WO2022226539A1 - Méthodes d'administration d'anticorps contre la protéine de spicule du sars-cov-2 - Google Patents

Méthodes d'administration d'anticorps contre la protéine de spicule du sars-cov-2 Download PDF

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Publication number
WO2022226539A1
WO2022226539A1 PCT/US2022/071875 US2022071875W WO2022226539A1 WO 2022226539 A1 WO2022226539 A1 WO 2022226539A1 US 2022071875 W US2022071875 W US 2022071875W WO 2022226539 A1 WO2022226539 A1 WO 2022226539A1
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seq
amino acid
acid sequence
antibody
antigen binding
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PCT/US2022/071875
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English (en)
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Matthew K. Robinson
Pavel Nikitin
Michael John MORIN
Jillian DIMUZIO
Ray HOWANSKI
John P. Dowling
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Immunome, Inc.
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Priority claimed from PCT/US2022/070026 external-priority patent/WO2022150809A1/fr
Application filed by Immunome, Inc. filed Critical Immunome, Inc.
Publication of WO2022226539A1 publication Critical patent/WO2022226539A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1002—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
    • 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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2 genomic RNA contains a large viral replicase gene, genes encoding non-structural proteins at its 5’ end, and a region encoding four major structural and multiple accessory proteins at the 3’ end.
  • Structural proteins include Spike or Surface glycoprotein (S), Membrane protein (M), Envelope protein (E) and Nucleocapsid protein (N) [Fehr & Perlman 2015].
  • the membrane surface glycoprotein S consists of two subunits, S1 and S2, that mediate viral binding to the host receptor ACE2 and fusion with the host cell membrane, respectively.
  • the S1 subunit contains the receptor binding domain (RBD) that directly interacts with ACE2 and is a target of multiple neutralizing antibodies currently in clinical trials [Lan et al. 2020, Robbiani et al. 2020].
  • RBD receptor binding domain
  • the vast majority of the ongoing efforts are all targeting the S protein.
  • Both passive (therapeutic antibodies) and active (vaccine) approaches directed at S protein are expected to promote virus neutralization, that is, inhibition of viral entry into healthy cells.
  • Variants of Interests which are defined as having specific genetic markers that are predicted to affect transmission, diagnostics, therapeutics, or immune escape. Data also demonstrates these variants of interest were the cause of an increased proportion of cases or outbreak, but they are of limited prevalence in the US or other countries (https://www.cdc.gov/coronavirus/2019-ncov/cases- updates/variant-surveillance/variant-info.html#Concern). [0007] Studies are described herein that elucidate the memory B cell antibody response in convalescent patients, using an approach that enables the generation of large, stable hybridoma libraries from primary human B cells.
  • Hybridoma libraries were generated from the memory B cells of convalescent COVID-19 blood donors who were eligible to donate convalescent plasma based upon their high titer of IgG antibodies against the SARS-CoV-2 virus. Monoclonal antibodies derived from those libraries were selected on the basis of their selective binding to one of multiple SARS-CoV-2 proteins used as targets in both cell-based and soluble protein-based screens. Characterization of these antibodies revealed broad responses to diverse viral antigens. Fewer than half of the antibodies were directed at S protein, while the remainder were directed at other viral proteins including N and ORF-encoded proteins.
  • anti-Spike antibodies were directed at highly diverse SARS-CoV-2 antigens, they were generally characterized as having variable levels of somatic hypermutation (SHM) and a diversity of VH and VL gene usage.
  • Functional properties of anti-Spike antibodies were successfully confirmed against reference strains (e.g., USA/WA_CDC-WA1/2020), as well as multiple variants including the CDC variants of concern, in series of tests ranging from in vitro neutralization of both pseudovirus and live virus isolates to in vivo neutralization activity in a hamster model of COVID-19.
  • Three anti-Spike antibodies were identified that when mixed together in a cocktail exhibited combinatorial effects against those variants.
  • kits for treating a SARS-CoV-2 infection in an immunocmpromised subject comprising administering to the subject at least first and send antibodies or antigen binding fragmetns thereof that specifically bind to distinct epitopes of a Spike protein a Spike protein of SARS-CoV-2, wherein the first antibody or antigen binding fragment thereof binds to an epitope in an ACE2 receptor binding site of the Spike protein and the second antibody or antigen binding fragment thereof binds to an epitope outside of the ACE2 receptor binding site of the Spike protein.
  • the antibodies disclosed herein are especially effective for treating immunocompromised individuals due to synergistic effects and their ability to fix complement.
  • the antibodies are able to effectively fix complement due to their specific binding sites on the Spike protein and orientation of binding.
  • the methods provided herein are effective for viral clearance in immunocompromised patients.
  • the methods provided herein are effective for treatment of individual who have decreased adaptive immune system function.
  • Also provided herein are methods of treating a SARS-CoV-2 infection in a subject comprising administering about 200 mg, about 400 mg, about 600 mg, or about 800 mg of one, two, three, or four antibodies or antigen binding fragments provided herein.
  • FIG. 1 depicts the breadth of antibodies isolated against a range of SARS-CoV-2 viral proteins.
  • FIG. 1 depicts the breadth of antibodies isolated against a range of SARS-CoV-2 viral proteins.
  • FIGS. 3A-3D depict in vitro pseudovirus neutralization activity of PR193_00018 (IMM20184), PR194_00232 (IMM20190), PR200_00622 (IMM20253), and PR190_00255 (IMM20279) against pseudoviruses expressing four different variations of Spike.
  • FIGS. 3A-3D depict in vitro pseudovirus neutralization activity of PR193_00018 (IMM20184), PR194_00232 (IMM20190), PR200_00622 (IMM20253), and PR190_00255 (IMM20279) against pseudoviruses expressing four different variations of Spike.
  • FIGS. 5A-5C depict in vitro neutralization activity of identified anti-Spike antibodies, as noted, against pseudovirus expressing the Spike protein from either the U.K.
