of claims 185 to 189, or a method according to any one of claims 190 to 194, wherein HCMV infection is associated with an inflammatory disease.
208. The antibody for use according to claim 207, or the composition for use according to claim 207, or use according to claim 207, or a method according to claim 207, wherein the patient has atherosclerosis.
209. The antibody for use according to claim 207 or claim 208, or the composition for use according to claim 207 or claim 208, or use according to claim 207 or claim 208, or a method according to claim 207 or claim 208, wherein the patient has previously undergone balloon angioplasty.
210. The antibody for use according to any one of claims 180 to 184 or 195 to 209, or the composition for use according to any one of claims 180 to 184 or 195 to 209, the use according to any one of claims 185 to 189 or 195 to 209, or the method according to any one of claims 190 to 210, wherein said method further comprises administration of a further therapeutic agent.
285
211. The antibody for use according to any one of claims 180 to 184 or 195 to 209, or the composition for use according to any one of claims 180 to 184 or 195 to 209, the use according to any one of claims 185 to 189 or 195 to 209, or the method according to any one of claims 190 to 210, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
212. The antibody for use according to claims 210 or 211, orthe composition for use according to claims 210 or 211, or use according to claims 210 or 211, or a method according to claims 210 or 211, wherein the further therapeutic agent is a further antibody.
213. The antibody for use according to claim 212, or the composition for use according to claim 212, or use according to claim 212, or a method according to claim 212, wherein the further antibody is a further antibody that specifically binds to ULI 6 protein, for example an antibody according to any of claims 1 to 164.
214. The antibody for use according to claim 212, or the composition for use according to claim 212, or use according to claim 212, or a method according to claim 212, wherein the further antibody is an antibody that specifically binds to UL141 protein, for example an antibody according to any of claims 220 to 332.
215. The antibody for use according to claim 212, or the composition for use according to claim 212, or use according to claim 212, or a method according to claim 212, wherein the further antibody is an antibody that specifically binds to US28 protein, for example an antibody according to any of claims 387 to 466.
216. The antibody for use according to claims 210 or 211, or the composition for use according to claims 210 or 211, or use according to claims 210 or 211, or a method according to claims 210 or 211, wherein the further therapeutic agent is an anti-viral agent.
217. The antibody for use according to claim 216, or the composition for use according to claim 216, or use according to claim 216, or a method according to claim 216, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X.
286
. The antibody for use according to any one of claims 180 to 184 or 195 to 209, or the composition for use according to any one of claims 180 to 184 or 195 to 209, the use according to any one of claims 185 to 189 or 195 to 209, or the method according to any one of claims 190 to 210, wherein said method further comprises administration of two or more further therapeutic agents. . The antibody for use according to any one of claims 180 to 184 or 195 to 209, or the composition for use according to any one of claims 180 to 184 or 195 to 209, the use according to any one of claims 185 to 189 or 195 to 209, or the method according to any one of claims 190 to 210, wherein said method further comprises administration of two or more further antibodies. . An antibody that specifically binds to a UL141 viral protein. . An antibody that specifically binds to the extracellular domain of a UL141 viral protein. . An antibody according to claim 220 or 221, wherein the antibody is a monoclonal antibody. . An antibody according to any one of claims 220 to 222, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain. . An antibody according to any one of claims 220 to 223, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains. . An antibody according to any one of claims 220 to 224, wherein the antibody mediates killing of cells infected with HCMV. . An antibody according to any one of claims 220 to 225, wherein the antibody mediates immune-mediated killing of cells infected with HCMV. . An antibody according to any one of claims 220 to 226, wherein the antibody mediates NK- cell killing of cells infected with HCMV. . An antibody according to any one of claims 220 to 227, wherein the antibody reduces viral load of cells infected with HCMV. . An antibody according to any one of claims 220 to 228, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay.
287
. An antibody according to any one of claims 220 to 229, wherein the antibody has CDC activity. . An antibody according to any one of claims 220 to 230, wherein the antibody has ADCP activity. . An antibody according to any one of claims 220 to 231, wherein the antibody competes for binding to UL141 protein with CD155, CD112 and/or TRAIL-R1/R2. . An antibody according to any one of claims 220 to 232, wherein the antibody blocks UL141 protein binding to CD155, CD112 and/or TRAIL-R1/R2. . An antibody according to any one of claims 220 to 233, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM- 0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM- 0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0101. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0102. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0103. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0201. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0202. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0203. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0204. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody
ARAM-0301.
