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WO2022159842A1 - Polythérapies à base d'anticorps contre une infection par sars-cov-2 - Google Patents

Polythérapies à base d'anticorps contre une infection par sars-cov-2 Download PDF

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Publication number
WO2022159842A1
WO2022159842A1 PCT/US2022/013568 US2022013568W WO2022159842A1 WO 2022159842 A1 WO2022159842 A1 WO 2022159842A1 US 2022013568 W US2022013568 W US 2022013568W WO 2022159842 A1 WO2022159842 A1 WO 2022159842A1
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Prior art keywords
antibody
cov
sars
amino acid
seq
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Inventor
Herbert W. Virgin
Davide Corti
Christy M. Hebner
Florian LEMPP
Erik MOGALIAN
Wendy YEH
Phillip S. Pang
Andrew Charles ADAMS
Bryan Edward Jones
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Eli Lilly and Co
Vir Biotechnology Inc
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Eli Lilly and Co
Vir Biotechnology Inc
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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
    • A61P31/14—Antivirals for RNA 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
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1002—Coronaviridae
    • C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/526—CH3 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—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
    • C07K2317/76—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
    • 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
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • SARS-CoV-2 A novel betacoronavirus emerged in Wuhan, China, in late 2019. As of January 18, 2022, approximately 333 million cases of infection by this virus (termed, among other names, SARS-CoV-2) had occurred worldwide, resulting in over 5.5 million deaths. Therapies for SARS-CoV-2 infection are needed.
  • Figure 1 shows neutralization of SARS-CoV-2 pseudotyped virus by antibody VIR-7831 (heavy chain of SEQ ID NO.:11, light chain of SEQ ID NO.: 12), as described in Example 2.
  • Figure 2 shows neutralization of live SARS-CoV-2 by antibody VIR-7831, as described in Example 3.
  • Figure 3 depicts the layout of a plate used for a microneutralization assay evaluating the combination of antibodies bamlanivimab ("LY-CoV-555"; heavy chain of SEQ ID NO. : 1, light chain of SEQ ID NO. :2) and VIR-7831 at the indicated concentrations, as described in Example 5.
  • bamlanivimab ("LY-CoV-555"; heavy chain of SEQ ID NO. : 1, light chain of SEQ ID NO. :2) and VIR-7831 at the indicated concentrations, as described in Example 5.
  • FIG. 4 summarizes results from studies investigating whether combining bamlanivimab (LY-CoV-555) with VIR-7831 has synergistic or antagonistic effects on neutralizing activity of these antibodies, as described in Example 5.
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (b) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (b) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and, optionally, (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining
  • the present disclosure provides a composition
  • a composition comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a composition
  • a composition comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • CDRH1 complementarity determining region
  • the present disclosure provides a combination comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively and is capable of specifically binding to SARS-CoV-2 S protein, for use in method for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, for use in method for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively and is capable of specifically binding to SARS-CoV-2 S protein, for use in the manufacture of a medicament for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, for use in the manufacture of a medicament for treating a SARS CoV-2 infection in a subject.
  • a method for treating a SARS CoV-2 infection in a subject comprising administering to the subject: (i) an anti- SARS-CoV-2 antibody (a) and an anti-SARS-CoV-2 antibody (b), and optionally an anti -SARS -CoV-2 antibody (c); (ii) an anti-SARS-CoV-2 antibody (b) and an anti- SARS-CoV-2 antibody (c); (iii) an anti-SARS-CoV-2 antibody (a), an anti-SARS-CoV- 2 antibody (b), and an anti-SARS-CoV-2 antibody (c); (iv) an anti-SARS-CoV-2 antibody (a), wherein the subject has received an anti-SARS-CoV-2 antibody (b) and has optionally received an anti-SARS-CoV-2 antibody (c); (v) an anti-SARS-CoV-2 antibody (b), wherein the subject has received an anti-SARS-CoV-2 antibody (a) and has optionally received an anti-SARS-CoV-2 antibody
  • the anti-SARS-CoV-2 antibody (a) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:9 and 10, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: l and 2, respectively.
  • the anti-SARS-CoV-2 antibody (a) comprises a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (b) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.: 19 and 20, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: 11 and 12, respectively.
  • the anti-SARS-CoV-2 antibody (b) comprises a human IgGl isotype, optionally an IgGlml7 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (b) comprises M428L and N434S mutations in the heavy chain CH3.
  • the anti-SARS- CoV-2 antibody (c) comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:29 and 30, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs:21 and 22, respectively.
  • the anti-SARS-CoV-2 antibody (c) comprises a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • a composition that comprises: (i) an anti- SARS-CoV-2 antibody (a) and an anti-SARS-CoV-2 antibody (b), and optionally an anti-SARS-CoV-2 antibody (c); (ii) an anti-SARS-CoV-2 antibody (b) and an anti- SARS-CoV-2 antibody (c); or (iii) an anti-SARS-CoV-2 antibody (a), an anti-SARS- CoV-2 antibody (b), and an anti-SARS-CoV-2 antibody (c).
  • the anti-SARS-CoV-2 antibody (a) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:9 and 10, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: 1 and 2, respectively.
  • the anti-SARS-CoV-2 antibody (a) comprises a humann IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (b) comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.: 19 and 20, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: 11 and 12, respectively.
  • the anti-SARS-CoV-2 antibody (b) comprises a human IgGl isotype, optionally an IgGlml7 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (c) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:29 and 30, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs:21 and 22, respectively.
  • the anti-SARS- CoV-2 antibody (c) comprises a humann IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • a combination comprises: (i) an anti- SARS-CoV-2 antibody (a) and an anti-SARS-CoV-2 antibody (b), and optionally an anti-SARS-CoV-2 antibody (c); (ii) an anti-SARS-CoV-2 antibody (b) and an anti- SARS-CoV-2 antibody (c); or (iii) an anti-SARS-CoV-2 antibody (a), an anti-SARS- CoV-2 antibody (b), and an anti-SARS-CoV-2 antibody (c).
  • the anti-SARS-CoV-2 antibody (a) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:9 and 10, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: 1 and 2, respectively.
  • the anti-SARS-CoV-2 antibody (a) comprises a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (b) comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.: 19 and 20, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs: 11 and 12, respectively.
  • the anti-SARS-CoV-2 antibody (b) comprises a human IgGl isotype, optionally an IgGlml7 allotype, and a human kappa light chain constant domain.
  • the anti-SARS-CoV-2 antibody (c) comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and optionally comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:29 and 30, respectively, and further optionally comprises HC and LC amino acid sequences as set forth in SEQ ID NOs:21 and 22, respectively.
  • the anti-SARS- CoV-2 antibody (c) comprises a humann IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • a method for treating a SARS CoV-2 infection in a subject comprising administering to the subject: (b) about 175 mg to about 500 mg of an antibody that comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively, and one or both of (a) about 175 mg to about 700 mg of an antibody that comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively, and (c) about 350 mg to about 1400 mg of an antibody that comprises VH and VL amino acid sequences as set forth in SEQ ID NOS.:29 and 30, respectively.
  • antibody (a) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively;
  • antibody (b) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively;
  • antibody (c) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.:29 and 30, respectively.
  • antibody (a) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively.
  • antibody (b) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively.
  • antibody (c) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:29 and 30, respectively.
  • antibody (a) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively, antibody (b) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively, and antibody (c) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:29 and 30, respectively.
  • antibody (a) can comprise a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain
  • antibody (b) can comprise a human IgGl isotype, optionally an IgGlml7 allotype, and a human kappa light chain constant domain
  • antibody (c) can comprise a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • antibody (a) can comprise heavy chain (HC) and/or light chain (LC) amino acid sequences as set forth in SEQ ID NOs.: l and 2, respectively;
  • antibody (b) can comprise HC and/or LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively;
  • antibody (c) can comprise HC and/or LC amino acid sequences as set forth in SEQ ID NOs.:21 and 22, respectively.
  • antibody (a) comprises heavy chain (HC) and light chain (LC) amino acid sequences as set forth in SEQ ID NOs.: l and 2, respectively.
  • antibody (b) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively.
  • antibody (c) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.:21 and 22, respectively.
  • antibody (a) comprises heavy chain (HC) and light chain (LC) amino acid sequences as set forth in SEQ ID NOs.: l and 2, respectively, antibody (b) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively, and antibody (c) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.:21 and 22, respectively.
  • SARS-CoV-2 also originally referred to as "Wuhan coronavirus", “Wuhan seafood market pneumonia virus”, or “Wuhan CoV”, “novel CoV”, or “nCoV”, or “2019 nCoV”, or “Wuhan nCoV”, or a variant thereof, is a betacoronavirus of lineage B (sarbecovirus). SARS-CoV-2 was first identified in Wuhan, Hubei province, China, in late 2019 and spread within China and to other parts of the world by early 2020.
  • SARS CoV-2 infection can result in a disease known as COVID-19; symptoms of COVID-19 include fever or chills, dry cough, dyspnea, fatigue, body aches, headache, new loss of taste or smell, sore throat, congestions or runny nose, nausea or vomiting, diarrhea, persistent pressure or pain in the chest, new confusion, inability to wake or stay awake, and bluish lips or face.
  • SARS-CoV-2 comprises a "spike” or surface (“S") type I transmembrane glycoprotein containing a receptor binding domain (RBD).
  • SARS- CoV-2 comprises a "spike” or surface (“S") type I transmembrane glycoprotein containing a receptor binding domain (RBD).
  • RBD is believed to mediate entry of the lineage B SARS coronavirus to respiratory epithelial cells by binding to the cell surface receptor angiotensin-converting enzyme 2 (ACE2).
  • ACE2 cell surface receptor angiotensin-converting enzyme 2
  • RBM receptor binding motif
  • the amino acid sequence of the Wuhan-Hu- 1 surface glycoprotein is provided in SEQ ID NO.:33.
  • the amino acid sequence of the Wuhan-Hu-1 RBD is provided in SEQ ID NO.:34.
  • Wuhan-Hu-1 S protein has approximately 73% amino acid sequence identity with SARS-CoV.
  • the amino acid sequence of Wuhan-Hu- 1 RBM is provided in SEQ ID NO.:35.
  • SARS-CoV-2 Wuhan-Hu- 1 refers to a virus comprising the amino acid sequence set forth in any one or more of SEQ ID NOs.:32, 33, 34, and 35, and optionally comprises the genomic sequence set forth in SEQ ID NO.:31.
  • SARS-CoV-2 variants are also known. Some SARS-CoV-2 variants contain a N439K mutation, which can enhance binding affinity to the human ACE2 receptor (Thomson, E.C., et al., The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity. bioRxiv, 2020). Some SARS-CoV- 2 variants contain a N501 Y mutation, which has been associated with increased transmissibility, including the lineages B.
  • l.1.7 also known as 20I/501Y.V1 and VOC 202012/01; (del69-70, dell44, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H mutations)
  • B.1.351 also known as 20H/501Y.V2; L18F, D80A, D215G, R246I, K417N, E484K, N501 Y, D614G, and A701 V mutations
  • SARS-CoV-2 severe acute respiratory syndrome-related coronavirus 2
  • B.1.351 also include two other mutations in the RBD domain of SARS-CoV2 spike protein, K417N and E484K (Tegally, H., et al., Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, 2020: p. 2020.12.21.20248640).
  • SARS-CoV-2 variants include B.1.351.2, B.1.351.3, the so-called Delta (B.1.617.2, AY. l, AY.2, AY.3; see also Mlcochova, P., Kemp, S.A., Dhar, M.S. et al. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature (2021). doi.org/10.1038/s41586-021- 03944-y)), Gamma (P.
  • SARS-CoV-2 variants include a SARS CoV-2 of clade 19A; SARS CoV-2 of clade 19B; a SARS CoV-2 of clade 20A; a SARS CoV-2 of clade 20B; a SARS CoV-2 of clade 20C; a SARS CoV-2 of clade 20D; a SARS CoV-2 of clade 20E (EU1); a SARS CoV-2 of clade 20F; a SARS CoV-2 of clade 20G; and SARS CoV-2 Bl.1.207; and other SARS CoV-2 lineages described in Rambaut, A., et al., A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol 5, 1403-1407 (2020).