  • FIGS. 6A-6C depict the concentration-dependent ability of the triple antibody cocktail (IMM20184/IMM20190/IMM20253) and the two antibody cocktail (IMM20184/IMM20253) to neutralize pseudoviruses expressing the reference (WA1/2020), alpha/UK, beta/S. African, gamma/Brazilian, or Epsilon/Californian Spike proteins.
  • FIGS. 7A-7C depict the combinatorial activity of the IMM20184 / IMM20190 / IMM20253 triple combination against pseudoviruses expressing the Spike protein from the reference strain (WA_CDC-WA1/2020), U.K.
  • FIG. 8 depicts the crystal structure of the SARS-CoV-2 RBD (RCSB PDB: 7A97) represented in cartoon with the epitopes of IMM20184, IMM20190, and IMM20253 depicted in black spheres.
  • FIG. 10 depicts in vitro neutralization activity triple antibody cocktail (IMM20184 / IMM20190 / IMM20253) against pseudovirus expressing either the WA1/2020 (REF), B1.617(L452R, E484Q), B.1.617.2 (delta), or lambda (C.37) Spike proteins.
  • FIG. 10 depicts in vitro neutralization activity triple antibody cocktail (IMM20184 / IMM20190 / IMM20253) against pseudovirus expressing the Spike protein from the reference strain (WA_CDC-WA1/2020), D614G, B.1.1.7 (alpha/U.K.), B.1.351 (beta/S.
  • FIGS. 11A-11D depict in vitro neutralization activity of the triple (IMM20184 / IMM20190 / IMM20253) and double (IMM20184 / IMM20253) combinations of antibodies against three live virus strains as measured by plaque forming assays; the reference strain (WA_CDC-WA1/2020)(FIG. 11A), U.K.
  • FIG. 12 depicts lung titer per gram tissue, as measured by plaque forming units, as an assessment of in vivo activity of the identified anti-Spike antibody PR194_00232, alone and in combination with either PR193_00018 or PR200_00622, against the live virus isolate SAR-CoV-2/human/USA/WA_CDC-WA1/2020, when dosed in the prophylactic setting.
  • FIG. 12 depicts lung titer per gram tissue, as measured by plaque forming units, as an assessment of in vivo activity of the identified anti-Spike antibody PR194_00232, alone and in combination with either PR193_00018 or PR200_00622, against the live virus isolate SAR-CoV-2/human/USA/WA_CDC-WA1/2020, when dosed in the prophylactic setting.
  • FIG. 13 depicts lung titer per gram tissue, as measured by plaque forming units, as an assessment of in vivo activity of various combinations of anti-Spike antibodies, dosed in a therapeutic setting, in the hamster model of COVID-19. Error bars represent the median +/- 95% CI.
  • FIG. 14 depicts lung titer per gram tissue, measured by TCID50 assays, as an assessment of in vivo activity of the triple combination ofIMM20184/IMM20190/IMM20253, at two different ratios, dosed in a therapeutic setting, in hamster model of COVID-19. Error bars represent the median +/- interquartile range.
  • FIG. 14 depicts lung titer per gram tissue, measured by TCID50 assays, as an assessment of in vivo activity of the triple combination ofIMM20184/IMM20190/IMM20253, at two different ratios, dosed in a therapeutic setting, in hamster model of COVID-19
  • FIGS. 16A-16B depict lung titer per gram of tissue, as measured by plaque forming units. Hamsters infected with either the (FIG. 16A) WA1/2020 or (FIG. 16B) Beta isolate were treated in prophylactic setting with
  • FIGS. 18A-18C depict the ability of IMM20184, IMM20190, and IMM20253 to bind to the isolated RBD and intact trimer of SARS-CoV-2 reference strain (WA1/2020) as measured by surface plasmon resonance.
  • FIGS. 18A-18C depict the ability of IMM20184, IMM20190, and IMM20253 to bind to the isolated RBD and intact trimer of SARS-CoV-2 reference strain (WA1/2020) as measured by surface plasmon resonance.
  • FIGS. 20A-20C depict in vitro complement fixation activity of PR193_00018 (IMM20184), PR194_00190 (IMM20190), PR200_00253 (IMM20253), the two antibody cocktail of IMM20184/IMM20253, and the triple antibody cocktail (IMM20184/IMM20190/IMM20253) relative to control antibodies when assessed at defined (FIG. 20A-20B) concentrations and in a concentration-dependent (FIG. 20C) manners.
  • FIG. 21 depicts in vitro phagocytosis activity of IMM20184, IMM20190, IMM20253, the IMM20184/IMM20253 two -antibody cocktail, and IMM-BCP-01 (three antibody cocktail) relative to isotype control antibodies when assessed across a range of concentrations.
  • FIG. 22 depicts antibody-dependent cellular cytotoxicity activity of IMM20184, IMM20190, IMM20253, the two antibody cocktail of IMM20184/IMM20253, and the triple antibody cocktail (IMM20184/IMM20190/IMM20253; IMM-BCP-01) relative to isotype control antibodies when assessed in a concentration-dependent manner.
  • FIG. 23A-23B depict time-dependent conformational change in Spike protein, as measured by dynamic light scattering, upon binding of IMM20253 or IMM20190.
  • FIG. 24 depicts time-dependent protease digestion of Spike and Spike in complex with ACE2, IMM20253, or IMM20190.
  • FIGS. 25A-25C depict the combinatorial neutralization activity of IMM20253 in combination with IMM20184, REGN987, or REGN933 against pseudoviruses expressing the Spike protein from the Delta Plus (B.1.617.2 ay1/2) variant. Dark grey area represent regions of synergy. Bottom portion of the figure lists the overall HSA scores for each combination.