288
. The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0302. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0303. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0401. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0501. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0601. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0701. . The antibody according to claim 234, wherein the HCDR3 is the HCDR3 of antibody ARAM-0801. . An anti-UL 141 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. . An antibody according to any one of claims 220 to 250, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0101. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0102. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0103.
289
. An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0201. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0202. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0203. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0204. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0301. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0302. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0303. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0401. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0501. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0601. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0701. . An antibody according to claim 250 or claim 251, wherein the antibody has the CDRs of antibody ARAM-0801. . An antibody according to any one of claims 220 to 266, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
290
. An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0102, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0103, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0202, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0203, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0204, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations
291 outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0302, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0303, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody ARAM-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 267, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence
292 of antibody ARAM-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to any one of claims 220 to 282, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0101, provided that the antibody has the CDRs of antibody ARAM-0101. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0102 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0102, provided that the antibody has the CDRs of antibody ARAM-0102. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0103 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0103, provided that the antibody has the CDRs of antibody ARAM-0103. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0201, provided that the antibody has the CDRs of antibody ARAM-0201. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0202 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0202, provided that the antibody has the CDRs of antibody ARAM-0202. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0203 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0203, provided that the antibody has the CDRs of antibody ARAM-0203. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0204 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0204, provided that the antibody has the CDRs of antibody ARAM-0204. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0301, provided that the antibody has the CDRs of antibody ARAM-0301. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0302 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0302, provided that the antibody has the CDRs of antibody ARAM-0302. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0303 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0303, provided that the antibody has the CDRs of antibody ARAM-0303. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0401, provided that the antibody has the CDRs of antibody ARAM-0401. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0501, provided that the antibody has the CDRs of antibody ARAM-0501.
. The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0601, provided that the antibody has the CDRs of antibody ARAM-0601. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0701, provided that the antibody has the CDRs of antibody ARAM-0701. . The antibody according to claim 283, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody ARAM- 0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody ARAM-0801, provided that the antibody has the CDRs of antibody ARAM-0801. . An antibody according to any one of claims 220 to 298, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody ARAM-0101, ARAM-0102, ARAM-0103, ARAM-0201, ARAM-0202, ARAM-0203, ARAM-0204, ARAM-0301, ARAM-0302, ARAM-0303, ARAM-0401, ARAM-0501, ARAM-0601, ARAM-0701, or ARAM-0801. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0101. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0102. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0103. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0201. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0202. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0203.
295
. The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0204. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0301. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0302. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0303. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0401. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0501. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0601. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0701. . The antibody according to claim 299, wherein the antibody comprises the VH domain and VL domain sequences of antibody ARAM-0801. . The antibody according to any one of claims 220 to 314, wherein the antibody is a human IgGl. . The antibody according to claim 315, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. . The antibody according to claim 315, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. . The antibody according to claim 317, wherein the antibody is a human IgGl having S239D and I332E mutations. . The antibody according to claim 318, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364. . The antibody according to any one of claims 220 to 319 wherein the antibody comprises kappa (K) light chain constant regions.
296
. An antibody that specifically binds to a UL141 protein, wherein said antibody competes for binding to a UL141 protein with a reference antibody, where the reference antibody is an antibody according to any one of claims 220 to 320. . An antibody that specifically binds to the same epitope on a UL141 protein as the epitope on a UL141 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of claims 220 to 320. . The antibody according to any one of claims 220 to 322, comprising VH and/or VL domain framework regions of human germline gene segment sequences. . The antibody according to any one of claims 220 to 323, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02; and/or the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR3 aligns with human germline V gene segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of claims 220 to 324, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV4-31*03, IGHV4- 59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02, a human heavy chain D gene segment and a human heavy chain J gene segment, or
297 ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV4-31*03, IGHV4-59*01, IGHV4-4*02, IGHV5-51*01, IGHV4-31*03, or IGHV3-48*02 with up to 1, 2, 3, 4 or 5 amino acid alterations.