  • Treating a SARS CoV-2 infection in accordance with the present disclosure includes treating infection by any one or more of the aforementioned SARS-CoV-2 viruses.
  • Variants of concern treatable in accordance with the present disclosure include, for example, the Alpha (B.1.1.7), Beta (B.1.351, B.1.351.2, B.1.351.3), Delta (B.1.617.2, AY.l, AY.2, AY.3; see also Mlcochova, P., Kemp, S.A., Dhar, M.S. et al. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature (2021). https://doi.org/10.1038/s41586-021-03944-y), Gamma (P.
  • SARS-CoV-2 see https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html).
  • SARS-CoV-2 variants, and the amino acid and nucleotide sequences thereof, are incorporated herein by reference.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • the term “about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more" of the enumerated components.
  • a protein domain, region, or module e.g., an antibody variable domain
  • a protein "consists essentially of a particular amino acid sequence when the amino acid sequence of a domain, region, module, or protein includes extensions, deletions, mutations, or a combination thereof (e.g., amino acids at the amino- or carboxy-terminus or between domains) that, in combination, contribute to at most 20% (e.g., at most 15%, 10%, 8%, 6%, 5%, 4%, 3%, 2% or 1%) of the length of a domain, region, module, or protein and do not substantially affect (i.e., do not reduce the activity by more than 50%, such as no more than 40%, 30%, 25%, 20%, 15%, 10%, 5%, or 1%) the activity of the domain(s), region(s),
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g, hydroxyproline, y-carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • mutation refers to a change in the sequence of a nucleic acid molecule or polypeptide molecule as compared to a reference or wild-type nucleic acid molecule or polypeptide molecule, respectively.
  • a mutation can result in several different types of change in sequence, including substitution, insertion or deletion of nucleotide(s) or amino acid(s).
  • a “conservative substitution” refers to amino acid substitutions that do not significantly affect or alter binding characteristics of a particular protein. Generally, conservative substitutions are ones in which a substituted amino acid residue is replaced with an amino acid residue having a similar side chain. Conservative substitutions include a substitution found in one of the following groups: Group 1 : Alanine (Ala or A), Glycine (Gly or G), Serine (Ser or S), Threonine (Thr or T); Group 2: Aspartic acid (Asp or D), Glutamic acid (Glu or Z); Group 3 : Asparagine (Asn or N), Glutamine (Gin or Q); Group 4: Arginine (Arg or R), Lysine (Lys or K), Histidine (His or H); Group 5: Isoleucine (He or I), Leucine (Leu or L), Methionine (Met or M), Valine (Vai or V); and Group 6: Phenylalanine (Phe or F), Tyrosine (Tyr
  • amino acids can be grouped into conservative substitution groups by similar function, chemical structure, or composition (e.g., acidic, basic, aliphatic, aromatic, or sulfur-containing).
  • an aliphatic grouping may include, for purposes of substitution, Gly, Ala, Vai, Leu, and He.
  • Other conservative substitutions groups include: sulfur-containing: Met and Cysteine (Cys or C); acidic: Asp, Glu, Asn, and Gin; small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, Glu, and Gin; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, He, Vai, and Cys; and large aromatic residues: Phe, Tyr, and Trp. Additional information can be found in Creighton (1984) Proteins, W.H. Freeman and Company.
  • protein or “polypeptide” refers to a polymer of amino acid residues. Proteins apply to naturally occurring amino acid polymers, as well as to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, and non-naturally occurring amino acid polymers.
  • Nucleic acid molecule or “polynucleotide” or “polynucleic acid” refers to a polymeric compound including covalently linked nucleotides, which can be made up of natural subunits (e.g., purine or pyrimidine bases) or non-natural subunits (e.g., morpholine ring).
  • Purine bases include adenine, guanine, hypoxanthine, and xanthine
  • pyrimidine bases include uracil, thymine, and cytosine.
  • Nucleic acid molecules include polyribonucleic acid (RNA), which includes mRNA, microRNA, siRNA, viral genomic RNA, and synthetic RNA, and polydeoxyribonucleic acid (DNA), which includes cDNA, genomic DNA, and synthetic DNA, either of which may be single or double stranded. If single-stranded, the nucleic acid molecule may be the coding strand or non-coding (anti-sense) strand.
  • a nucleic acid molecule encoding an amino acid sequence includes all nucleotide sequences that encode the same amino acid sequence. Some versions of the nucleotide sequences may also include intron(s) to the extent that the intron(s) would be removed through co- or post-transcriptional mechanisms. In other words, different nucleotide sequences may encode the same amino acid sequence as the result of the redundancy or degeneracy of the genetic code, or by splicing.
  • isolated means that the material is removed from its original environment (e.g., the natural environment if it is naturally occurring).
  • a naturally occurring nucleic acid or polypeptide present in a living animal is not isolated, but the same nucleic acid or polypeptide, separated from some or all of the co-existing materials in the natural system, is isolated.
  • nucleic acid could be part of a vector and/or such nucleic acid or polypeptide could be part of a composition (e.g., a cell lysate), and still be isolated in that such vector or composition is not part of the natural environment for the nucleic acid or polypeptide.
  • gene means the segment of DNA or RNA involved in producing a polypeptide chain; in certain contexts, it includes regions preceding and following the coding region (e.g., 5’ untranslated region (UTR) and 3’ UTR) as well as intervening sequences (introns) between individual coding segments (exons).
  • regions preceding and following the coding region e.g., 5’ untranslated region (UTR) and 3’ UTR
  • intervening sequences introns between individual coding segments (exons).
  • the term "engineered,” “recombinant,” or “non-natural” refers to an organism, microorganism, cell, nucleic acid molecule, or vector that includes at least one genetic alteration or has been modified by introduction of an exogenous or heterologous nucleic acid molecule, wherein such alterations or modifications are introduced by genetic engineering (i.e., human intervention).
  • Genetic alterations include, for example, modifications introducing expressible nucleic acid molecules encoding functional RNA, proteins, fusion proteins or enzymes, or other nucleic acid molecule additions, deletions, substitutions, or other functional disruption of a cell’s genetic material. Additional modifications include, for example, non-coding regulatory regions in which the modifications alter expression of a polynucleotide, gene, or operon.
  • expression refers to the process by which a polypeptide is produced based on the encoding sequence of a nucleic acid molecule, such as a gene.
  • the process may include transcription, post-transcriptional control, post-transcriptional modification, translation, post-translational control, post- translational modification, or any combination thereof.
  • An expressed nucleic acid molecule is typically operably linked to an expression control sequence (e.g., a promoter).
  • operably linked refers to the association of two or more nucleic acid molecules on a single nucleic acid fragment so that the function of one is affected by the other.
  • a promoter is operably linked with a coding sequence when it is capable of affecting the expression of that coding sequence (i.e., the coding sequence is under the transcriptional control of the promoter).
  • Unlinked means that the associated genetic elements are not closely associated with one another and the function of one does not affect the other.
  • more than one heterologous nucleic acid molecule can be introduced into a host cell as separate nucleic acid molecules, as a plurality of individually controlled genes, as a polycistronic nucleic acid molecule, as a single nucleic acid molecule encoding a protein (e.g, a heavy chain of an antibody), or any combination thereof.
  • a protein e.g, a heavy chain of an antibody
  • two or more heterologous nucleic acid molecules can be introduced as a single nucleic acid molecule (e.g., on a single vector), on separate vectors, integrated into the host chromosome at a single site or multiple sites, or any combination thereof.
  • the number of referenced heterologous nucleic acid molecules or protein activities refers to the number of encoding nucleic acid molecules or the number of protein activities, not the number of separate nucleic acid molecules introduced into a host cell.
  • construct refers to any polynucleotide that contains a recombinant nucleic acid molecule.
  • a (polynucleotide) construct may be present in a vector (e.g., a bacterial vector, a viral vector) or may be integrated into a genome.
  • a "vector” is a nucleic acid molecule that is capable of transporting another nucleic acid molecule.
  • Vectors may be, for example, plasmids, cosmids, viruses, a RNA vector or a linear or circular DNA or RNA molecule that may include chromosomal, non-chromosomal, semi -synthetic or synthetic nucleic acid molecules.
  • Vectors of the present disclosure also include transposon systems (e.g., Sleeping Beauty, see, e.g., Geurts et al., Mol. Ther. 5:108, 2003: Mates et al., Nat. Genet. 41'.753, 2009).
  • Exemplary vectors are those capable of autonomous replication (episomal vector), capable of delivering a polynucleotide to a cell genome (e.g., viral vector), or capable of expressing nucleic acid molecules to which they are linked (expression vectors).
  • expression vector refers to a DNA construct containing a nucleic acid molecule that is operably linked to a suitable control sequence capable of effecting the expression of the nucleic acid molecule in a suitable host.
  • control sequences include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control termination of transcription and translation.
  • the vector may be a plasmid, a phage particle, a virus, or simply a potential genomic insert.
  • the vector may replicate and function independently of the host genome, or may, in some instances, integrate into the genome itself or deliver the polynucleotide contained in the vector into the genome without the vector sequence.
  • plasmid "expression plasmid,” “virus,” and “vector” are often used interchangeably.
  • the term "introduced” in the context of inserting a nucleic acid molecule into a cell means “transfection", “transformation,” or “transduction” and includes reference to the incorporation of a nucleic acid molecule into a eukaryotic or prokaryotic cell wherein the nucleic acid molecule may be incorporated into the genome of a cell (e.g., chromosome, plasmid, plastid, or mitochondrial DNA), converted into an autonomous replicon, or transiently expressed (e.g., transfected mRNA).
  • a cell e.g., chromosome, plasmid, plastid, or mitochondrial DNA
  • transiently expressed e.g., transfected mRNA
  • a polynucleotide may be operatively linked to certain elements of a vector.
  • polynucleotide sequences that are needed to effect the expression and processing of coding sequences to which they are ligated may be operatively linked.
  • Expression control sequences may include appropriate transcription initiation, termination, promoter, and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequences); sequences that enhance protein stability; and possibly sequences that enhance protein secretion.
  • Expression control sequences may be operatively linked if they are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.
  • a vector can comprise a plasmid vector or a viral vector (e.g., a lentiviral vector or a y-retroviral vector).
  • Viral vectors include retrovirus, adenovirus, parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses such as picornavirus and alphavirus, and double-stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g., vaccinia, fowlpox, and canarypox).
  • orthomyxovirus e
  • viruses include, for example, Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus.
  • retroviruses include avian leukosissarcoma, mammalian C-type, B-type viruses, D type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996).
  • “Retroviruses” are viruses having an RNA genome, which is reverse-transcribed into DNA using a reverse transcriptase enzyme, the reverse-transcribed DNA is then incorporated into the host cell genome.
  • “Gammaretrovirus” refers to a genus of the retroviridae family. Examples of gammaretroviruses include mouse stem cell virus, murine leukemia virus, feline leukemia virus, feline sarcoma virus, and avian reticuloendotheliosis viruses.
  • Lentiviral vectors include HIV-based lentiviral vectors for gene delivery, which can be integrative or non-integrative, have relatively large packaging capacity, and can transduce a range of different cell types. Lentiviral vectors are usually generated following transient transfection of three (packaging, envelope, and transfer) or more plasmids into producer cells. Like HIV, lentiviral vectors enter the target cell through the interaction of viral surface glycoproteins with receptors on the cell surface. On entry, the viral RNA undergoes reverse transcription, which is mediated by the viral reverse transcriptase complex. The product of reverse transcription is a double-stranded linear viral DNA, which is the substrate for viral integration into the DNA of infected cells.
  • a viral vector can be a gammaretrovirus, e.g., Moloney murine leukemia virus (MLV)-derived vectors.
  • the viral vector can be a more complex retrovirus-derived vector, e.g., a lentivirus-derived vector.
  • HIV- 1 -derived vectors belong to this category.
  • Other examples include lentivirus vectors derived from HIV-2, FIV, equine infectious anemia virus, SIV, and Maedi-Visna virus (ovine lentivirus).
  • viral vectors also can be used for polynucleotide delivery including DNA viral vectors, including, for example adenovirus-based vectors and adeno-associated virus (AAV)- based vectors; vectors derived from herpes simplex viruses (HSVs), including amplicon vectors, replication-defective HSV and attenuated HSV (Krisky et al., Gene Ther. 5: 1517, 1998).