  • FIG. 25A-25C depict the combinatorial neutralization activity of IMM20253 in combination with IMM20184, REGN987, or REGN933 against pseudoviruses expressing the Spike protein from the Delta Plus (B.1.617.2 ay1/2) variant. Dark grey area represent regions of synergy. Bottom portion of the figure
  • FIGS. 27A-27D depict the in vitro binding activity of individual antibodies (FIG. 27A) IMM20184, (FIG. 27B) IMM20190, (FIG. 27C) IMM20253, and (FIG. 27D) IMM20279 to the SARS-CoV-2 Spike-RBD Omicron variant relative to the reference strain.
  • FIG. 27A depicts the in vitro binding activity of individual antibodies (FIG. 27A) IMM20184, (FIG. 27B) IMM20190, (FIG. 27C) IMM20253, and (FIG. 27D) IMM20279 to the SARS-CoV-2 Spike-RBD Omicron variant relative to the reference strain.
  • FIG. 28 depicts the in vitro neutralization activity of the IMM20253 antibody against pseudovirus expressing the Spike protein from the reference strain (SARS-CoV- 2/human/USA/WA CDC-WA1/2020), DG14G (SARS-CoV-2/human/Germany/BavPat 1/2020), B.1.351 (beta/S. African), B.1.617.2 Ay.2 (Delta Plus) and B.1.1.529 (Omicron) variants of SARS-CoV-2. [0039] FIG.
  • FIGS. 30A-30B depict the 3 Fab fragments of IMM20190 bound to an intact spike trimer corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC- WA1/2020) of SARS-CoV-2 solved by cryoEM and visualized using PyMOL.
  • SARS-CoV-2 trimer is depicted in light grey cartoon.
  • IMM20190 Fab fragments are depicted in black cartoon.
  • FIG. 30A is the side view and FIG. 30B is the top view.
  • FIGS. 31A-31B depict the 3 Fab fragments of IMM20184 bound to an intact spike trimer corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC- WA1/2020) of SARS-CoV-2 solved by cryoEM and visualized using PyMOL.
  • SARS-CoV-2 trimer is depicted in light grey cartoon.
  • IMM20184 Fab fragments are depicted in black cartoon.
  • FIG. 31A is the side view and FIG. 31B is the top view.
  • FIG. 32A-32B depict a single Fab fragment of IMM20253 bound to an intact spike trimer corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC- WA1/2020) of SARS-CoV-2 solved by cryoEM and visualized using PyMOL.
  • SARS-CoV-2 trimer is depicted in light grey cartoon.
  • IMM20253 Fab fragments are depicted in black cartoon.
  • FIG. 32A is the side view and FIG. 32B is the top view. [0043] FIG.
  • FIG. 33 depicts a 3.9 Angstrom structure of the variable domains of IMM20184 and IMM20253 bound to an isolated receptor binding domain (RBD) corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC-WA1/2020) of SARS-CoV-2 solved by cryoEM and visualized using PyMOL.
  • RBD receptor binding domain
  • SARS-CoV-2 trimer is depicted in light grey cartoon.
  • IMM20184 variable domains are depicted in black cartoon.
  • IMM20253 variable domains are depicted in dark grey cartoon.
  • RBD residues predicted to be within 4 Angstroms of IMM20184 are visualized in black spheres.
  • RBD residues predicted to be within 4 Angstroms of IMM20253 are depicted in dark grey spheres.
  • FIGS. 35A-35B depict an isolated receptor binding domain (RBD) corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC-WA1/2020) of SARS-CoV-2 with (FIG. 34A) predicted IMM20184 contact residues depicted in black spheres and (FIG. 34B) predicted IMM20253 contact residues depicted in dark grey spheres.
  • FIGS. 35A-35B depict the 3 Fab fragments of IMM20279 bound to an intact spike trimer corresponding to the reference strain (SARS-CoV-2/human/USA/WA CDC- WA1/2020) of SARS-CoV-2 solved by cryoEM and visualized using PyMOL. SARS-CoV-2 trimer is depicted in light grey cartoon.
  • FIG. 35A depicts lung titers of hamsters dosed prophylactically with IMM20253, IMM20253/IMM20184 or IMM20253/IMM20279 one day prior to inoculation with Omicron BA.1.
  • FIG. 36 depicts lung titers of hamsters dosed prophylactically with IMM20253, IMM20253/IMM20184 or IMM20253/IMM20279 one day prior to inoculation with Omicron BA.1.
  • Methods of treating the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) virus are described herein.
  • the methods comprise treating an immunocompromised subject.
  • the subject has a high risk for contracting SARS-CoV2.
  • the subject has a suppressed immune system.
  • the individual is being treated with an immunosuppressive agent.
  • These antibodies may be used to neutralize SARS-CoV-2 by preventing the virus from infecting new host cells. Therefore, the inventions disclosed here also relate to pharmaceutical compositions that contain one or more antibodies of the invention, as well as relate to methods of preventing or treating a SARS-CoV-2 infection in a subject in need thereof. Accordingly, the inventions disclosed herein also relate to methods of administering antibody compositions of the invention to a subject in need thereof. [0048] In some embodiments, the antibodies, compositions, and kits provided herein are especially effective for treating and/or preventing SARS-CoV-2 due to particular novel properties.
  • antibodies that bind to the Spike protein at multiple different locations are provided herein. This is beneficial because SARS-CoV-2 variants may have one or more mutations in the Spike protein to evade the immune system. Thus providing multiple antibodies that bind to multiple different locations in the Spike protein allows binding and neutralization of such variants. [0049] Moreover, some of the antibodies provided herein bind to an ACE2 binding site in the Spike protein, while others bind outside the ACE2 binding site. Without being bound by theory, providing multiple antibodies, some of which target the ACE2 binding site and some of which target regions outside of the ACE2 binding site may combine to provide more effective treatment for SARS-CoV-2.
  • a method of treating or preventing SARS-CoV-2 comprising administering multiple antibodies that bind to non- overlapping epitopes on the Spike protein.
  • the method comprises administering an antibody that binds to an ACE2 binding site of the Spike protein and an antibody that binds to an epitope outside of the ACE2 binding site of the Spike protein.