326. The antibody according to any one of claims 220 to 325, wherein the J gene segment is IGHJ5*02, IGHJ4*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ5*02, IGHJ4*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
327. The antibody according to any one of claims 220 to 326, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV2-23*dO2, IGLV 1-51*01, IGKV3-l l*01, IGLV3- 19*01, IGKV2-24*01, or IGKV3-15*01, and/or the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations, FR2 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4, or 5 amino acid alterations FR3 aligns with human germline V gene segment IGLV2-23*dO2, IGLVl-51*01, IGKV3-11*01, IGLV3-19*01, IGKV2-24*01, or IGKV3-15*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
328. The antibody according to any one of claims 220 to 327, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV2-23*dO2, IGLV 1-51*01, IGKV3-l l*01, IGLV3- 19*01, IGKV2-24*01, or IGKV3-15*01, and optionally the J gene segment is IGLJ3*02, IGKJ5*01, IGLJ2*01, IGKJ3*01, or IGKJl*01.
329. The antibody according to any one of claims 220 to 328, wherein the antibody is linked to a cytotoxic agent.
298
. The antibody according to claim 329, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC- 1065, duocarmycins and anthracyclines. . The antibody according to any one of claims 220 to 328, wherein the antibody is linked to an anti-viral agent. . The antibody according to claim 331, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A pharmaceutical composition comprising an antibody according to any one of claims 220 to 332 and a pharmaceutically acceptable excipient. . A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of claims 220 to 332 and a pharmaceutically acceptable excipient. . The pharmaceutical composition according to claims 333 or 334, further comprising at least one further therapeutic agent. . The pharmaceutical composition of claim 335, wherein the further therapeutic agent is a further antibody. . The pharmaceutical composition of claim 336, wherein the further antibody is selected from: d. an antibody that specifically binds to ULI 6 protein; e. an antibody that specifically binds to UL141 protein; and f. an antibody that specifically binds to US28 protein. . The pharmaceutical composition of claim 336, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. . The pharmaceutical composition of claim 336, wherein the further antibody is selected from: d. an antibody that specifically binds to ULI 6 protein according to any of claims 1 to 164; e. an antibody that specifically binds to UL141 protein according to any of claims 220 to 332; and f. an antibody that specifically binds to US28 protein according to any of claims 387 to 466.
299
. A pharmaceutical composition comprising a first antibody according to any one of claims 220 to 332 and a second antibody according to any one of claims 387 to 466. . The pharmaceutical composition of claim 335, wherein the further therapeutic agent is an antiviral agent. . The pharmaceutical composition of claim 341, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The pharmaceutical composition according to any one of claims 333 to 342, further comprising two or more further therapeutic agents. . The pharmaceutical composition according to claim 343, wherein the two or more further therapeutic agents are two or more further antibodies. . The pharmaceutical composition according to any one of claims 333 to 344, formulated for intravenous, intramuscular or subcutaneous administration. . The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use as a medicament. . The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. . The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient.
300
. The antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, for use in a method of treating congenital HCMV infection. . Use of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345, in the manufacture of a medicament for use in a method of treating congenital HCMV infection. . A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345.
301
. A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345. . A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 220 to 332, or the composition according to any one of claims 333 to 345. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is a transplant recipient. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is a transplant donor. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is immunosuppressed.
302
. The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is immunocompromised. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is HIV positive. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient has previously been treated with an anti-viral agent. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein the patient is a pregnant woman. . The antibody for use according to any one of claims 347 to 351, or the composition for use according to any one of claims 347 to 351, or use according to any one of claims 352 to 356, or a method according to any one of claims 357 to 361, wherein HCMV infection is associated with an inflammatory disease. . The antibody for use according to claim 374 or the composition for use according to claim 374, or use according to claim 374, or a method according to claim 374, wherein the patient has atherosclerosis. . The antibody for use according to claim 374 or claim 375 or the composition for use according to claim 374 or claim 375, or use according to claim 374 or claim 375, or a method according to claim 374 or claim 375, wherein the patient has previously undergone balloon angioplasty.
303
377. The antibody for use according to any one of claims 347 to 351 or 362 to 376, or the composition for use according to any one of claims 347 to 351 or 362 to 376, or use according to any one of claims 352 to 356 or 362 to 376, or a method according to any one of claims 357 to 376, wherein said method further comprises administration of a further therapeutic agent.
378. The antibody for use according to any one of claims 347 to 351 or 362 to 376, or the composition for use according to any one of claims 347 to 351 or 362 to 376, or use according to any one of claims 352 to 356 or 362 to 376, or a method according to any one of claims 357 to 376, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
379. The antibody for use according to claims 377 or 378, or the composition for use according to claims 377 or 378, or use according to claims 377 or 378, or a method according to claims 377 or 378, wherein the further therapeutic agent is a further antibody.