  • DNA viral vectors including, for example adenovirus-based vectors and adeno-associated virus (AAV)- based vectors; vectors derived from herpes simplex viruses (HSVs), including amplicon vectors, replication-defective HSV and attenuated HSV (Krisky et al., Gene Ther. 5: 1517, 1998).
  • HSVs herpes simplex viruses
  • vectors include those derived from baculoviruses and a-viruses. (Jolly, D J. 1999. Emerging Viral Vectors, pp 209-40 in Friedmann T. ed. The Development of Human Gene Therapy. New York: Cold Spring Harbor Lab), or plasmid vectors (such as sleeping beauty or other transposon vectors).
  • the viral vector may also comprise additional sequences between the two (or more) transcripts allowing for bicistronic or multi ci str onic expression.
  • additional sequences used in viral vectors include internal ribosome entry sites (IRES), furin cleavage sites, viral 2A peptide, or any combination thereof.
  • the term "host” refers to a cell or microorganism targeted for genetic modification with a heterologous nucleic acid molecule to produce a polypeptide of interest (e.g., an antibody of the present disclosure).
  • a host cell may include any individual cell or cell culture which may receive a vector or the incorporation of nucleic acids or express proteins. The term also encompasses progeny of the host cell, whether genetically or phenotypically the same or different. Suitable host cells may depend on the vector and may include mammalian cells, animal cells, human cells, simian cells, insect cells, yeast cells, and bacterial cells. These cells may be induced to incorporate the vector or other material by use of a viral vector, transformation via calcium phosphate precipitation, DEAE-dextran, electroporation, microinjection, or other methods. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 2d ed. (Cold Spring Harbor Laboratory, 1989).
  • a "host” refers to a cell or a subject infected with SARS CoV-2.
  • Antigen refers to an immunogenic molecule that provokes an immune response. This immune response may involve antibody production, activation of specific immunologically-competent cells, activation of complement, antibody dependent cytotoxicicity, or any combination thereof.
  • An antigen immunogenic molecule
  • An antigen may be, for example, a peptide, glycopeptide, polypeptide, glycopolypeptide, polynucleotide, polysaccharide, lipid, or the like. It is readily apparent that an antigen can be synthesized, produced recombinantly, or derived from a biological sample. Exemplary biological samples that can contain one or more antigens include tissue samples, stool samples, cells, biological fluids, or combinations thereof.
  • Antigens can be produced by cells that have been modified or genetically engineered to express an antigen. Antigens can also be present in a SARS CoV-2 (e.g., a surface glycoprotein or portion thereof), such as present in a virion, or expressed or presented on the surface of a cell infected by the SARS CoV-2.
  • SARS CoV-2 e.g., a surface glycoprotein or portion thereof
  • epitope includes any molecule, structure, amino acid sequence, or protein determinant that is recognized and specifically bound by a cognate binding molecule, such as an immunoglobulin, or other binding molecule, domain, or protein.
  • Epitopic determinants generally contain chemically active surface groupings of molecules, such as amino acids or sugar side chains, and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
  • the epitope can be comprised of consecutive amino acids (e.g., a linear epitope), or can be comprised of amino acids from different parts, portions, areas, or regions of the protein that are brought into proximity by protein folding (e.g., a discontinuous or conformational epitope), or noncontiguous amino acids that are in close proximity irrespective of protein folding.
  • presently disclosed antibody methods, compositions (and uses of the same), and combinations (and uses of the same) can comprise one or more antibodies that are capable of specifically binding to SARS-CoV-2 S protein.
  • antibody refers to an intact antibody comprising two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • antibody herein includes polyclonal and monoclonal antibodies, and intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof (IgGl, IgG2, IgG3, IgG4), IgM, IgE, IgA, and IgD.
  • any of the disclosed antibodies may be an IgGl isotype, such as a human IgGl isotype. It will be understood that an IgGl Fc comprising the amino acid mutations M428L and N434S is considered to be of the IgGl isotype.
  • VL or “VL” and “ VH” or “VH” refer to the variable binding region from an antibody light chain and an antibody heavy chain, respectively.
  • a VL is a kappa (K) class (also “VK” herein).
  • the variable binding regions comprise discrete, well-defined sub-regions known as “complementarity determining regions” (CDRs) and “framework regions” (FRs).
  • CDR complementarity determining region
  • HVR hypervariable region
  • an antibody VH comprises four FRs and three CDRs arranged as follows: FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR4; and an antibody VL comprises four FRs and three CDRs arranged as follows: FR1-LCDR1- FR2-LCDR2-FR3-LCDR3-FR4.
  • the VH and the VL together form the antigen-binding site through their respective CDRs.
  • Numbering of CDR and framework regions may be according to any known method or scheme, such as the Kabat, Chothia, EU, IMGT, Martin (Enhanced Chothia), AHo numbering schemes (see, e.g., Kabat et al., "Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5 th ed.; Chothia and Lesk, J. Mol. Biol. 796:901-917 (1987)); Lefranc et al., Dev. Comp. Immunol. 27:55, 2003; Honegger and Pliickthun, J. Mol. Bio.
  • Antibody methods, compositions (and uses thereof) and combinations (and uses thereof) according to the present disclosure include one, two, three, or more antibodies.
  • antibody (a) “antibody (b)”, and “antibody (c)”, which are three different antibodies that bind to different epitopes on SARS-CoV-2 S protein. These antibodies may also be referred-to herein as “the antibody of (a)”, “the antibody of (b)”, and “the antibody of (c)”, respectively.
  • Antibody (a) comprises the three HCDRs of the VH amino acid sequence set forth in SEQ ID NO.:9, and the three LCDRs of the VL amino acid sequence set forth in SEQ ID NO.: 10.
  • antibody (a) comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively.
  • antibody (a) comprises the VH ammo acid sequence set forth in SEQ ID NO.:9 and the VL amino acid sequence set forth in SEQ ID NO.: 10.
  • Antibody (b) comprises the three HCDRs of the VH amino acid sequence set forth in SEQ ID NO. : 19, and the three LCDRs of the VL amino acid sequence set forth in SEQ ID NO.:20. Using the IMGT definition, antibody (b) comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively.
  • antibody (b) comprises the VH amino acid sequence set forth in SEQ ID NO.: 19 and the VL amino acid sequence set forth in SEQ ID NO.:20.
  • Antibody (c) comprises the three HCDRs of the VH amino acid sequence set forth in SEQ ID NO.:29, and the three LCDRs of the VL amino acid sequence set forth in SEQ ID NO.:30. Using a hybrid of Kabat and North definitions, antibody (c) comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively.
  • antibody (c) comprises the VH amino acid sequence set forth in SEQ ID NO.:29 and the VL amino acid sequence set forth in SEQ ID NO.:30.
  • CL refers to an "immunoglobulin light chain constant region” or a "light chain constant region,” z.e., a constant region from an antibody light chain.
  • CH refers to an "immunoglobulin heavy chain constant region” or a "heavy chain constant region,” which is further divisible, depending on the antibody isotype, into CHI, CH2, and CH3 (IgA, IgD, IgG), or CHI, CH2, CH3, and CH4 domains (IgE, IgM).
  • the Fc region of an antibody heavy chain is described further herein.
  • antibodies of the present disclosure further comprise a CL, a CHI, a CH2, and a CH3.
  • the “Fc” fragment or Fc polypeptide comprises the carboxy-terminal portions (z.e., the CH2 and CH3 domains of IgG) of both antibody H chains held together by disulfides.
  • Antibody effector functions refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding (including FcRn binding); antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.
  • an antibody of the present disclosure may be of any allotype or combination of allotypes.
  • Allotype refers to the allelic variation found among the IgG subclasses.
  • an IgGl allotype may comprise Glml (or Glm(a)), Glm2 (or Glm(x)), Glm3 (or Glm(f)), Glml7 (or Gm(z))m, Glm27, and/or Glm28 (Glm27 and Glm28 have been described as "alloallotypes").
  • the Glm3 and Glml7 allotypes differ in multiple positions in the CHI and CH3 domains.
  • Glm3 comprises R214 (EU), E356 (EU) and M358 (EU); while Glml7 comprises K214 (EU), D356 (EU) and L358 (EU) (Jefferis R., et al., mAbs 1(4): 1-7, 2009; Webster C., et al., mAbs 2016, 8 (2): 253- 263).
  • Glm allotypes, alloallotypes, and features thereof are known in the art and described at, for example, www.imgt.org/IMGTrepertoire/Proteins/allotypes/human/IGH/IGHC/Glm_allotypes.ht ml and Lefranc, M.-P. and Lefranc, G.
  • the Glml allotype may be combined, for example, with the Glm3, Glm 17, Glm27, Glm2, and/or Glm28 allotype.
  • an allotype is Glm3.
  • an allotype is Glml7,l allotype.
  • an allotype is Glm3,l.
  • an allotype is Glml7 with no Glml (Glml7,-1).
  • these allotypes may be combined (or not combined) with the Glm2, Glm27 or Glm28 allotype.
  • an allotype may be Glml7,l,2.
  • antibody (b) comprises M428L and N434S Fc mutations (EU numbering) to improve affinity of antibody (b) for human FcRn and improve in vivo half-life of antibody (b). Accordingly, in certain embodiments, antibody (b) comprises the heavy chain (HC) amino acid sequence set forth in SEQ ID NO. : 11 and the light chain (LC) amino acid sequence set forth in SEQ ID NO. : 12; such an antibody is also referred-to as VIR-7831.
  • HC heavy chain
  • LC light chain amino acid sequence set forth in SEQ ID NO. : 12
  • antibody (a) comprises the heavy chain (HC) amino acid sequence set forth in SEQ ID NO.: 1 and the light chain (LC) amino acid sequence set forth in SEQ ID NO.:2; such an antibody is also referred-to as bamlanivimab or LY- CoV555 or LY3819253.
  • antibody (c) comprises the heavy chain (HC) amino acid sequence set forth in SEQ ID NO.:21 and the light chain (LC) amino acid sequence set forth in SEQ ID NO.:22; such an antibody is also referred-to as etesevimab or LY- C0VOI6 or CB6.
  • affinity may be defined as an equilibrium dissociation constant (Kd) of a particular binding interaction with units of M (e.g., 10' 5 M to 10' 13 M).
  • assays are known for identifying antibodies of the present disclosure that bind a particular target, as well as determining binding domain or binding protein affinities, such as Western blot, ELISA (e.g., direct, indirect, or sandwich), analytical ultracentrifugation, spectroscopy, and surface plasmon resonance (Biacore®) analysis (see, e.g., Scatchard et al., Ann. N.Y. Acad. Sci. 57:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 53:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent).
  • An example of an instrument for assessing binding kinetics is the CARTERRA® LSATM instrument, which is a fully integrated HT-SPRTM (high-throughput surface plasmon resonance) system (Brown et al., 2020. Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors. PLoS One 15(3): e0229206). Assays for assessing affinity or apparent affinity or relative affinity are known.
  • an "anti-SARS-CoV-2 antibody” is an antibody that binds to SARS-CoV-2 S protein, and optionally binds to S protein of one or more other sarbecovirus (e.g. SARS- CoV), in a sample.
  • an anti-SARS-CoV-2 antibody does not substantially bind to a molecule in the sample that is not a sarbecovirus S protein, such as a SARS-CoV-2 S protein or a SARS-CoV S protein.
  • binding can be determined by recombinantly expressing a SARS-CoV-2 antigen in a host cell (e.g., by transfection) and immunostaining the e.g., fixed, or fixed and permeabilized) host cell with antibody and analyzing binding by flow cytometry e.g., using a ZE5 Cell Analyzer (BioRad®) and FlowJo software (TreeStar).
  • positive binding can be defined by differential staining by antibody of SARS-CoV-2-expressing cells versus control e.g., mock) cells.
  • a “neutralizing antibody” is one that can neutralize, i.e., prevent, inhibit, reduce, impede, or interfere with, the ability of a pathogen to initiate and/or perpetuate an infection in a host.
  • neutralizing antibody and “an antibody that neutralizes” or “antibodies that neutralize” are used interchangeably herein.
  • a subject receiving treatment according to the present disclosure receives a e.g. at least) sufficient amount of total antibody (e.g., the total amount of antibodies (a), (b), and/or (c)) to neutralize a SARS-CoV-2 infection.