  • the method comprises administering an antibody that neutralizes SARS- CoV-2 through an ACE2-dependent mechanism and an antibody that neutralizes SARS-CoV- 2 through an ACE2-independent mechanism.
  • dose refers to the amount of a single agent (such as an antibody).
  • total dose is used to refer to a total amount of multiple agents that are delivered as a combination therapy (for example, an antibody cocktail).
  • an antibody cocktail comprising three antibodies each delivered at a dose of 200 mg is considered to be administered at a total dose of 600 mg.
  • the multiple agents in such a combination therapy can be administered in the same or different compositions and simultaneously or sequentially.
  • the method comprises administering one antibody provided herein. In some embodiments, the method comprises administering two or more antibodies provided herein. In some embodiments, the method comprises administering three or more, or four or more antibodies provided herein. In some embodiments, the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the methods provided herein comprise treating an immunocompromised subject with one or more antibodies provided herein (such as two, three, or four antibodies).
  • the antibodies provided herein are especially advantageous for treatment of immunocompromised individuals because they facilitate viral clearance from the subject.
  • the antibodies are able to engage in complement fixation.
  • the antibodies provided herein bind to a Spike protein in an orientation that allows for complement fixation.
  • the antibodies bind to a Spike protein in an orientation that provides synergy between the Fc and the antigen binding domain.
  • the antibodies effectively neutralize SARS-CoV-2.
  • the subject is administered one, two, three, or four antibodies provided herein to treat a SARS-CoV-2 infection.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • the immunocompromised subject has an impaired immune system.
  • the immunocompromised subject has decreased resistance to an infection, such as SARS-CoV-2 infection.
  • the subject has one or more markers of low immune function.
  • the number or activity of T, B, and/or NK cells in the subject is below normal.
  • one or more functional markers of immune function is altered in the immunocompromised subject.
  • the subject is administered one, two, three, or four antibodies or antigen binding fragments thereof provided herein to treat a SARS-CoV-2 infection.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • the subject has an immunodeficiency disease.
  • the immunodeficiency disease is a primary immunodeficiency disease.
  • the immunodeficiency results in decreased antibody production and/or decrease of amount or activity of one or more types of immune cells.
  • the immunodeficiency disease is an acquired immunodeficiency condition.
  • the acquired immunodeficiency condition is caused by another disease or a treatment of another disease.
  • the subject has received a solid organ transplant and being treated with one or more immunosuppressants.
  • the subject has received a bone marrow transplant.
  • the subject is a cancer patient undergoing active chemotherapy.
  • the subject is undergoing treatment with an EGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a BRAF inhibitor, a RET inhibitor, a MET inhibitor, a NTRK inhibitor, a BTK inhibitor, a PI3K inhibitor, or a BCL-2 inhibitor and or radiation therapy.
  • the subject is on dialysis.
  • th e subject has end stage renal disease and is on dialysis.
  • the individual has multiple sclerosis and is receiving anti-CD20 therapy.
  • the subject has an inflammatory disease.
  • the subject has an inflammatory disease and is being treated with a maintenance therapy.
  • the subject has an inflammatory disease and is being treated with an immunosuppressant maintenance therapy.
  • the inflammatory disease is arthritis, psoriasis, or Crohn’s disease.
  • the subject has rheumatoid arthritis.
  • the inflammatory disease is an auto inflammatory disease.
  • the inflammatory disease is selected from the group consisting of ankylosing spondylitis arthritis, osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, ulcerative colitis, Cryopyrin-Associated Periodic Syndromes (CAPS) including Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome, Systemic Juvenile Idiopathic Arthritis, giant cell arteritis, Paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (a-HUS), vasculitis.
  • ankylosing spondylitis arthritis rheumatoid arthritis (RA), psoriatic arthritis, asthma, athe
  • the subject is receiving steroids, sulfasalazine, methotrexate, mycophenolate mofetil (IMPDH inhibitor), azathioprine, Anti-IL-1 biologics (anakinra (Kineret®), canakinumab (Ilaris®), rilonacept (Arcalyst®), a TNF ⁇ inhibitors [ Infliximab (Remicade®), Adalimumab (Humira®), Golimumab (Simponi®), Etanercept (Enbrel®), Certolizumab (Cimzia®)], Anti-IL-6 Biologics: Tocilizumab (Actemra®), Sarilumab (Kevzara®); Complement inhibitors: Eculizumab, Anti-CD20 Biologics: Rituximab (Rituxan), BLyS inhibitor (Belimumab (Benlysta®)), Calcineurin inhibitor (cyclospor
  • the antibodies or antigen binding fragments thereof that bind to a Spike protein comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is administered one, two, three, or four antibodies or antigen binding fragments thereof provided herein to treat a SARS-CoV-2 infection.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • provided herein are methods of treating a subject who is at high risk for contracting SARS-CoV-2 comprising administering one, two, three, or four antibodies or antigen binding fragments thereof provided herein to the subject.
  • the subject has a high risk for contracting severe SARS-CoV-2.
  • the subject is immunocompromised.
  • the subject has one or more risk factors for contracting SARS-CoV-2.
  • the subject has one or more risk factors such as, old age, serious heart or lung conditions, weakened immune system, obesity, or diabetes.
  • the individual is obese.
  • the individual is pregnant.
  • the subject has a high risk for contracting other serious respiratory illnesses, such as the flu.
  • the individual is age 65 or older.
  • the individual has COPD, lung cancer, cystic fibrosis, pulmonary fibrosis, asthma, pulmonary hypertension, pulmonary embolism, cardiomyopathy, congenital heart disease, heart failure, coronary artery disease, Type 1 diabetes, Type 2 diabetes, a high body mass index, HIV/AIDS, chronic kidney or liver diseases, sickle cell or anemia.
  • the subject has chronic kidney disease, hypertension, severe neurodevelopment disorders, dementia, Alzheimers disease, multiple co- morbidities, and/or is a nursing home resident.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • provided herein is a method of treating a SARS-CoV-2 infection in a subject that has cancer comprising administering one, two, three, or four antibodies or antigen binding fragments thereof provided herein to the subject.