380. The antibody for use according to claim 379, or the composition for use according to claim 379, or use according to claim 379, or a method according to claim 379, wherein the further antibody is an antibody that specifically binds to ULI 6 protein, for example an antibody according to any of claims 1 to 164.
381. The antibody for use according to claim 379, or the composition for use according to claim 379, or use according to claim 379, or a method according to claim 379, wherein the further antibody is an further antibody that specifically binds to UL141 protein, for example an antibody according to any of claims 220 to 332.
382. The antibody for use according to claim 379, or the composition for use according to claim 379, or use according to claim 379, or a method according to claim 379, wherein the further antibody is an antibody that specifically binds to US28 protein, for example an antibody according to any of claims 387 to 466.
383. The antibody for use according to claims 377 or 378, or the composition for use according to claims 377 or 378, or use according to claims 377 or 378, or a method according to claims 377 or 378, wherein the further therapeutic agent is an anti-viral agent.
384. The antibody for use according to claim 383, or the composition for use according to claim
383, or use according to claim 383, or a method according to claim 383, wherein the anti-viral agent is
304 selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The antibody for use according to any one of claims 347 to 351 or 362 to 376, or the composition for use according to any one of claims 347 to 351 or 362 to 376, or use according to any one of claims 352 to 356 or 362 to 376, or a method according to any one of claims 357 to 376, wherein said method further comprises administration of two or more further therapeutic agents. . The antibody for use according to any one of claims 347 to 351 or 362 to 376, or the composition for use according to any one of claims 347 to 351 or 362 to 376, or use according to any one of claims 352 to 356 or 362 to 376, or a method according to any one of claims 357 to 376, wherein said method further comprises administration of two or more further antibodies. . An antibody that specifically binds to a US28 viral protein. . An antibody that specifically binds to the extracellular domain of a US28 viral protein. . An antibody according to claim 387 or 388, wherein the antibody is a monoclonal antibody. . An antibody according to any one of claims 387to 389, wherein the antibody comprises at least one heavy protein chain domain and at least one light protein chain domain. . An antibody according to any one of claims 387 to 390, wherein the antibody is a full antibody comprising two heavy protein chains and two light protein chains. . An antibody according to any one of claims 387 to 391, wherein the antibody mediates killing of cells infected with HCMV. . An antibody according to any one of claims 387 to 392, wherein the antibody mediates immune-mediated killing of cells infected with HCMV. . An antibody according to any one of claims 387 to 393, wherein the antibody reduces viral load of cells infected with HCMV. . An antibody according to claim 394, wherein the cells are lytically infected cells. . An antibody according to claim 394, wherein the cells are latently infected cells.
305
. An antibody according to any one of claims 387 to 396, wherein the antibody reduces frequency of viral reactivation in cells latently infected with HCMV. . An antibody according to any one of claims 387 to 397, wherein the antibody has ADCC activity, for example as measured in an Fc Effector Reporter Assay. . An antibody according to any one of claims 387 to 398, wherein the antibody has CDC activity. . An antibody according to any one of claims 387 to 399, wherein the antibody has ADCP activity. . An antibody according to any one of claims 387 to 400, wherein the antibody competes for binding to US28 protein with CX3CL1 and/or other chemokines. . An antibody according to any one of claims 387 to 401, wherein the antibody blocks US28 protein binding to CX3CL1 and/or other chemokines. . An antibody according to any one of claims 387 to 402, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0101. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0201. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0301. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0401. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT-
0501.
306
. The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0601. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0701. . The antibody according to claim 403, wherein the HCDR3 is the HCDR3 of antibody PORT- 0801. . An anti-US28 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801. . An antibody according to any one of claims 387 to 412, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the CDRs are those of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT- 0501, PORT-0601, PORT-0701, or PORT-0801. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0101. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0201. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0301. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0401. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0501. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0601. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0701. . An antibody according to claim 412 or claim 413, wherein the antibody has the CDRs of antibody PORT-0801.