  • mAb monoclonal antibody
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present, in some cases in minor amounts.
  • Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • polyclonal antibody preparations that include different antibodies directed against different epitopes, each monoclonal antibody is directed against a single epitope of the antigen.
  • the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
  • monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature 256 :495 (1975), or may be made using recombinant DNA methods in bacterial, eukaryotic animal, or plant cells (see, e.g., U.S. Pat. No. 4,816,567).
  • Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example.
  • Monoclonal antibodies may also be obtained using methods disclosed in PCT Publication No. WO 2004/076677A2.
  • human antibody is an antibody containing only sequences that are present in an antibody that is produced by a human.
  • human antibodies may comprise residues or modifications not found in a naturally occurring human antibody (e.g., an antibody that is isolated from a human), including those modifications and variant sequences described herein. These are typically made to further refine or enhance antibody performance.
  • human antibodies are produced by transgenic animals. For example, see U.S. Pat. Nos. 5,770,429; 6,596,541 and 7,049,426.
  • an antibody of the present disclosure is human.
  • Antibodies can be produced using host cells according to known methods. Examples of such cells include but are not limited to, eukaryotic cells, e.g., yeast cells, animal cells, insect cells, plant cells; and prokaryotic cells, including E. coli.
  • the cells are mammalian cells.
  • the cells are a mammalian cell line such as CHO cells (e.g., DHFR- CHO cells (Urlaub et al., PNAS 77:4216 (1980)), human embryonic kidney cells (e.g., HEK293T cells), PER.C6 cells, Y0 cells, Sp2/0 cells.
  • human liver cells e.g. Hepa RG cells, myeloma cells or hybridoma cells.
  • mammalian host cell lines include mouse sertoli cells (e.g., TM4 cells); monkey kidney CV1 line transformed by SV40 (COS-7); baby hamster kidney cells (BHK); African green monkey kidney cells (VERO-76); monkey kidney cells (CV1); human cervical carcinoma cells (HELA); human lung cells (W138); human liver cells (Hep G2); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); mouse mammary tumor (MMT 060562); TRI cells; MRC 5 cells; and FS4 cells.
  • mouse sertoli cells e.g., TM4 cells
  • COS-7 monkey kidney CV1 line transformed by SV40
  • BHK baby hamster kidney cells
  • African green monkey kidney cells VEO-76
  • monkey kidney cells CV1
  • HELA human cervical carcinoma cells
  • W138 human lung cells
  • Hep G2 human liver cells
  • Mammalian host cell lines suitable for antibody production also include those described in, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).
  • a host cell can be a prokaryotic cell, such as an E. coli.
  • the expression of peptides in prokaryotic cells such as E. coli is well established (see, e.g., Pluckthun, A. Bio/Technology 9:545-551 (1991).
  • prokaryotic cells such as E. coli
  • antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
  • For expression of antibodies in bacteria see, e.g., U.S. Pat. Nos. 5,648,237; 5,789,199; and 5,840,523.
  • a host cell may be transfected with a vector according to the present description with an expression vector.
  • transfection refers to the introduction of nucleic acid molecules, such as DNA or RNA (e.g. mRNA) molecules, into cells, such as into eukaryotic cells.
  • RNA e.g. mRNA
  • transfection encompasses any method known to the skilled person for introducing nucleic acid molecules into cells, such as into eukaryotic cells, including into mammalian cells.
  • Such methods encompass, for example, electroporation, lipofection, e.g., based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle based transfection, virus based transfection, or transfection based on cationic polymers, such as DEAE-dextran or polyethylenimine, etc. Introduction can be non-viral.
  • host cells may be transfected stably or transiently with a vector for expressing an antibody.
  • Host cells may be stably transfected with the vector as described herein.
  • cells may be transiently transfected with a vector according to the present disclosure encoding an antibody.
  • Insect cells useful for expressing an antibody include, for example, Spodoptera frugipera Sf9 cells, Trichoplusia ni BTI-TN5B1-4 cells, and Spodoptera frugipera SfSWTOl “MimicTM” cells. See, e.g., Palmberger et al., J. Biotechnol. 753(3-4): 160- 166 (2011). Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spoaoptera frugiperda cells.
  • Eukaryotic microbes such as filamentous fungi or yeast are also suitable hosts for cloning or expressing protein-encoding vectors, and include fungi and yeast strains with "humanized” glycosylation pathways, resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004); Li et al., Nat. Biotech. 24:210-215 (2006).
  • Plant cells can also be utilized as hosts for expressing a binding protein of the present disclosure.
  • PLANTIBODIESTM technology (described in, for example, U.S. Pat. Nos. 5,959,177; 6,040,498; 6,420,548; 7,125,978; and 6,417,429) employs transgenic plants to produce antibodies.
  • Particular host cells include mammalian cells, such as, for example, a CHO cell, a HEK293 cell, a PER.C6 cell, a Y0 cell, a Sp2/0 cell, a NSO cell, a human liver cell, a myeloma cell, or a hybridoma cell.
  • mammalian cells such as, for example, a CHO cell, a HEK293 cell, a PER.C6 cell, a Y0 cell, a Sp2/0 cell, a NSO cell, a human liver cell, a myeloma cell, or a hybridoma cell.
  • Methods useful for isolating and purifying recombinantly produced antibodies may include obtaining supernatants from suitable host cell/vector systems that secrete the recombinant antibody into culture media and then concentrating the media using a commercially available filter. Following concentration, the concentrate may be applied to a single suitable purification matrix or to a series of suitable matrices, such as an affinity matrix or an ion exchange resin. One or more reverse phase HPLC steps may be employed to further purify a recombinant polypeptide. These purification methods may also be employed when isolating an immunogen from its natural environment.
  • Methods for large scale production of one or more of the isolated/recombinant antibody described herein include batch cell culture, which is monitored and controlled to maintain appropriate culture conditions. Purification of soluble antibodies may be performed according to methods described herein and known in the art and that comport with laws and guidelines of domestic and foreign regulatory agencies.
  • compositions that comprise antibodies (a) and (b), in accordance with the presently disclosed methods and uses.
  • a composition further comprises antibody (c).
  • the compositions can further comprise a pharmaceutically acceptable carrier, excipient, or diluent. Carriers, excipients, and diluents are discussed in further detail herein.
  • the present disclosure provides antibody-based methods, antibody compositions, and antibody combinations for use in treating a SARS-CoV-2 infection in a subject, or for use in the manufacture of a medicament for treating a SARS-CoV-2 infection in a subject.
  • Treatment refers to medical management of a disease, disorder, or condition of a subject (e.g., a human or non-human mammal, such as a primate, horse, cat, dog, goat, mouse, or rat).
  • a subject e.g., a human or non-human mammal, such as a primate, horse, cat, dog, goat, mouse, or rat.
  • an appropriate dose or treatment regimen comprising an antibody, antibodies, or composition of the present disclosure is administered in an amount sufficient to elicit a therapeutic benefit.
  • Therapeutic benefit includes improved clinical outcome; lessening or alleviation of symptoms associated with a disease; decreased occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease, stabilization of disease state; delay or prevention of disease progression; remission; survival; prolonged survival; or any combination thereof.
  • therapeutic benefit includes reduction or prevention of hospitalization for treatment of a SARS-CoV-2 infection (i.e., in a statistically significant manner). In certain embodiments, therapeutic benefit includes a reduced duration of hospitalization for treatment of a SARS-CoV-2 infection (i.e., in a statistically significant manner). In certain embodiments, therapeutic benefit includes a reduced or abrogated need for respiratory intervention, such as intubation and/or the use of a respirator device. In certain embodiments, therapeutic includes reversing a late-stage disease pathology and/or reducing mortality.
  • a “therapeutically effective amount” or “effective amount” of an antibody, combination, or composition of this disclosure refers to an amount of the composition or molecule sufficient to result in a therapeutic effect, including improved clinical outcome; lessening or alleviation of symptoms associated with a disease; decreased occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease, stabilization of disease state; delay of disease progression; remission; survival; or prolonged survival in a statistically significant manner.
  • an "effective amount” or a “therapeutically effective amount” of an individual antibody of the present disclosure refers to the effect(s) of the antibody in the context of the identified therapy or subject.
  • an effective amount of antibody (c) is an amount sufficient to provide a therapeutic effect in that subject, and is not necessarily the same as an amount of antibody (c) that is sufficient to provide a therapeutic effect in a reference subject that has not been administered antibody (a) and antibody (b).
  • a therapeutically effective amount refers to the combined amount of the antibodies that is sufficient to result in a therapeutic effect, whether administered serially, sequentially, or simultaneously.
  • a method can comprise administering an effective amount of (an antibody (a) and an antibody (b)).
  • the effective amount administered is the combined amount of antibody (a) with antibody (b) that results in a therapeutic effect.
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (b) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (b) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • a method for treating a SARS-CoV-2 infection in a subject comprising administering to the subject an effective amount of (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and, optionally, (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining
  • the present disclosure provides a composition
  • a composition comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a composition
  • a composition comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • CDRH1 complementarity determining region
  • compositions to treat a SARS- CoV-2 infection in a subject, and/or in the manufacture of a medicament for treating a SARS-CoV-2 infection in a subject.
  • a composition is formulated for intravenous administration. In certain embodiments, a composition is formulated for subcutaneous administration. In some embodiments, a composition comprising an antibody according to a presently disclosed combination is formulated for intravenous administration and a composition comprising a different antibody is formulated for subcutaneous administration. In some embodiments, one antibody is administered via one route and another antibody or antibodies is administered via a different route.
  • a composition further comprises: PBS pH 7.4 (KC1: 0.2g/L, NaCl: 8.0g/L, KH2PO4: 0.2g/L, Na2HPO4 12H2O: 2.9g/L).
  • the composition can comprise antibody (b), comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, optionally comprising VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively, further optionally comprising HC and LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively.
  • the present disclosure provides a combination comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively and is capable of specifically binding to SARS-CoV-2 S protein, for use in method for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, for use in method for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively and is capable of specifically binding to SARS-CoV-2 S protein, for use in the manufacture of a medicament for treating a SARS CoV-2 infection in a subject.
  • CDR complementarity determining region
  • the combination further comprises (c) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • CDR complementarity determining region
  • the present disclosure provides a combination comprising: (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively and is capable of specifically binding to SARS-CoV-2 S protein; and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, for use in the manufacture of a medicament for treating a SARS CoV-2 infection in a subject.
  • a method for treating a SARS CoV-2 infection in a subject comprising administering to the subject: (b) about 175 mg to about 500 mg of an antibody that comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively, and one or both of (a) about 175 mg to about 700 mg of an antibody that comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively, and (c) about 350 mg to about 1400 mg of an antibody that comprises VH and VL ammo acid sequences as set forth in SEQ ID NOS.:29 and 30, respectively.
  • antibody (a) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively;
  • antibody (b) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively;
  • antibody (c) can comprise VH and/or VL amino acid sequences as set forth in SEQ ID NOs.:29 and 30, respectively.
  • antibody (a) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:9 and 10, respectively.
  • antibody (b) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.: 19 and 20, respectively.
  • antibody (c) comprises VH and VL amino acid sequences as set forth in SEQ ID NOs.:29 and 30, respectively.
  • antibody (a) can comprise a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain
  • antibody (b) can comprise a human IgGl isotype, optionally an IgGlml7 allotype, and a human kappa light chain constant domain
  • antibody (c) can comprise a human IgGl isotype, optionally an IgGlm3 allotype, and a human kappa light chain constant domain.
  • the antibody of (b) can comprise a M428L mutation and a N434S mutation, wherein positions 428 and 434 are according to the EU numbering system.
  • antibody (a) can comprise heavy chain (HC) and/or light chain (LC) amino acid sequences as set forth in SEQ ID NOs.: l and 2, respectively;
  • antibody (b) can comprise HC and/or LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively;
  • antibody (c) can comprise HC and/or LC amino acid sequences as set forth in SEQ ID NOs.:21 and 22, respectively.
  • antibody (a) comprises heavy chain (HC) and light chain (LC) amino acid sequences as set forth in SEQ ID NOs.: l and 2, respectively.
  • antibody (b) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.: 11 and 12, respectively.
  • antibody (c) comprises HC and LC amino acid sequences as set forth in SEQ ID NOs.:21 and 22, respectively.