  • the subject is being treated with more chemotherapeutic agents.
  • the subject has recently received treatment with one or more chemotherapeutic agents. In some embodiments, the subject is receiving or has recently received radiation therapy.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1. In some embodiments, the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • provided herein is a method of treating a SARS-CoV-2 infection in a subject that has received a solid organ transplant comprising administering one, two, three, or four antibodies or antigen binding fragments thereof provided herein to the subject.
  • the subject is on one or more immunosuppressive drugs.
  • the subject has recently received one or more immunosuppressive drugs.
  • the subject is receiving or has recently received an antirejection drug.
  • the subject has received a calcineurin inhibitor, an antiproliferative agent, a mTOR inhibitor, and/or a steroid.
  • the subject is receiving or has recently received corticosteroid treatment.
  • the subject is being treated or has recently received treatment with an IMPDH inhibitor.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • provided herein is a method of treating a SARS-CoV-2 infection in a subject comprising administering one, two, three, or four antibodies or antigen binding fragments thereof provided herein to the subject, wherein the antibodies or antigen binding fragments thereof neutralize the SARS-CoV-2 virus.
  • the antibodies block viral infection of human cells.
  • the antibodies are able to clear SARS-CoV2 viral particles.
  • viral clearance is observed within 28 days, or within 12 weeks of administering the antibodies.
  • viral load is decreased upon administration of the antibodies or antigen binding fragments thereof.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • Also provided herein are method of treating subjects with moderate or mild SARS- CoV-2 infections comprising administering one, two, three, or four antibodies or antigen binding fragments thereof provided herein to the subject.
  • the subject does not have severe COVID-19, is not at increased risk of severe COVID-19, and does not have an active infection.
  • the subject does not have cancer (basal cell carcinoma and prostate carcinoma in situ [Gleason ⁇ 6] are acceptable), chronic kidney disease, chronic obstructive pulmonary disease, heart condition (congestive heart failure II, III and IV as per New York Heart Association: coronary disease and any other cardiac condition that imposes high risk of developing severe COVID-19), immunocompromised state from solid organ transplant, sickle cell disease, or other condition, autoimmune disease, use of immunosuppressants (including high doses of systemic corticosteroids), type 1 or type 2 diabetes mellitus, current or prior history of smoking or vaping any product, including nicotine or THC.
  • cancer basic cell carcinoma and prostate carcinoma in situ [Gleason ⁇ 6] are acceptable
  • chronic kidney disease chronic obstructive pulmonary disease
  • heart condition congestive heart failure II, III and IV as per New York Heart Association: coronary disease and any other cardiac
  • the individual has not received a previous therapy to treat SARS-CoV-2.
  • the antibodies comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the one, two, three, or four antibodies or antigen binding fragments thereof are administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg each.
  • the method comprises administering a single dose of the antibody or antigen binding fragment thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 200 mg of an antibody or antigen binding fragment thereof provided herein that binds to a SARS-CoV-2 Spike protein.
  • the antibody or antigen binding fragment thereof comprises CDR sequence of an antibody disclosed in Table 1.
  • the antibody or antigen binding fragment thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibody or antigen binding fragment thereof.
  • a SARS-CoV-2 infection in a subject comprising administering to the subject about 400 of an antibody or antigen binding fragment thereof provided herein that binds to a SARS-CoV-2 Spike protein.
  • the antibody or antigen binding fragment thereof comprises CDR sequence of an antibody disclosed in Table 1.
  • the antibody or antigen binding fragment thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibody or antigen binding fragment thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 600 mg of an antibody or antigen binding fragment thereof provided herein that binds to a SARS-CoV-2 Spike protein.
  • the antibody or antigen binding fragment thereof comprises CDR sequence of an antibody disclosed in Table 1.
  • the antibody or antigen binding fragment thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibody or antigen binding fragment thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 800 mg of an antibody or antigen binding fragment thereof provided herein that binds to a SARS-CoV-2 Spike protein.
  • the antibody or antigen binding fragment thereof comprises CDR sequence of an antibody disclosed in Table 1. In some embodiments, the antibody or antigen binding fragment thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1In some aspects, the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the method comprises administering a single dose of the antibody or antigen binding fragment thereof.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 200 mg of two antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 400 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 400 mg of two antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein. In some embodiments, a total dose of 800 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject. In some embodiments, the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 600 mg of two antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 1200 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 800 mg of two antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 1600 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the method comprises administering a single dose of the antibodies or antigen binding fragments thereof. [0071] In some aspects, provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 200 mg of three antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein. In some embodiments, a total dose of 600 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject. In some embodiments, the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 400 mg of three antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 1200 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 600 of three antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 1800 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 800 mg of three antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein. In some embodiments, a total dose of 2400 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject. In some embodiments, the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 200 mg of four antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 800 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 400 mg of four antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 1600 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the method comprises administering a single dose of the antibodies or antigen binding fragments thereof. [0077] In some aspects, provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 600 of four antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein. In some embodiments, a total dose of 2400 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject. In some embodiments, the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • provided herein are method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject about 800 mg of four antibodies or antigen binding fragments thereof provided herein that bind to a SARS-CoV-2 Spike protein.
  • a total dose of 3200 mg of anti-Spike antibodies or antigen binding fragments thereof is administered to the subject.
  • the antibodies or antigen binding fragments thereof comprise CDR sequence of antibodies disclosed in Table 1.
  • the antibodies or antigen binding fragments thereof comprises the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • the first, second, and third antibodies are administered at a ratio of about 1:1:1.
  • the antibodies or antigen binding fragments thereof are administered in a flat dose fashion.
  • the first second, and third antibodies are administered at a total dose of about 600 mg to about 2400 mg.
  • the antibodies are delivered at a total dose of about 600 mg.