307
. An antibody according to any one of claims 387 to 421, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT- 0601, PORT-0701, or PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence. . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0101, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0201, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0301, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0501, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
308
. An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0601, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0701, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to claim 422, wherein the antibody comprises a variable heavy (VH) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody PORT-0801, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs). . An antibody according to any one of claims 387 to 430, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801, provided that the antibody has the CDRs of antibody PORT-0101, PORT-0201, PORT-0301, PORT- 0401, PORT-0501, PORT-0601, PORT-0701, or PORT-0801. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0101 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0101, provided that the antibody has the CDRs of antibody PORT-0101. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0201 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0201, provided that the antibody has the CDRs of antibody PORT-0201. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT-
309 0301 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0301, provided that the antibody has the CDRs of antibody PORT-0301. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0401 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0401, provided that the antibody has the CDRs of antibody PORT-0401. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0501 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0501, provided that the antibody has the CDRs of antibody PORT-0501. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0601 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0601, provided that the antibody has the CDRs of antibody PORT-0601. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0701 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0701, provided that the antibody has the CDRs of antibody PORT-0701. . The antibody according to claim 431, wherein the variable heavy (VH) domain sequence comprises a sequence having at least 90% identity to the VH domain sequence of antibody PORT- 0801 and the variable light (VL) domain sequence comprises a sequence having at least 90% identity to the VL domain sequence of antibody PORT-0801, provided that the antibody has the CDRs of antibody PORT-0801. . An antibody according to any one of claims 387 to 439, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody PORT-0101, PORT-0201, PORT-0301, PORT-0401, PORT-0501, PORT-0601, PORT- 0701, or PORT-0801.
310
. The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0101. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0201. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0301. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0401. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0501. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0601. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0701. . The antibody according to claim 440, wherein the antibody comprises the VH domain and VL domain sequences of antibody PORT-0801. . The antibody according to any one of claims 387 to 448, wherein the antibody is a human IgGl. . The antibody according to claim 449, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 363. . The antibody according to claim 449, wherein the antibody is a human IgGl comprising an Fc effector enhanced constant region. . The antibody according to claim 451, wherein the antibody is a human IgGl having S239D and I332E mutations. . The antibody according to claim 452, wherein the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 364. . The antibody according to any one of claims 387 to 453 wherein the antibody comprises kappa (K) light chain constant regions.
311
. An antibody that specifically binds to a US28 protein, wherein said antibody competes for binding to a US28 protein with a reference antibody, where the reference antibody is an antibody according to any one of claims 387 to 454. . An antibody that specifically binds to the same epitope on a US28 protein as the epitope on a US28 protein that is bound by a reference antibody, where the reference antibody is an antibody according to any one of claims 387 to 454. . The antibody according to any one of claims 387 to 456, comprising VH and/or VL domain framework regions of human germline gene segment sequences. . The antibody according to any one of claims 387 to 457, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03; and/or the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR2 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR3 aligns with human germline V gene segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with up to 1, 2, 3, 4 or 5 amino acid alterations. . The antibody according to any one of claims 387 to 458, comprising an antibody VH domain which i) is derived from recombination of a human heavy chain V gene segment IGHV2-5* 10, IGHV4- 39*01, IGHVl-18*01, IGHVl-8*01, IGHV3-13*01, IGHV6-l*01, or IGHV3-21*03, a human heavy chain D gene segment and a human heavy chain J gene segment, or
312 ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein FR1, FR2 and FR3 each align with human germline V segment IGHV2-5* 10, IGHV4-39*01, IGHVl-18*01, IGHVl-8*01, IGHV3- 13*01, IGHV6-l*01, or IGHV3-21*03 with up to 1, 2, 3, 4 or 5 amino acid alterations.
460. The antibody according to any one of claims 387 to 459, wherein the J gene segment is IGHJ4*02, IGHJ5*02, or IGHJ6*02, or wherein the VH domain framework region FR4 aligns with human germline J gene segment IGHJ4*02, IGHJ5*02, or IGHJ6*02 with 1, 2, 3, 4 or 5 amino acid alterations.
461. The antibody according to any one of claims 387 to 460, comprising an antibody VL domain which i) is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and/or the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01; or ii) comprises framework regions FR1, FR2, FR3 and FR4, wherein
FR1 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations,
FR2 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4, or 5 amino acid alterations
FR3 aligns with human germline V gene segment IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01 with up to 1, 2, 3, 4 or 5 amino acid alterations, and/or
FR4 aligns with human germline J gene segment IGLJ3*02, IGKJ4*01, or IGLJ2*01 with up to 1, 2, 3, 4 or 5 amino acid alterations.