  • the subject may be a human subject.
  • the subject can be male or female and can be any suitable age, e.g. an infant, juvenile, adolescent, adult, or geriatric subject.
  • a subject treated according to the present disclosure comprises one or more risk factors.
  • a human subject treated according to the present disclosure is an infant, a child, a young adult, an adult of middle age, or an elderly person. In certain embodiments, a human subject treated according to the present disclosure is less than 1 year old, or is 1 to 5 years old, or is between 5 and 125 years old (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 125 years old, including any and all ages therein or therebetween).
  • a human subject treated according to the present disclosure is 0- 19 years old, 20-44 years old, 45-54 years old, 55-64 years old, 65-74 years old, 75-84 years old, or 85 years old, or older. Persons of middle, and especially of elderly age are believed to be at particular risk.
  • the human subject is 45-54 years old, 55-64 years old, 65-74 years old, 75-84 years old, or 85 years old, or older.
  • the human subject is 65 years of age or older.
  • the human subject is male.
  • the human subject is female.
  • a human subject treated according to the present disclosure is a resident of a nursing home or a long-term care facility, is a hospice care worker, is a healthcare provider or healthcare worker, is a first responder, is a family member or other close contact of a subject diagnosed with or suspected of having a SARS-CoV-2 infection, is overweight or clinically obese, is or has been a smoker, has or had chronic obstructive pulmonary disease (COPD), is asthmatic (e.g., having moderate to severe asthma), has an autoimmune disease or condition (e.g., diabetes), and/or has a compromised or depleted immune system e.g., due to AIDS/HIV infection, a cancer such as a blood cancer, a lymphodepleting therapy such as a chemotherapy, a bone marrow or organ transplantation, or a genetic immune condition), has chronic liver disease, has cardiovascular disease, has a pulmonary or heart defect, works or otherwise spends time in close proximity with others, such as in a factory, shipping center
  • COPD
  • a subject treated according to the present disclosure has received a vaccine for SARS-CoV-2 and the vaccine is determined to be ineffective, e.g., by post-vaccine infection or symptoms in the subject, by clinical diagnosis or scientific or regulatory criteria.
  • a subject treated according to the present disclosure has received a vaccine for SARS-CoV-2.
  • treatment is administered to a subject (e.g., human subjects) with mild-to-moderate disease (e.g., mild-to-moderate COVID-19), which may be in an outpatient setting.
  • a subject e.g., human subjects
  • mild-to-moderate disease e.g., mild-to-moderate COVID-19
  • human subjects with mild COVID-19 can include individuals who have any of various signs and symptoms, e.g., fever, cough, sore throat, malaise, headache, muscle pain, without shortness of breath, dyspnea, or abnormal imaging.
  • Human subjects with moderate COVID-19 can include individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) greater than (>)93 percent (%) on room air at sea level.
  • the subject is at risk for contracting COVID-19.
  • the subject has COVID-19, e.g., a subject who has a positive SARS- CoV-2 viral testing result.
  • the human subject is at high risk for progressing to severe COVID-19 and/or hospitalization, e.g., the human subject (i) is 65 years of age or older (> 65); (ii) has a body mass index (BMI) of 35 or greater (> 35); (iii) has chronic kidney disease; (iv) has diabetes; (v) has immunosuppressive disease, (vi) is receiving immunosuppressive treatment; (vii) is 55 years of age or older (> 55) and has cardiovascular disease, hypertension, chronic obstructive pulmonary disease, or other chronic respiratory disease; or (viii) is 12 - 17 years of age and have a BMI >85% for their age and gender, or sickle cell disease, congenital or acquired heart disease, neurodevelopmental disorders (e.g., cerebral palsy), a medical-related technological dependence (e.g.,
  • Typical routes of administering a presently disclosed antibody, antibodies, or compositions thus include, without limitation, parenteral routes.
  • parenteral includes subcutaneous injections and intravenous, intramuscular, intrasternal, or intrathecal injection or infusion techniques.
  • administering comprises administering by a route that is selected from intravenous, intragastric, intrapleural, intrapulmonary, intrarectal, intradermal, intraperitoneal, intratumoral, subcutaneous, topical, transdermal, intracisternal, intrathecal, intranasal, and intramuscular.
  • compositions according to certain embodiments of the present invention are formulated so as to allow the active ingredient or ingredients contained therein to be bioavailable upon administration of the composition to a subject.
  • Compositions that will be administered to a subject or subject may take the form of one or more dosage units. Methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • the composition to be administered will, in any event, contain an effective amount of an antibody, antibodies, or composition of the present disclosure, for treatment of SARS-CoV-2 in accordance with teachings herein.
  • a composition may be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an injectable liquid.
  • the composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for delivery by injection, as two examples.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • Liquid pharmaceutical compositions may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid composition intended for parenteral administration should contain an amount of an antibody as herein disclosed such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of the antibody in the composition.
  • pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of antibody prior to dilution.
  • a composition may include various materials which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the composition in solid or liquid form may include an agent that binds to the antibody of the disclosure and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include monoclonal or polyclonal antibodies, one or more proteins or a liposome.
  • the pharmaceutical compositions may be prepared by methodology well known in the pharmaceutical art.
  • a composition intended to be administered by injection can be prepared by combining a composition that comprises an antibody or antibodies as described herein and optionally, one or more of salts, buffers and/or stabilizers, with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the peptide composition so as to facilitate dissolution or homogeneous suspension of the antibody or antibodies in the aqueous delivery system.
  • an appropriate dose and treatment regimen provide the composition(s) in an amount sufficient to provide therapeutic benefit (such as described herein, including an improved clinical outcome).
  • Treatment benefit of the compositions administered according to the methods described herein can be determined by performing clinical studies and analyzing data obtained therefrom by appropriate statistical, biological, and clinical methods and techniques, all of which can readily be practiced by a person skilled in the art.
  • Compositions are administered in an effective amount (e.g., to treat a SARS- CoV-2 infection), which will vary depending upon a variety of factors including the activity of the specific compound or compounds employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the subject; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • tollowing administration of therapies according to the formulations and methods of this disclosure test subjects will exhibit about a 10% up to about a 99% reduction in one or more symptoms associated with the disease or disorder being treated as compared to placebo-treated or other suitable control subjects.
  • a method according to the present disclosure comprises administering to the subject: (i) about 175 mg to about 700 mg of the antibody of (a); and/or (11) about 175 mg to about 500 mg of the antibody of (b); and/or (iii) about 350 mg to about 1400 mg of the antibody of (c).
  • a method comprises administering to the subject: (i) 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, or 700 mg of the antibody of (a); and/or (ii) 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg of the antibody of (b); and/or (iii) 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 13
  • a method comprises administering to the subject: (i) 700 mg of the antibody of (a); and (ii) 500 mg of the antibody of (b).
  • a method comprises administering to the subject: (i) 700 mg of the antibody of (a); (ii) 500 mg of the antibody of (b); and (iii) 1400 mg of the antibody of (c).
  • a method comprises administering to the subject:
  • a method comprises administering to the subject: (i) 175 mg of the antibody of (a); (ii) 175 mg of the antibody of (b); and (iii) 350 mg of the antibody of (c).
  • a method comprises administering to the subject:
  • the antibody of (a) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: l and 2, respectively;
  • the antibody of (b) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: 11 and 12, respectively;
  • the optional antibody of (c) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: 21 and 22, respectively.
  • the method comprises administering to the subject: (i) 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, or 700 mg of the antibody of (a); and/or (ii) 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg of the antibody of (b); and/or
  • (iii) 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, or 1400 mg of the antibody of (c).
  • the method comprises administering to the subject: (i) 700 mg of the antibody of (a); and (ii) 500 mg of the antibody of (b).
  • the method comprises administering to the subject: (i) 700 mg of the antibody of (a); (ii) 500 mg of the antibody of (b); and (iii) 1400 mg of the antibody of (c).
  • the method comprises administering to the subject: (i) 350 mg of the antibody of (a); (ii) 500 mg of the antibody of (b); and (iii) 700 mg of the antibody of (c).
  • the method comprises administering to the subject: (i) 175 mg of the antibody of (a); (ii) 175 mg of the antibody of (b); and (iii) 350 mg of the antibody of (c).
  • the method comprises administering the antibody or antibodies, the composition, or the combination, respectively, to the subject by intravenous administration.
  • the method comprises administering the antibody or antibodies, the composition, or the combination, respectively, to the subject by subcutaneous administration.
  • the SARS CoV-2 infection comprises any one or more of: SARS CoV-2 Wuhan-Hu-1; a SARS-CoV-2 variant comprising a N439K mutation; a SARS-CoV-2 variant comprising a N501 Y mutation, such as a SARS-CoV-2 of lineage B.l.1.7 (also known as 20I/501Y.V1 and VOC 202012/01) and/or B.1.351 (also known as 20H/501Y.V2); a SARS-CoV-2 variant comprising a K417N mutation and/or a E484K mutation, such as of lineage B.1.35 la SARS-CoV-2 comprising a L452R mutation; a SARS-CoV-2 of lineage B.1.1.28; a SARS-CoV-2 variant P.
  • SARS CoV-2 of clade 19A SARS CoV-2 of clade 19B; a SARS CoV-2 of clade 20A; a SARS CoV-2 of clade 20B; a SARS CoV-2 of clade 20C; a SARS CoV-2 of clade 20D; a SARS CoV-2 of clade 20E (EU1); a SARS CoV-2 of clade 20F; a SARS CoV-2 of clade 20G; and SARS CoV-2 Bl.1.207; and a SARS CoV-2 lineage described in Rambaut, A., et al., A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol 5, 1403-1407 (2020), which lineages are incorporated herein by reference.
  • the SARS CoV-2 infection comprises an Alpha (B.l.1.7), Beta (B.1.351, B.1.351.2, B.1.351.3), Delta (B.1.617.2, AY. l, AY.2, AY.3; see also Mlcochova, P., Kemp, S.A., Dhar, M.S. et al. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature (2021). https://doi.org/10.1038/s41586- 021-03944-y), Gamma (P. l, P.1.1, P.1.2) or Omicron (B.1.1.529 and BA lineages) variant of SARS-CoV-2.
  • the subject having a SARS- CoV-2 infection has mild-to-moderate COVID-19; is experiencing any one or more of: fever; cough; fatigue; shortness of breath or difficulty breathing; muscle aches; chills; sore throat; runny nose; headache; chest pain; loss of taste and/or smell; and pink eye (conjunctivitis); malaise; and abnormal imaging; has evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) greater than (>)93 percent (%) on room air at sea level, has a positive SARS-CoV-2 viral testing result, and/or (iii)(3) is at high risk for progressing to severe COVID-19 and/or hospitalization, e.g., the human subject (1) is 65 years of age or older (> 65); has a body mass index (BMI) of 35 or greater (> 35); has chronic kidney disease; has diabetes; (5) has immunosuppressive disease, is receiving immunosuppressive treatment; is 55 years of age or older
  • Two or more antibodies or antibody compositions may also be administered simultaneously with, prior to, or after administration of one or more other antibody or antibody composition.
  • Such combination therapy may include administration of a single pharmaceutical dosage formulation which contains an antibody or antibodies of the disclosure and one or more additional active agents, as well as administration of separate compositions comprising an antibody of the disclosure and each active agent in its own separate dosage formulation.
  • a first antibody as described herein and a second antibody as described herein can be administered to the subject together in a single parenteral dosage composition such as in a saline solution or other physiologically acceptable solution, or each agent administered in separate parenteral dosage formulations.
  • compositions comprising a first antibody and one or more additional antibodies can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially and in any order; combination therapy is understood to include all these regimens.
  • two or more antibodies of the present disclosure are administered simultaneously (e.g., over the course of 1, 3, 5, 10, 15, 20, 30, 60, or 90 minutes), or from 30 seconds to 5 minutes apart, or from 30 seconds to 15 minutes apart, or from 30 seconds to 30 minutes apart, or up to 1 hour apart, up to 2 hours apart, up to 6 hours apart, up to 12 hours apart, or up to 24 hours apart.
  • the present disclosure also provides the following non-limiting enumerated Embodiments.