  • the antibodies are delivered at a dose about 200 mg each (e.g.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject at least first, second, and third antibodies or antigen binding active fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the antibodies or antigen binding fragments thereof are administered at a total dose of about 1200 mg.
  • the antibodies are administered at a dose of about 400 mg each (e.g. 1200 mg total).
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, and IMM 20190 as set forth in Table 1.
  • the subject is immunocompromised.
  • the method comprises administering a single dose of the antibodies or antigen binding fragments thereof.
  • the administration is intravenous administration.
  • Provided herein are methods of treating a SARS-CoV-2 infection in a subject, comprising administering to the subject at least first, second, and third antibodies or antigen binding active fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the antibodies or antigen binding fragments thereof are administered at a total dose of about 1800 mg.
  • the antibodies are administered at a dose of about 600 mg each (e.g. 1800 mg total).
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, and IMM 20190 as set forth in Table 1.
  • the subject is immunocompromised.
  • kits for treating a SARS-CoV-2 infection in a subject comprising administering to the subject at least first, second, and third antibodies or antigen binding active fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the antibodies or antigen binding fragments thereof are administered at a total dose of about 2400 mg.
  • the antibodies are administered at a dose of about 800 mg each (e.g. 2400 mg total).
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, and IMM 20190 as set forth in Table 1.
  • the subject is immunocompromised.
  • methods of treating a SARS-CoV-2 infection in a subject comprising administering to the subject at least first, second, and third antibodies or antigen binding fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the antibodies or antigen binding fragments thereof are administered at a total dose of about 3 mg/kg to about 6 mg/kg each. In some embodiments, the antibodies or antigen binding fragments thereof are administered at a total dose of about 3 mg/kg each.
  • the antibodies or antigen binding fragments thereof are administered at a total dose of about 6 mg/kg each.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, IMM 20190 and/or IMM20279 set forth in Table 1.
  • the antibodies or antigen binding fragments thereof comprise the CDR sequences of IMM20184, IMM20253, and IMM 20190 as set forth in Table 1.
  • the subject is immunocompromised.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 comprising the amino acid sequence of SEQ ID NO:62, and a HCDR3 comprising the amino acid
  • the first, second, and third antibodies are administered at a dose of about 200 mg each.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 compris
  • the first, second, and third antibodies or antigen binding fragments thereof are administered at a dose of about 400 mg each.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61,
  • the first, second, and third antibodies or antigen binding fragments thereof are delivered at a dose of about 600 mg each.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61,
  • the first, second, and third antibodies or antigen binding fragments thereof are delivered at a dose of about 800 mg each.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55); a HCDR2 comprising the amino acid sequence TIREDGSEKYYVD (SEQ ID NO: 56); and a HCDR3 comprising the amino acid sequence ARSKWLRGSFDY (SEQ ID NO: 57); wherein the antibody comprises a LCDR1 comprising the amino acid sequence TRRSGSIASNYVQ (SEQ ID NO: 58); a LCDR2 comprising the amino acid sequence YEDNQRPS (SEQ ID NO: 59); and a LCDR3
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. [0089] In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184 as a monotherapy. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184 as a combination therapy.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184 in combination with one or more additional antibodies provided herein.
  • the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184 is administered simultaneously with one or more additional antibodies provided herein.
  • the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20184 is administered sequentially with one or more additional antibodies provided herein.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTVSSNYMS (SEQ ID NO: 61); a HCDR2 comprising the amino acid sequence VIYAGGSTF (SEQ ID NO: 62); and a HCDR3 comprising the amino acid sequence ARDRGGYLDY (SEQ ID NO: 63); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQGISNYLA (SEQ ID NO: 64); a LCDR2 comprising the amino acid sequence YAASTLQS (SEQ ID NO: 65); and a LCD
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. [0091] In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190 as a monotherapy.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190 as a combination therapy. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190 in combination with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190 is administered simultaneously with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20190 is administered sequentially with one or more additional antibodies provided herein.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence TASGFTFSTYGMH (SEQ ID NO: 67); a HCDR2 comprising the amino acid sequence VISYDGSSKH (SEQ ID NO: 68); and a HCDR3 comprising the amino acid sequence ARDGQPPGWGNYFDY (SEQ ID NO: 69); wherein the antibody comprises a LCDR1 comprising the amino acid sequence GGNGIGSKSVY (SEQ ID NO: 70); a LCDR2 comprising the amino acid sequence YDDSDRPS (SEQ ID NO: 71); and a LCDR3 comprising the amino acid sequence QVWDSSSDPWV (SEQ ID NO: 72).
  • VH variable heavy chain
  • VL variable light chain
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the individual is immunocompromised.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing an infection with an Omicron variant of SARS-CoV-2 in a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence TASGFTFSTYGMH (SEQ ID NO: 67); a HCDR2 comprising the amino acid sequence VISYDGSSKH (SEQ ID NO: 68); and a HCDR3 comprising the amino acid sequence ARDGQPPGWGNYFDY (SEQ ID NO: 69); wherein the antibody comprises a LCDR1 comprising the amino acid sequence GGNGIGSKSVY (SEQ ID NO: 70); a LCDR2 comprising the amino acid sequence YDDSDRPS (SEQ ID NO: 71); and a LCDR3 comprising the amino acid sequence QVWDSSSDPWV (SEQ ID NO: 72
  • the method further comprises administering a second antibody.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253 as a monotherapy.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253 as a combination therapy. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253 in combination with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253 is administered simultaneously with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20253 is administered sequentially with one or more additional antibodies provided herein.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the individual is immunocompromised.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTYGMH (SEQ ID NO: 109); a HCDR2 comprising the amino acid sequence VIWYNGINKH (SEQ ID NO: 110); and a HCDR3 comprising the amino acid sequence ARDWGTLTTLFDF (SEQ ID NO: 111); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQSISSHLN (SEQ ID NO: 112); a LCDR2 comprising the amino acid sequence YGASSLQS (SEQ ID NO: 113); and a LCDR3 comprising the amino acid sequence QQSYSTPPWT (SEQ ID NO: 114).