462. The antibody according to any one of claims 387 to 461, comprising an antibody VL domain derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein: the V gene segment is IGLV3-10*01, IGKV3-20*01, IGLV3-27*01, IGLV3-9*01, or IGLV3-l*01, and optionally the J gene segment is IGLJ3*02, IGKJ4*01, or IGLJ2*01.
463. The antibody according to any one of claims 387 to 462, wherein the antibody is linked to a cytotoxic agent.
313
. The antibody according to claim 463, wherein the cytotoxic agent is selected from the group consisting of MMAE, DM-1, maytansinoids, doxorubicin derivatives, auristatins, calcheamicin, CC- 1065, duocarmycins and anthracyclines. . The antibody according to any one of claims 387 to 462, wherein the antibody is linked to an anti-viral agent. . The antibody according to claim 465, wherein the anti-viral agent is letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A pharmaceutical composition comprising an antibody according to any one of claims 387 to 466 and a pharmaceutically acceptable excipient. . A pharmaceutical composition comprising an isolated nucleic acid encoding an antibody according to any one of claims 387 to 466 and a pharmaceutically acceptable excipient. . The pharmaceutical composition according to claims 467 or 468, further comprising at least one further therapeutic agent. . The pharmaceutical composition of claim 469, wherein the further therapeutic agent is a further antibody. . The pharmaceutical composition of claim 470, wherein the further antibody is selected from: e. an antibody that specifically binds to ULI 6 protein; f. an antibody that specifically binds to UL141 protein; g. an antibody that specifically binds to US28 protein; and h. an antibody that specifically binds to VEGF, for example bevacizumab. . The pharmaceutical composition of claim 470, wherein the further antibody is an antibody that specifically binds the same target protein as the first antibody. . The pharmaceutical composition of claim 470, wherein the further antibody is selected from: e. an antibody that specifically binds to UL16 protein according to any of claims 1 to 164; f. an antibody that specifically binds to UL141 protein according to any of claims 220 to 332; g. an antibody that specifically binds to US28 protein according to any of claims 387 to 466; and h. an antibody that specifically binds to VEGF.
314
. A pharmaceutical composition comprising a first antibody according to any one of claims 387 to 466 and a second antibody that specifically binds to VEGF. . The pharmaceutical composition of claim 469, wherein the further therapeutic agent is an antiviral agent. . The pharmaceutical composition of claim 475, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The pharmaceutical composition according to any one of claims 467 to 476, further comprising two or more further therapeutic agents. . The pharmaceutical composition according to claim 477, wherein the two or more further therapeutic agents are two or more further antibodies. . The pharmaceutical composition according to any one of claims 467 to 478, formulated for intravenous, intramuscular or subcutaneous administration. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use as a medicament. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of treating HCMV infection, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of reducing HCMV viral load in a patient, said method comprising administering the antibody or composition to the patient. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of reducing frequency of HCMV virus reactivation in the patient, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of treating HCMV-positive glioblastoma multiforme (GBM), said method comprising administering the antibody or composition to a patient.
315
. The antibody for use according to claim 484, or the composition for use according to claim 484, wherein said method further comprises administration of chemotherapy or radiotherapy. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of preventing HCMV infection in a patient at risk of thereof, said method comprising administering the antibody or composition to a patient. . The antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, for use in a method of treating congenital HCMV infection. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of treating HCMV infection. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of reducing HCMV viral load in a patient. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of reducing frequency of HCMV virus reactivation in a patient. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient. . The use of an antibody according to claim 491, or the use of a composition according to claim 491, wherein said method further comprises administration of chemotherapy or radiotherapy. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of preventing HCMV infection in a patient at risk of thereof. . Use of antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479, in the manufacture of a medicament for use in a method of treating congenital HCMV infection.
316
. A method of treating HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . A method of reducing HCMV viral load in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . A method of reducing frequency of HCMV virus reactivation in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . A method of treating HCMV-positive glioblastoma multiforme (GBM) in a patient, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . The method of claim 498, wherein said method further comprises administration of chemotherapy or radiotherapy. . A method of preventing HCMV infection in a patient at risk of thereof, comprising administering to said human a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . A method of treating congenital HCMV infection in a patient, comprising administering to said patient a therapeutically effective amount of an antibody according to any one of claims 387 to 466, or the composition according to any one of claims 467 to 479. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient shows one or more symptoms of HCMV infection. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is a transplant recipient.