  • Embodiment 1 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of: (a) an antibody that comprises complementarity determining region (CDR)H1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1,
  • Embodiment 2 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of:
  • Embodiment 3 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of (a) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV- 2 S protein and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV- 2 S protein
  • Embodiment 4 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of (b) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and, optionally, has received (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV- 2 S protein
  • Embodiment 5 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of (c) an antibody that comprises complementarity determining region (CDR)Hl, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received:
  • CDR complementarity determining region
  • Embodiment 6 A method for treating a SARS-CoV-2 infection in a subject, the method comprising administering to the subject an effective amount of: (a) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:3-8, respectively, and is capable of specifically binding to SARS-CoV-2 S protein and (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, wherein the subject has received (b) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively, and is capable of specifically binding to SARS-CoV- 2 S protein.
  • Embodiment 7 A composition comprising:
  • an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13- 18, respectively, and is capable of specifically binding to SARS-CoV-2 S protein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Embodiment 8 The composition of Embodiment 7, further comprising (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • Embodiment 9 The composition of Embodiment 7 or 8 for use in method for treating a SARS-CoV-2 infection in a subject.
  • Embodiment 10 The composition of Embodiment 7 or 8 for use in the manufacture of a medicament for treating a SARS-CoV-2 infection in a subject.
  • a combination comprising:
  • an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.: 13-18, respectively and is capable of specifically binding to SARS-CoV-2 S protein, for use in the manufacture of a medicament for treating a SARS CoV-2 infection in a subject.
  • Embodiment 13 The combination for use of Embodiment 11 or 12, further comprising (c) an antibody that comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences as set forth in SEQ ID NOs.:23-28, respectively, and is capable of specifically binding to SARS-CoV-2 S protein.
  • Embodiment 14 The method of any one of Embodiments 1-6, the composition of Embodiment 7 or 8, the composition for use of Embodiment 9 or 10, or the combination for use of any one of Embodiments 11-13, wherein:
  • the antibody of (a) comprises the heavy chain variable domain (VH) amino acid sequence set forth in SEQ ID NO.:9 and/or the light chain variable domain (VL) amino acid sequence set forth in SEQ ID NO.: 10;
  • the antibody of (b) comprises the VH amino acid sequence set forth in SEQ ID NO.: 19 and/or the VL amino acid sequence set forth in SEQ ID NO.:20; and/or
  • the antibody of (c) comprises the VH amino acid sequence set forth in SEQ ID NO.:29 and/or the VL amino acid sequence set forth in SEQ ID NO.:30.
  • Embodiment 15 The method of any one of Embodiments 1-6 and 14, the composition of Embodiment 7, 8, or 14, the composition for use of Embodiment 9, 10, or 14, or the combination for use of any one of Embodiments 11-14, wherein the antibody of (b) comprises a M428L mutation and a N434S mutation, wherein positions 428 and 434 are according to the EU numbering system.
  • Embodiment 16 The method of any one of Embodiments 1-6, 14, and 15, the composition of Embodiment 7, 8, 14, or 15, the composition for use of Embodiment 9, 10, 14, or 15, or the combination for use of any one of Embodiments 11-15, wherein:
  • the antibody of (a) comprises the heavy chain (HC) amino acid sequence set forth in SEQ ID NO.: 1 and/or the light chain (LC) amino acid sequence set forth in SEQ ID NO.: 2; and/or
  • the antibody of (b) comprises the HC amino acid sequence set forth in SEQ ID NO. : 11 and/or the LC amino acid sequence set forth in SEQ ID NO. : 12; and/or
  • the antibody of (c) comprises the HC amino acid sequence set forth in SEQ ID NO.:21 and/or the LC amino acid sequence set forth in SEQ ID NO.:22.
  • Embodiment 17 The method of any one of Embodiments 1-6 and 14-16, the composition for use of any one of Embodiments 9 and 14-16, or the combination for use of any one of Embodiments 11 and 13-16, wherein the method comprises administering to the subject:
  • Embodiment 18 The method of Embodiment 17, the composition for use of Embodiment 17, or the combination for use of Embodiment 17, wherein the method comprises administering to the subject:
  • Embodiment 19 The method of Embodiment 17 or 18, the composition for use of Embodiment 17 or 18, or the combination for use of Embodiment 17 or 18, wherein the method comprises administering to the subject:
  • Embodiment 20 The method of Embodiment 17 or 18, the composition for use of Embodiment 17 or 18, or the combination for use of Embodiment 17 or 18, wherein the method comprises administering to the subject:
  • Embodiment 21 The method of Embodiment 17 or 18, the composition for use of Embodiment 17 or 18, or the combination for use of Embodiment 17 or 18, wherein the method comprises administering to the subject:
  • Embodiment 22 The method of Embodiment 17 or 18, the composition for use of Embodiment 17 or 18, or the combination for use of Embodiment 17 or 18, wherein the method comprises administering to the subject:
  • Embodiment 23 A method for treating a SARS CoV-2 infection in a subject, the method comprising administering to the subject:
  • Embodiment 24 The method of Embodiment 23, wherein:
  • the antibody of (a) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: l and 2, respectively;
  • the antibody of (b) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: 11 and 12, respectively;
  • the optional antibody of (c) comprises the HC and LC amino acid sequences set forth in SEQ ID NOs.: 21 and 22, respectively.
  • Embodiment 25 The method of Embodiment 23 or 24, wherein the method comprises administering to the subject:
  • Embodiment 26 The method of Embodiment 25, wherein the method comprises administering to the subject:
  • Embodiment 27 The method of Embodiment 25, wherein the method comprises administering to the subject:
  • Embodiment 28 The method of Embodiment 25, wherein the method comprises administering to the subject:
  • Embodiment 29 The method of Embodiment 25, wherein the method comprises administering to the subject:
  • Embodiment 30 The method of any one of Embodiments 1-6 and 14-29, the composition for use of any one of Embodiments 9 and 14-22, or the combination for use of any one of Embodiments 13-22, wherein the method comprises administering the antibody or antibodies, the composition, or the combination, respectively, to the subject by intravenous administration.
  • Embodiment 31 The method of any one of Embodiments 1-6 and 13-29, the composition for use of any one of Embodiments 9 and 14-22, or the combination for use of any one of Embodiments 13-22, wherein the method comprises administering the antibody or antibodies, the composition, or the combination, respectively, to the subject by subcutaneous administration.
  • Embodiment 32 The method of any one of Embodiments 1-6 and 14-31, the composition for use of any one of Embodiments 9, 10, 14-22, 30, and 31, or the combination for use of any one of Embodiments 11-22, 30, and 31, wherein the SARS CoV-2 infection comprises any one or more of: SARS CoV-2 Wuhan-Hu-1; a SARS- CoV-2 variant comprising a N439K mutation; a SARS-CoV-2 variant comprising a N501Y mutation, such as a SARS-CoV-2 of lineage B. l.1.7 (also known as 201/501 Y.
  • B.1.351 also known as 20H/501Y.V2
  • SARS-CoV-2 variant comprising a K417N mutation and/or a E484K mutation, such as of lineage B.1.351, a SARS-CoV-2 comprising a L452R mutation; a SARS-CoV-2 of lineage B.1.1.28; a SARS-CoV-2 variant P.
  • SARS CoV-2 of clade 19 A SARS CoV-2 of clade 19B; a SARS CoV-2 of clade 20 A; a SARS CoV-2 of clade 20B; a SARS CoV-2 of clade 20C; a SARS CoV-2 of clade 20D; a SARS CoV-2 of clade 20E (EU1); a SARS CoV-2 of clade 20F; a SARS CoV-2 of clade 20G; SARS CoV-2 Bl.1.207; a SARS-CoV-2 Delta (B.1.617.2, AY.l, AY.2, AY.3) variant; and a SARS-CoV-2 Omicron (B.1.1.529 and BA lineages) variant.
  • SARS CoV-2 Omicron B.1.1.529 and BA lineages
  • Embodiment 33 The method of any one of Embodiments 1-6 and 14-32, the composition for use of any one of Embodiments 9, 10, 14-22, 30, 31, and 32, or the combination for use of any one of Embodiments 11-22, 30, 31, and 32, wherein the subject having a SARS-CoV-2 infection:
  • (iii) (iii)(l) has evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) greater than (>)93 percent (%) on room air at sea level, (iii)(2) has a positive SARS-CoV-2 viral testing result, and/or (iii)(3) is at high risk for progressing to severe COVID-19 and/or hospitalization, e.g., the human subject (1) is 65 years of age or older (> 65); (2) has a body mass index (BMI) of 35 or greater (> 35); (3) has chronic kidney disease; (4) has diabetes; (5) has immunosuppressive disease, (6) is receiving immunosuppressive treatment; (7) is 55 years of age or older (> 55) and has cardiovascular disease, hypertension, chronic obstructive pulmonary disease, or other chronic respiratory disease; and/or (8) is 12 - 17 years of age and has a BMI >85% for their age and gender, or sickle cell disease, congenital or acquired heart disease, neurodevel opmental
  • Embodiment 34 The composition of Embodiment 7 or 8 or the composition for use of any one of Embodiments 9, 10, and 14-22, which is formulated for intravenous administration.
  • Embodiment 35 The composition of Embodiment 7 or 8 or the composition for use of any one of Embodiments 9, 10, and 14-22, which is formulated for subcutaneous administration.
  • Bamlanivimab (also known as LY-CoV555 and LY3819253) is a fully human IgGl monoclonal antibody (mAb) that binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein.
  • the heavy chain and light chain variable region (VH and VL) sequences of bamlanivimab were identified from a convalescent patient who recovered from COVID-19, converted to full-length human IgGl isotype (e.g., IgGlm3 allotype), and recombinantly produced.
  • Bamlanivimab binds to SARS-CoV-2 spike protein with high affinity and is a potent neutralizing antibody of SARS-CoV-2.
  • bamlanivimab In a non-human primate model of COVID-19, bamlanivimab was shown to provide protection against both the lower and upper respiratory tract infection with SARS-CoV- 2 (see Jones BE, et al. LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model ofSARS-CoV-2 infection. 2020:2020.09.30.318972.).
  • bamlanivimab neutralizes SARS- CoV-2 with an EC50 value of 0.03 pg/ml and an EC90 value of 0.09 pg/ml bamlanivimab.
  • Bamlanivimab was authorized by the FDA for emergency use for the treatment of mild to moderate COVID-19 in November 2020.
  • Bamlanivimab heavy chain amino acid sequence is shown in SEQ ID NO.: 1 below.
  • the heavy chain variable domain is in bold font and the human IgGl Glm3 constant domain is in normal font.
  • the IgGl hinge region is underlined.
  • the heavy chain CDR (HCDR) sequences are shown using borders.
  • Bamlanivimab light chain amino acid sequence is shown in SEQ ID NO.:2 below.
  • the light chain variable domain is in bold font and the human kappa constant domain is in normal font.
  • the light chain CDR (LCDR) sequences are shown using borders.
  • GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC (SEQ ID NO.: 2)
  • the CDR amino acid sequences of bamlanivimab were determined using a hybrid of Kabat and North definitions ((See Kabat et al., "Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); and North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)).
  • the heavy chain CDR amino acid sequences of bamlanivimab are set forth in SEQ ID NOs.:3-5, respectively
  • the light chain CDR amino acid sequences are set forth in SEQ ID NOs.:6-8, respectively.
  • VIR-7831 is an engineered IgGlK variant of a human monoclonal antibody ("S309") identified from a memory B cell obtained from a recovered SARS CoV patient.
  • S309 binds to immobilized SARS CoV-2 RBD and to the ectodomain trimer of the S glycoprotein with sub-picomolar and picomolar avidities, respectively (see Pinto D et al. "Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody” Nature 583 https://doi.org/10.1038/s41586-020-2349-y (2020)).
  • S309 is cross-reactive to SARS-CoV and SARS-CoV-2, and potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as live SARS-CoV-2.
  • VIR-7831 can block SARS-CoV-2 viral entry into healthy cells and clear infected cells, binds to an epitope that is conserved in SARS-CoV- 1, and has potent effector function.
  • VIR-7831 has potent neutralizing activity against SARS-CoV-2 Alpha, Beta, Gamma, Delta, and Kappa variants, as well as against virus encoding individual Omicron substitutions. See Cathcart et al.
  • VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2", BioRxiv (first posted December 1, 2021); doi.org/10.1101/2021.03.09.434607)
  • VIR-7831 includes a N55Q mutation in CDRH2 (IMGT numbering), and M428L and N434S mutations in the Fc region to improve in vivo half-life (see e.g. Zalevsky J et al. "Enhanced antibody half-life improves in vivo activity.” Nat Biotechnol. 2010 Feb;28(2):157-9. doi: 10.1038/nbt.l601. Epub 2010 Jan 17. PMID: 20081867; PMCID: PMC2855492.
  • VIR-7831 is also referred-to as "S309_N55Q_MLNS" or "S309_N55Q_LS”.
  • VIR-7831 heavy chain amino acid sequence is shown in SEQ ID NO.: 11 below. The heavy chain variable domain is in bold font and the constant domain is in normal font. The heavy chain CDR (HCDR) sequences are shown using borders.
  • VIR-7831 light chain amino acid sequence is shown in SEQ ID NO.: 12 below.
  • the light chain variable domain is in bold font and the human kappa constant domain is in normal font.
  • the light chain CDR (LCDR) sequences are shown using borders.
  • the CDR amino acid sequences of VIR-7831 were determined using IMGT definitions ((See e.g. LeFranc MP et al., “IMGT, the international ImMunoGeneTics database,” Nucleic Acids Res. 27(1): 209-212 (1999)).
  • IMGT the international ImMunoGeneTics database
  • the heavy chain CDR amino acid sequences of VIR-7831 are set forth in SEQ ID NOs.: 13-15, respectively
  • the light chain CDR amino acid sequences are set forth in SEQ ID NOs.: 16-18, respectively.
  • Etesevimab (also known as LY-C0VOI6 and CB6) is a fully human IgGl monoclonal antibody (mAb) that binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein.
  • Etesevimab recognizes an epitope that overlaps with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 receptor binding domain (RBD), thereby interfering with the virus/receptor interactions by both steric hindrance and direct interface-residue competition.
  • ACE2 angiotensin converting enzyme 2
  • VH and VL sequences of etesevimab were identified from a convalescent patient who recovered from COVID- 19, converted to full-length human IgGl isotype. Etesevimab demonstrated potent SARS-CoV-2-specific neutralization activity in vitro against SARS-CoV-2. In addition, etesevimab inhibited SARS-CoV-2 infection in rhesus monkeys at both prophylactic and treatment settings, (see Shi R, et al. A human neutralizing antibody targets the receptor binding site of AH QAAL-2. Nature. 2020. https://doi.org/10.1038/s41586-020- 2381-y).
  • Etesevimab heavy chain amino acid sequence is shown in SEQ ID NO.:21 below.
  • the heavy chain variable domain is in bold font and the human IgGl Glm3 constant chain is in normal font.
  • the IgGl hinge region is underlined.
  • the heavy chain CDR (HCDR) sequences are shown using borders.
  • the CDR amino acid sequences of etesevimab were determined using a hybrid of Kabat and North definitions ((See Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); and North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)).
  • the heavy chain CDR amino acid sequences of etesevimab are set forth in SEQ ID NOs.:23-25, respectively
  • the light chain CDR amino acid sequences of etesevimab are set forth in SEQ ID NOs.:26-28, respectively.
  • VSV vesicular stomatitis virus
  • G protein glycoprotein of VSV, which is responsible for the attachment and entry of VSV, is not expressed. Envelope proteins of other viruses can be expressed in trans instead of the G protein to produce pseudotyped VSV.
  • a luciferase reporter VSV pseudotyped with SARS-CoV-2 spike protein was used to determine neutralization by VIR-7831 in an in vitro neutralization assay. Table 2. Description of Test Article VIR-7831
  • Table 4 Description of Vero E6 Cell Line for Pseudovirus Neutralization
  • Table 5 Description of Pseudovirus and Reagents a All plasmid and virus stocks were produced at Vir Biotechnology, San Francisco, CA
  • Lenti-XTM 293T cells were seeded in 10-cm dishes for 80% next day confluency. The next day, cells were transfected with the plasmid pcDNA-WuhanCoV- S-D19 (encoding the SARS-CoV-2 spike protein) using the transfection reagent TransIT®-Lenti according to the manufacturer’s instructions. One day post-transfection, cells were infected with VSV-luc(VSV-G) at an MOI of 3. The cell supernatant containing SARS-CoV-2 pseudotyped virus was collected at day 2 post-transfection, centrifuged at 1000 x g for 5 minutes to remove cellular debris, aliquoted and frozen at -80°C.
  • the SARS-CoV-2 pseudotyped virus preparation was quantified using VeroE6 cells seeded at 20,000 cells/well in clear bottom black 96 well plates the previous day. Cells were infected with 1 : 10 dilution series of pseudotyped virus in 50 pL DMEM for 1 hour at 37°C. An additional 50 pL of DMEM was added and cells were incubated overnight at 37°C. Luciferase activity was quantified with Bio-GioTM reagent by adding 100 pL of Bio-GioTM (diluted 1 : 1 in PBS), incubated at room temperature for 5 minutes, and relative light units (RLU) were read on an EnSightTM plate reader.
  • Bio-GioTM reagent by adding 100 pL of Bio-GioTM (diluted 1 : 1 in PBS), incubated at room temperature for 5 minutes, and relative light units (RLU) were read on an EnSightTM plate reader.
  • Vero E6 cells were seeded into clear-bottom black walled 96-well plates at 20,000 cells/well in 100 pL medium and cultured overnight at 37°C. Twenty-four hours later, 1 :4 9-point serial dilutions of VIR-7831 were prepared in media, with each dilution tested in duplicate on each plate (range: 10 pg/mL to 0.15 ng/mL final concentration). Pseudovirus was diluted 1 :25 in media and added 1 : 1 to 110 pL of each antibody dilution. Pseudovirus: antibody mixtures were incubated for 1 hour at 37°C. Media was removed from the Vero E6 cells and 50 pL of pseudovirus: antibody mixtures were added to the cells.
  • SARS-CoV-2 pseudotyped virus was used (Figure 1). Dose-dependent viral neutralization was observed, with an average EC50 value of 24.06 ng/mL (range: 20.56 - 28.60 ng/mL) and an average EC90 value of 107.72 ng/mL (range: 83.37 - 144.7 ng/mL).
  • Table 8 Description of VeroE6 Cell Line for Neutralization Assay
  • Table 9 Description of SARS-CoV-2 Stocks a Deposited by the Centers for Disease Control and Prevention and obtained through BEI Resources, NIAID, NIH: SARS-Related Coronavirus 2, Isolate USA- WA1/2020, NR-52281.
  • VeroE6 cells were seeded at 10xl0 6 cells in T175 flasks in growth media and infected the next day at a MOI of 0.001 in virus propagation media. Virus was adsorbed for 1 hour at 37°C. Virus inoculum was removed, flasks were washed once with PBS, 25 mL of infection media was added to the cells and flasks were incubated at 37°C. Supernatants were collected at 72 hours post-infection once cytopathic effect was visible, centrifuged at 500 x g for 5 minutes, followed by a second centrifugation at 1000 x g for 5 minutes.
  • Virus titers were determined using a 1.2% Avicel plaque assay on VeroE6 cells, using standard methods. Briefly, 10-fold dilutions of virus stock were incubated in 6 well plates with 1.2% Avicel overlay for 24 hours. Cells were fixed with 4% PF A for 30 minutes at room temperature (RT), blocked and permeabilized with SuperBlockTM containing 0.125% Triton X-100, stained with anti-SARS-CoV-2 nucleocapsid antibody at 1 :5000 and goat anti-rabbit IgG HRP at 1 :5000. Plaque forming units (PFU) were visualized with TrueBlueTM reagent.
  • PFU Plaque forming units
  • VeroE6 cells were seeded into flat bottom 96-well plates at 20,000 cells/well and cultured overnight at 37°C. Twenty-four hours later, 9-point 1 :4 serial dilutions of VIR-7831 were prepared in PBS and each dilution was tested in quadruplicate per plate (range: 25,600 to 0.390 ng/mL final concentration). SARS-CoV-2 virus stock was diluted in infection media for a final concentration of 200 plaque forming units (PFU) per well. Antibody dilutions were added to the virus and incubated for 30 minutes at 37°C. Media was removed from the VeroE6 cells, mAb-virus complexes were added, and cells were incubated at 37°C overnight.
  • PFU plaque forming units
  • cells were fixed with 250 pL 4% PF A, incubated for 30 minutes at RT, then washed 3 times with PBS to remove residual PF A.
  • the cells were permeabilized with 50 pL of 0.125% Triton X- 100 in PBS for 30 minutes at RT, followed by blocking with 300 pL blocking buffer for 30 minutes at RT.
  • the blocking buffer was removed, 50 pL of SARS-CoV-2 nucleocapsid antibody at 1 :3,000 in blocking buffer was added, and plate was incubated for 1 hour at RT.
  • Plates were washed 3 times with PBS and then incubated for 1 hour at RT with 50 pL/well of goat anti-rabbit-Alexa647 secondary antibody at a final dilution of 1 :3,000 in blocking buffer. After washing 5 times with PBS, 100 pL of fresh PBS was added for imaging. Plates were imaged on a Cytation5 plate reader. Whole well images were acquired (12 images at 4X magnification per well) and nucleocapsid- positive cells were counted using the manufacturer’s software.
  • Bamlanivimab and VIR-7831 both potently neutralize SARS-CoV-2 infection.
  • the three dimensional structures of both bamlanivimab and VIR-7831 bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein have been determined previously, and therefore, it is known that these antibodies possess nonoverlapping epitopes on the RBD.
  • the positive control antibody MAB1 which is known to bind to a different domain on the spike protein, is observed to bind to spike protein captured by surface-coupled bamlanivimab or VIR-7831; and bamlanivimab and VIR-7831 are able to bind to spike protein captured by the control antibody MAB1. Additionally, all three antibodies are observed to compete with themselves for binding (i.e., the antibody was unable to bind to SARS-CoV-2 spike protein that had already been captured by the same antibody when surface-coupled).
  • VIR-7831 was observed to bind SARS-CoV-2 spike protein captured by bamlanivimab, which is expected based on the previously determined epitopes of bamlanivimab (Jones BE, et al., 2020. LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection. 2020:2020.09.30.318972.), and VIR-7831 (Pinto, D. et al., 2020. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583: 290-295).
  • the reference spike protein sequence used was from the strain hCoV- 19/Wuhan/IVDC-HB-01/2019 (EPI ISL 402119).
  • the stabilized form of the SARS- CoV-2 spike protein ectodomain was used for binding studies (Wrapp et al., 2020. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 367(6483): 1260-1263).
  • the protein was produced in mammalian cells by transient transfection (using an expression plasmid provided by the Vaccine Research Center at the National Institutes of Health), and purified by Ni+-based immobilized metal affinity chromatography, followed by size-exclusion chromatography; recombinant protein was obtained either from the Vaccine Research Center at the National Institutes of Health (produced from human embryonic kidney cells), or produced in-house using CHO cells and an in-house chemically defined media.
  • a CARTERRA® LSATM instrument, a fully integrated HT-SPRTM (high- throughput surface plasmon resonance) system (Brown et al., 2020. Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors.
  • PLoS One 15(3): e0229206 was used for binding kinetics measurement of bamlanivimab and VIR-7831 binding to trimeric SARS-CoV-2 spike protein.
  • the assays were performed according to the manufacturer’s provided operational guidelines.
  • the instrument uses a multi-channel buffer of 25 mM 2-(N-morpholino) ethanesulfonic acid (MES) at pH 5.5, and a single-channel buffer consisting of 10 mM 2-[4-(2- hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), 150 nM NaCl, 3 mM EDTA, and 0.05% v/v Surfactant P20 (HBS-EP+).
  • the HC30M chips were used and the array preparation was performed according to the CARTERRA® protocol, including chip activation for 7 minutes in activation buffer (100 pL l-ethyl-3-(3- dimethylaminopropyl) carbodiimide + 100 pL Hydroxy-2, 5-dioxopyrrolidine-3- sulfonicacid sodium salt + 100 pL 25mM MES, pH 5.5), coupling mAbs diluted 10 pg/mL in 10 mM acetate, pH 4.0, for 10 minutes, and deactivation for 7 minutes in 1 M ethanolamine, pH 8.5.