  • VH variable heavy chain
  • VL variable light chain
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing an infection with an Omicron variant of SARS-CoV-2 a subject comprising administering an antibody that binds to a Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTYGMH (SEQ ID NO: 109); a HCDR2 comprising the amino acid sequence VIWYNGINKH (SEQ ID NO: 110); and a HCDR3 comprising the amino acid sequence ARDWGTLTTLFDF (SEQ ID NO: 111); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQSISSHLN (SEQ ID NO: 112); a LCDR2 comprising the amino acid sequence YGASSLQS (SEQ ID NO: 113); and a LCDR3 comprising the amino acid sequence QQSYSTPPWT (SEQ ID NO: 114).
  • VH variable heavy chain
  • VL variable light chain
  • the method further comprises administering a second antibody.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279 as a monotherapy.
  • the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279 as a combination therapy. In some embodiments, the method comprises administering an antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279 in combination with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279 is administered simultaneously with one or more additional antibodies provided herein. In some embodiments, the antibody comprising one or more CDR sequences and/or VH and VL sequences of IMM20279 is administered sequentially with one or more additional antibodies provided herein. In some embodiments, the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of two antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the amino acid sequence of VISYDGSSKH (SEQ ID NO: 68), and a HCDR3 comprising the amino acid sequence of ARDGQPPGWGNYFDY (SEQ ID NO: 69); and a VL comprising a LCDR1 comprising the amino acid sequence of GGNGIGSKSVY (SEQ ID NO: 70), a LCDR2 comprising the amino acid sequence of YDDSDRPS (SEQ ID NO: 71), and a LCDR3 comprising the amino acid sequence of QVWDSSSDPWV (SEQ ID NO: 72); and a second antibody comprising a first antibody comprising a VH compris
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of three antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of Y
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, a total dose of about 600 mg, about 1200 mg, about 1800 mg, or about 2400 mg is administered. In some embodiments, the antibodies or antigen binding fragments thereof are administered in a single composition. In some embodiments, the antibodies or antigen binding fragments are administered intravenously.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of three antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, a total dose of about 600 mg, about 1200 mg, about 1800 mg, or about 2400 mg is administered. In some embodiments, the antibodies or antigen binding fragments thereof are administered in a single composition. In some embodiments, the antibodies or antigen binding fragments are administered intravenously.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of three antibodies that bind to a Spike protein comprising a first antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFT
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, a total dose of about 600 mg, about 1200 mg, about 1800 mg, or about 2400 mg is administered. In some embodiments, the antibodies or antigen binding fragments thereof are administered in a single composition. In some embodiments, the antibodies or antigen binding fragments are administered intravenously.
  • a method of treating or preventing a SARS-CoV-2 infection in a subject comprising administering a combination of four antibodies that bind to a Spike protein comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, a total dose of about 800 mg, about 1600 mg, about 2400 mg, or about 3200 mg is administered. In some embodiments, the antibodies or antigen binding fragments thereof are administered in a single composition. In some embodiments, the antibodies or antigen binding fragments are administered intravenously.
  • the method comprises administering one or more of IMM20184, IMM20190, IMM20253, and/or IMM20279 and an additional agent selected from the group consisting of casirivimab, imdevimab, bamlanivimab, etesevimab and sotrovimab.
  • an additional agent selected from the group consisting of casirivimab, imdevimab, bamlanivimab, etesevimab and sotrovimab.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering two or more antibodies provided herein to the subject.
  • the SARS-CoV-2 infection is caused by SARS-CoV-2 variant.
  • the SARS-CoV-2 is the Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS-CoV-2, the Gammma (Brazilian/P.1) variant of SARS-CoV-2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Episolon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B.1.1.529) variant of SARS-CoV-2.
  • the variant has one or more mutations in a Spike protein.
  • 3 or more, 4 or more, 5 or more, or 6 or more antibodies provided herein are administered to the subject.
  • the antibodies comprise a HCVR comprising three heavy chain complementarity determining regions (CDRs), (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 1, and a LCVR comprising three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 2; a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 3, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 3, and
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, each antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating an Omicron variant of SARS-CoV-2 in a subject comprising administering two or antibodies provided herein.
  • the Omicron variant includes a combination of mutations in the Spike protein. In some embodiments, the mutations include a large number of changes that form a ring around the ACE2 binding site.
  • an advantage of the present methods is the ability to target epitopes within and outside of the ACE2 binding site such that the treatment is effective in variants, such as Omicron which harbor mutations within the Spike protein including in the ACE2 binding site.
  • variants such as Omicron which harbor mutations within the Spike protein including in the ACE2 binding site.
  • the combinations of antibodies provided herein are especially effective for treating variants such as Omicron because they bind to non-overlapping epitopes.
  • the Omicron variant has one or more modifications that make the Spike protein more susceptible to cleavage and/or cause pre-cleavage of the Spike protein.
  • the antibodies provided herein are able to bind to pre-cleaved Spike proteins, or Spike proteins that are more susceptible to cleavage with high affinity.
  • provided herein is a method of treating a Delta variant of SARS-CoV-2 in a subject comprising administering two or antibodies provided herein.
  • the Omicron variant includes a combination of mutations in the Spike protein.
  • the mutations include a large number of changes that form a ring around the ACE2 binding site.
  • an advantage of the present methods is the ability to target epitopes within and outside of the ACE2 binding site such that the treatment is effective in variants, such as Omicron which harbor mutations within the Spike protein including in the ACE2 binding site.
  • the combinations of antibodies provided herein are especially effective for treating variants such as Delta because they bind to non-overlapping epitopes.
  • the Delta variant has one or more modifications that make the Spike protein more susceptible to cleavage and/or cause pre-cleavage of the Spike protein.
  • the antibodies provided herein, for example IMM20253 are able to bind to pre-cleaved Spike proteins, or Spike proteins that are more susceptible to cleavage with high affinity.