317
. The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is a transplant donor. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the transplant is a solid organ transplant. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the transplant is a stem cell transplant. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the transplant is a haematopoietic stem cell transplant (HSCT). . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is immunosuppressed. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is immunocompromised. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is HIV positive. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient has previously been treated with an anti-viral agent. . The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a
318 method according to any one of claims 495 to 501, wherein the patient has a HCMV infection which is refractory to at least one anti-viral agent.
513. The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient is a pregnant woman.
514. The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein HCMV infection is associated with an inflammatory disease.
515. The antibody for use according to claim 514 or the composition for use according to claim 514, or use according to claim 514, or a method according to claim 514, wherein the patient has atherosclerosis.
516. The antibody for use according to claim 514 or claim 515 or the composition for use according to claim 514 or claim 515, or use according to claim 514 or claim 515, or a method according to claim 514 or claim 515, wherein the patient has previously undergone balloon angioplasty.
517. The antibody for use according to any one of claims 481 to 487, or the composition for use according to any one of claims 481 to 487, or use according to any one of claims 488 to 494, or a method according to any one of claims 495 to 501, wherein the patient has glioblastoma multiforme (GBM).
518. The antibody for use according to any one of claims 481 to 487 or 502 to 517, or the composition for use according to any one of claims 481 to 487 or 502 to 517, or use according to any one of claims 488 to 494 or 502 to 517, or a method according to any one of claims 495 to 517, wherein said method further comprises administration of a further therapeutic agent.
519. The antibody for use according to any one of claims 481 to 487 or 502 to 517, or the composition for use according to any one of claims 481 to 487 or 502 to 517, or use according to any one of claims 488 to 494 or 502 to 517, or a method according to any one of claims 495 to 517, wherein said method further comprises administration of a further therapeutic agent, wherein the antibody or composition and the further therapeutic agent are administered simultaneously, separately, or sequentially.
319
. The antibody for use according to claims 518 or 519, or the composition for use according to claims 518 or 519, or use according to claims 518 or 519, or a method according to claims 518 or 519, wherein the further therapeutic agent is a further antibody. . The antibody for use according to claim 520, or the composition for use according to claim 520, or use according to claim 520, or a method according to claim 520, wherein the further antibody is an antibody that specifically binds to ULI 6 protein, for example an antibody according to any of claims 1 to 164. . The antibody for use according to claim 520, or the composition for use according to claim 520, or use according to claim 520, or a method according to claim 520, wherein the further antibody is an antibody that specifically binds to UL141 protein, for example an antibody according to any of claims 220 to 332. . The antibody for use according to claim 520, or the composition for use according to claim 520, or use according to claim 520, or a method according to claim 520, wherein the further antibody is a further antibody that specifically binds to US28 protein, for example an antibody according to any of claims 387 to 466. . The antibody for use according to claim 520, or the composition for use according to claim 520, or use according to claim 520, or a method according to claim 520, wherein the further antibody is an antibody that specifically binds to VEGF, for example bevacizumab. . The antibody for use according to claims 518 or 519, or the composition for use according to claims 518 or 519, or use according to claims 518 or 519, or a method according to claims 518 or 519, wherein the further therapeutic agent is an anti-viral agent. . The antibody for use according to claim 525, or the composition for use according to claim 525, or use according to claim 525, or a method according to claim 525, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . The antibody for use according to any one of claims 481 to 487 or 502 to 517, or the composition for use according to any one of claims 481 to 487 or 502 to 517, or use according to any one of claims 488 to 494 or 502 to 517, or a method according to any one of claims 495 to 517, wherein said method further comprises administration of two or more further therapeutic agents.