  • activation buffer 100 pL l-ethyl-3-(3- dimethylaminopropyl) carbodiimide + 100 pL Hydroxy-2, 5-dioxopyrrolidine-3- sulfonicacid sodium salt + 100 pL 25mM MES, pH 5.5
  • the antibody-coupled HC30M chip surface was exposed to injections of spike protein (Lot 36056sl), with an association period of 5 minutes and a dissociation period of 15 minutes at 25°C.
  • the tested concentrations of SARS-CoV-2 spike protein were 300 nM, 100 nM, 33.3 nM, 11.1 nM, 3.70 nM, 1.23 nM, 0.41 nM and 0.14 nM in HBS-EP+ containing 0.1 mg/mL BSA. Regeneration of the chip surface between the different concentrations were performed using 20 mM glycine, pH 2.0 for 30 seconds twice.
  • Kinetic data was analyzed using CARTERRA® KITTM software using a 1 : 1 Langmuir binding model.
  • spike protein (Lot 36056s 1 ) was diluted to 20 nM in HBS-EP+ containing 0.1 mg/mL BSA and premixed with antibodies diluted to 200nM in HBS-EP+ containing 0.1 mg/mL BSA. Complex was incubated for a minimum of 3 hours inside the LSA sample compartment set at 20C. Premixed sample was then associated to the antibodies on the chip's surface for 5 minutes and dissociated for 2 minutes at 25C. Regeneration of the chip surface between different injections was achieved using 20 mM glycine, pH 2.0 for 30 seconds twice.
  • a BiacoreTM 8K was used for binding kinetics measurement of antibody pairs co-binding to the same spike protein.
  • the assays were performed according to the manufacturer’s provided operational guidelines.
  • the instrument uses a 10 mM 2-[4-(2- hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), 150 nM NaCl, 3 mM EDTA, and 0.05% v/v Surfactant P20 (HBS-EP+) buffer.
  • CM4 chip was used and the surface preparation was performed according to the Biacore 8K protocol, including chip activation for 7 minutes in activation buffer (1 : 1 mixture of l-ethyl-3-(3- dimethylaminopropyl) carbodiimide and Hydroxy-2, 5-dioxopyrrolidine-3-sulfonicacid sodium salt), coupling antibodies diluted to 3 pg/mL in 10 mM acetate, pH 4.0, for 7 minutes, and deactivation for 7 minutes in 1 M ethanolamine, pH 8.5.
  • activation buffer 1 : 1 mixture of l-ethyl-3-(3- dimethylaminopropyl) carbodiimide and Hydroxy-2, 5-dioxopyrrolidine-3-sulfonicacid sodium salt
  • coupling antibodies diluted to 3 pg/mL in 10 mM acetate, pH 4.0, for 7 minutes and deactivation for 7 minutes in 1 M ethanolamine, pH 8.5.
  • spike protein (Lot# 36056s 1 ) was captured by the antibodies on the surface for 60 seconds at lOuL/min.
  • the chip was exposed to antibody dilutions for an association period of 150 seconds and a dissociation period of 300 seconds.
  • the tested concentrations of antibodies were 300 nM, 75 nM, 18.6 nM, 4.68 nM, 1.17 nM and 0.29 nM in HBS-EP+. Regeneration of the chip surface between the different concentrations were performed using 20 mM glycine, pH 2.0 for 30 seconds twice.
  • Kinetic data was analyzed using Biacore's Insight software using a 1 : 1 Langmuir binding model.
  • VIR-7831 may be utilized in combination with current FDA authorized medications used for the treatment of COVID-19.
  • the objectives of this study are to (1) assess the effects of VIR-7831 when combined with bamlanivimab at different concentration ratios and (2) assess the combined in vitro activity of VIR- 7831 by describing any additive, synergistic, or antagonistic interactions with bamlanivimab.
  • Table 14 Description of Test Article Bamlanivimab Test System Table 15: Description of VeroE6 Cell Line
  • Table 16 Description of Virus Stocks a SARS-CoV-2 Nano Luciferase virus encodes the nano luciferase in place of the viral ORF7.
  • the SARS-CoV-2 sequence was derived from the USA-WA1/2020 isolate.
  • VeroE6 cells were seeded into black-walled clear-bottom 96-well plates at 20,000 cells/well and cultured overnight at 37°C.
  • VIR-7831 original concentration 1.34 mg/ml
  • Bamlanivimab original concentration 1.07 mg/ml
  • Seven-fold 1 :3 serial dilutions of each antibody were then created in complete DMEM.
  • the virus compound mixtures were incubated for 30 minutes at 37°C. Media was removed from the VeroE6 cells, 100 pl of virus: compound mixtures were added, and cells were incubated at 37°C . At 6 hours post-infection, 100 pL (equal volume) Nano-Gio® Reagent was added to each well and incubated for 10 minutes at room temperature. Luminescence was read on a VICTOR® NivoTM plate reader at 1000 millisecond integration time. Three plates were run to obtain triplicates of each individual concentration combination.
  • VIR-7831 and bamlanivimab To assess possible combination effects of VIR-7831 and bamlanivimab, drug combination studies were performed in a checkerboard format.
  • the synergy plot shows no strong effect volumes indicating synergy or antagonism (Figure 4; bamlanivimab is identified as LY- CoV555 in this figure).
  • Total calculated scores for synergy and antagonism indicate that the drug combination effects of VIR-7831 and bamlanivimab are additive (Table 18).
  • VIR-7831 may be utilized in combination with current FDA-authorized medications used for the treatment of COVID-19.
  • Important for successful combination treatment of acute viral disease is a lack of cross-resistance between combined agents.
  • a previous SARS-CoV-2 in vitro resistance selection study identified variants at spike position E340 as mAb-associated resistance mutations (MARMs) conferring reduced susceptibility to VIR-7831.
  • MARMs mAb-associated resistance mutations
  • Pre-clinical selection studies using bamlanivimab identified MARMs at positions E484, F490, Q493 and S494 as conferring reduced susceptibility in vitro, with treatment-emergent E484, F490 and S494 variants observed in clinical trials.
  • the objective of this study is to determine neutralization activity of VIR-7831 and bamlanivimab individually and in combination against pseudotyped virus expressing variants in the SARS-CoV-2 spike protein.
  • Lenti-XTM 293T cells were seeded in 10-cm dishes for 80% next day confluency. The next day, cells were transfected with the plasmid pcDNA3.1(+)-spike- D19 (encoding the SARS-CoV-2 spike protein variants) using the transfection reagent TransIT®-Lenti according to the manufacturer’s instructions. One day posttransfection, cells were infected with VSV-luc (VSV-G) at an MOI of 3. The cell supernatant containing SARS-CoV-2 pseudotyped virus was collected at day 2 post- transfection, centrifuged at 1000 x g for 5 minutes to remove cellular debris, aliquoted and frozen at -80°C.
  • the SARS-CoV-2 pseudotyped virus preparation was quantified using VeroE6 cells seeded at 20,000 cells/well in clear bottom black 96 well plates the previous day. Cells were infected with 1 : 10 dilution series of pseudotyped virus in 50 pL DMEM for 1 hour at 37°C. An additional 50 pL of DMEM was added and cells were incubated overnight at 37°C. Luciferase activity was quantified with Bio-GioTM reagent by adding 100 pL of Bio-GioTM (diluted 1 : 1 in PBS), incubated at room temperature for 5 minutes, and relative light units (RLU) were read on an EnSightTM plate reader.
  • Bio-GioTM reagent by adding 100 pL of Bio-GioTM (diluted 1 : 1 in PBS), incubated at room temperature for 5 minutes, and relative light units (RLU) were read on an EnSightTM plate reader.
  • VIR-7831 Nine-point serial dilutions of VIR-7831 or bamlanivimab were prepared in media, with each dilution tested in triplicate on each plate (VIR-7831 final concentrations: 10 pg/mL to 0.15 ng/mL; bamlanivimab final concentrations: 2pg/ml to 0.03 ng/ml).
  • VIR-7831 final concentrations 10 pg/mL to 0.15 ng/mL
  • bamlanivimab final concentrations 2pg/ml to 0.03 ng/ml.
  • a 1 :5 ratio of bamlanivimab: VIR-7831 was used.
  • Pseudovirus was diluted 1 :8 in media and added 1 : 1 to 110 pL of each antibody dilution.
  • Pseudovirus:antibody mixtures were incubated for 1 hour at 37°C.
  • VIR-7831 and bamlanivimab display cross-resistance amino acid substitutions were introduced into the SARS-CoV-2 spike coding sequence and assessed in a SARS-CoV-2 pseudotyped virus neutralization assay. Consistent with prior data, VIR-7831 neutralized all pseudotype variants tested similarly to wild-type (2.6-fold difference or less in EC50 compared to wild-type) except those with amino acid changes at position E340. Reduced susceptibility was observed for bamlanivimab against pseudotyped virus with variants at positions V483, E484, G485, F490 and S494 but not for E340 variants.
  • VIR-7831 and bamlanivimab were used in combination, all variants were neutralized with EC50 values similar to those observed with wild-type (1.5-fold or less change in EC50). Taken together, these data indicate that VIR-7831 and bamlanivimab are not cross-resistant in vitro against the variants tested.
  • VIR-7831 and bamlanivimab do not display cross-resistance in vitro against the variants tested.
  • VIR-7831 and bamlanivimab in combination neutralized all variants tested similarly to wild-type pseudotyped virus even when one of the agents displayed reduced susceptibility when assessed individually.
  • a clinical study is performed to assess how well bamlanivimab and VIR-7831 work in combination against the virus that causes COVID-19.
  • Bamlanivimab and VIR- 7831 are given to participants with early symptoms of CO VID-19 (z.e., low-risk patients with mild-to-moderate CO VID-19).
  • Samples are taken from the back of the nose to determine how much virus is in the body at various times during the study. Symptom onset date, date of swab, and result of test are recorded.
  • Sample collection for a first CoV-2 test must be performed at least 3 days prior to treatment administration. Participation can last about 12 weeks and includes at least 1 visit to the study site, with the remainder of assessments performed in the home, local clinic, or by phone.
  • Dose of VIR-7831 500mg
  • Placebo Comparator Placebo o Placebo administered IV
  • PK Pharmacokinetics
  • bamlanivimab administered with VIR-7831 demonstrated a statistically significant reduction compared to placebo in important virological secondary endpoints of mean change from baseline to days 3, 5 and 7 in SARS-CoV-2 viral load. Because patients in this trial were at lower risk for progressing to severe COVID-19, there were no events for the secondary endpoint of CO VID-19 related hospitalization or death by day 29. One patient (in the treatment arm) visited the ER for COVID-19 related symptoms.
  • bamlanivimab and VIR-7831 were generally well tolerated with no serious adverse events and had a similar adverse event profile to placebo. These data indicate that the combination of bamlanivimab and VIR-7831 can be effective for treating COVID-19.
  • BAMLANIVIMAB, VIR-7831, AND ETESEVIMAB In a further arm of the clinical study described in Example 7, bamlamvimab, VIR-7831, and etesevimab are used in combination for treating COVID-19.
  • the combination includes single doses of:
  • VIR-7831 at 500 mg
  • bamlanivimab at 700 mg
  • etesevimab at 1400 mg
  • VIR-7831 at 500 mg
  • bamlanivimab at 350 mg
  • etesevimab at 700 mg
  • VIR-7831 at 175 mg
  • bamlanivimab at 175 mg
  • etesevimab at 350 mg
  • the primary outcome measure is percentage of participants who have a viral load greater than 5.27. Additional endpoints include change from baseline to Day 7 in SARS-CoV-2 viral load, percentage of participants who experience COVID-related hospitalization, ER visit or death from baseline through Day 29, as well as safety.

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Abstract

La présente divulgation concerne des combinaisons d'anticorps et des méthodes associées pour traiter une infection par SARS-CoV-2 chez un sujet ou pour fabriquer un médicament pour le traitement d'une infection par SARS-CoV-2. Dans certains aspects, une thérapie, une composition ou une combinaison peuvent comprendre deux ou trois anticorps qui se lient à différents épitopes sur une glycoprotéine de surface (S) de SARS-CoV-2. Les combinaisons d'anticorps peuvent neutraliser puissamment le SARS-CoV-2. L'invention concerne également des compositions d'anticorps comprenant de telles combinaisons.
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