320
. The antibody for use according to any one of claims 481 to 487 or 502 to 517, or the composition for use according to any one of claims 481 to 487 or 502 to 517, or use according to any one of claims 488 to 494 or 502 to 517, or a method according to any one of claims 495 to 517, wherein said method further comprises administration of two or more further antibodies. . A nucleic acid comprising a sequence that encodes a VH domain and/or an VL domain of an antibody as defined in any preceding claim. . A nucleic acid comprising a sequence that encodes the VH domain of an antibody as defined in any preceding claim. . A nucleic acid comprising a sequence that encodes the VL domain of an antibody as defined in any preceding claim. . A vector comprising the nucleic acid of any one of claims 529 to 531; optionally wherein the vector is a CHO vector. . A host cell comprising the nucleic acid of any one of claims 529 to 531 or the vector of claim 532. . A kit comprising the pharmaceutical composition of any one of claims 165 to 178, 333 to 345, or 467 to 479. . The kit according to claim 534 further comprising at least one further therapeutic agent. . The kit according to claim 535, wherein the further therapeutic agent is a further pharmaceutical composition comprising at least one, preferably one or two, further antibodies. . The kit according to claim 536, wherein the further antibody is selected from: e. an antibody that specifically binds to ULI 6 protein; f. an antibody that specifically binds to UL141 protein; g. an antibody that specifically binds to US28 protein; and h. an antibody that specifically binds to VEGF. . The kit according to claim 536, wherein the further antibody is selected from: a. an antibody that specifically binds to UL16 protein according to any of claims 1 to 164;
321 b. an antibody that specifically binds to UL141 protein according to any of claims 220 to 332; c. an antibody that specifically binds to US28 protein according to any of claims 387 to 466; and d. an antibody that specifically binds to VEGF. . The kit of claim 535, wherein the further therapeutic agent is an anti-viral agent. . The kit of claim 539, wherein the anti-viral agent is selected from letermovir, ganciclovir, valganciclovir, foscamet, cidofovir, acyclovir, formivirsen, maribavir, BAY 38-4766 or GW275175X. . A kit comprising a pharmaceutical composition comprising a first antibody according to any one of claims 1 to 164 and a pharmaceutical composition comprising a second antibody according to any one of claims 387 to 466. . A kit comprising a pharmaceutical composition comprising a first antibody according to any one of claims 220 to 332 and a pharmaceutical composition comprising a second antibody according to any one of claims 387 to 466. . A kit comprising a pharmaceutical composition comprising a first antibody 1 to 164, a pharmaceutical composition comprising a second antibody according to any one of claims 220 to 332, and a pharmaceutical composition comprising a third antibody according to any one of claims 387 to 466. . A kit comprising a pharmaceutical composition comprising a first antibody according to any one of claims 387 to 466 and a pharmaceutical composition comprising a second antibody that specifically binds to VEGF. . The kit according to any of claims 534 and 544, further comprising a label or instructions for use to treat and/or prevent HCMV infection in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody or fragment. . Use of an antibody according to any of claims 1 to 164, 220 to 332, or 387 to 466, determining the presence or absence of HCMV in a sample. . Use of an antibody according to any of claims 1 to 164 for determining the presence or absence of ULI 6 protein in a sample.
322
548. Use of an antibody according to any of claims 220 to 332 for determining the presence or absence of UL141 protein in a sample.
549. Use of an antibody according to any of claims 387 to 466 for determining the presence or absence of US28 protein in a sample.
550. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of claims 1 to 164; and testing for binding between the antibody and HCMV protein UU16 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
551. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of claims 220 to 332; and testing for binding between the antibody and HCMV protein UU141 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
552. A method of determining the presence or absence of HCMV, in a sample, the method comprising contacting the sample with an antibody according to any of claims 387 to 466; and testing for binding between the antibody and HCMV protein US28 in the sample; wherein detection of binding indicates the presence of HCMV in the sample and wherein absence of binding indicates the absence of HCMV in the sample.
553. Use according to any one of claims 546 to 549 or a method according to any one of claims 550 to 552, wherein the antibody comprises or is conjugated to a detectable label.
554. Use according to any one of claims 546 to 549 or 553, or a method according to any one of claims 550 to 553, wherein the sample has been obtained from a human who has been or is suspected of having been infected with HCMV.
555. Use according to any one of claims 546 to 549 or 553 to 554, or a method according to any one of claims 550 to 554, wherein the sample is a serum, plasma, or whole blood sample, or an oral or
323 nasal swab, urine, faeces, or cerebrospinal fluid (CFS), or wherein the sample is from any suspected HCMV infected organ or tissue. . A diagnostic kit for the use according to any one of claims 546 to 549 or 553 to 555, or the method according to any one of claims 550 to 555, comprising an antibody according to any of claims 1 to 164, 220 to 332, or 387 to 466, and optionally one or more buffering solutions. . A diagnostic kit according to claim 556, wherein the antibody comprises or is conjugated to a detectable label. . A diagnostic kit according to claim 556, comprising a first reagent comprising the antibody according to any of claims 1 to 164, 220 to 332, or 387 to 466, and a second reagent comprising a detector molecule that binds to the first reagent. . A diagnostic kit according to claim 558, wherein the detector molecule is an antibody that comprises or is conjugated to a detectable label.
324
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