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. [0112] In some embodiments, provided herein is a method of treating a SARS-CoV-2 infection in a subject comprising administering antibody IMM20184 to the subject.
  • the antibody comprises a HCVR comprising three heavy chain complementarity determining regions (CDRs), (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 1, and a LCVR comprising three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 2.
  • CDRs heavy chain complementarity determining regions
  • LCDR1, LCDR2 and LCDR3 three light chain complementarity determining regions
  • the antibody comprise a HCDR1, a HCDR2, and anHCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:1 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO: 2.
  • the method comprises administering 2 or more antibodies.
  • IMM20184 targets an epitope outside the ACE2 binding site and operates via an ACE2 dependent mechanism of action.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating an Omicron variant of SARS-CoV-2 in a subject comprising administering antibody IMM20253 to the subject.
  • the antibody comprises a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6.
  • the antibody comprises a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6.
  • IMM20253 targets an epitope outside the ACE2 binding site and operates via an ACE2 independent mechanism of action.
  • IMM20253 has high affinity for virus comprising pre-cleaved Spike proteins or Spike proteins that are more susceptible to cleavage, such as Omicron.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • provided herein is a method of treating a Delta variant of SARS-CoV-2 in a subject comprising administering antibody IMM20253 to the subject.
  • the antibody comprises a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6.
  • the antibody comprises a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6.
  • IMM20253 targets an epitope outside the ACE2 binding site and operates via an ACE2 independent mechanism of action. In some embodiments, IMM20253 targets an epitope outside the ACE2 binding site and operates via an ACE2 independent mechanism of action. In some embodiments, IMM20253 has high affinity for virus comprising pre-cleaved Spike proteins or Spike proteins that are more susceptible to cleavage, such as Delta. In some embodiments, the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating an Omicron variant of SARS-CoV-2 in a subject comprising administering antibody MM20190 to the subject.
  • the antibody comprises a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 3, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 4.
  • the antibody comprises a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO: 3 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:4.
  • IMM20190 targets an epitope within the ACE2 binding site and operates via an ACE2 dependent mechanism of action.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating a Delta variant of SARS-CoV-2 in a subject comprising administering antibody MM20190 to the subject.
  • the antibody comprises a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 3, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 4.
  • the antibody comprises a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO: 3 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:4.
  • IMM20190 targets an epitope within the ACE2 binding site and operates via an ACE2 dependent mechanism of action.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • a method of treating an Omicron variant of SARS-CoV-2 in a subject comprising administering antibody IMM20184 and IMM20253 to the subject.
  • the method comprises administering i) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6 and ii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6.
  • the method comprises administering i) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:1 and a LCDR1, a LCDR2, and LCRD3 of the LCVR amino acid sequence set forth in SEQ ID NO: 2 and ii) an antibody comprising a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • provided herein is a method of treating a Delta variant of SARS-CoV-2 in a subject comprising administering antibody IMM20184 and IMM20253 to the subject.
  • the method comprises administering i) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6 and ii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6.
  • the method comprises administering i) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:1 and a LCDR1, a LCDR2, and LCRD3 of the LCVR amino acid sequence set forth in SEQ ID NO: 2 and ii) an antibody comprising a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6.
  • the subject is immunocompromised.
  • the subject is receiving an immunosuppressant.
  • the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • provided herein is a method of treating an Omicron variant of SARS-CoV-2 in a subject comprising administering antibody IMM20184, IMM20253, and IMM20190 to the subject.
  • the method comprises administering i) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6 ii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6; and iii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the LCVR
  • the method comprises administering i) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:1 and a LCDR1, a LCDR2, and a LCRD3 of the LCVR amino acid sequence set forth in SEQ ID NO: 2 ii) an antibody comprising a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6, and iii) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO: 3 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:4.
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. [0120] In some embodiments, provided herein is a method of treating a Delta variant of SARS-CoV-2 in a subject comprising administering antibody IMM20184, IMM20253, and IMM20190 to the subject.
  • the method comprises administering i) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6 ii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 5, and a LCVR comprising three CDRs, (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 6; and iii) an antibody comprising a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the LCVR
  • the method comprises administering i) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:1 and a LCDR1, a LCDR2, and a LCRD3 of the LCVR amino acid sequence set forth in SEQ ID NO: 2 ii) an antibody comprising a HCDR1, a HCDR2 and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO:5 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:6, and iii) an antibody comprising a HCDR1, a HCDR2, and a HCDR3 of the HCVR amino acid sequence set forth in SEQ ID NO: 3 and a LCDR1, a LCDR2, and a LCDR3 of the LCVR amino acid sequence set forth in SEQ ID NO:4.
  • the subject is immunocompromised. In some embodiments, the subject is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. [0121] ”
  • Subjects refers to any person who has been infected with, or has the potential to be infected with the SARS-CoV-2 virus. In some embodiments of the invention those subjects may be of high risk for contracting the virus as a result of being immunocompromised through genetic mutation or drug treatment.
  • subjects may be being treated with immunosuppressive medications as a result of being a solid organ transplant recipient or having a chronic inflammatory disease (e.g. rheumatoid arthritis, psoriasis, chrohn’s disease). They may be being treated with chemotherapeutic, radiation, or targeted agents that suppress immune function for treatment of diseases such as cancer. Subjects may also have conditions that place them into high-risk categories for developing severe COVID-19, such as diabetes, chronic pulmonary conditions, chronic cardiovascular conditions, obesity, or pregnancy. [0122] "Preventing" a disease refers to inhibiting the full development of a disease. Other terms, such as “prophylaxis”, are also understood to refer to the concept of preventing a disease.
  • Treating refers to a therapeutic intervention that ameliorates, (i.e., reduces the severity), a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the antibodies or antigen-binding fragments thereof contained in the pharmaceutical composition treat or prevent the a SARS-CoV-2 infection by neutralizing SARS-CoV-2 virus and/or a SARS-CoV-2 variant.
  • SARS-CoV-2 variants that are responsive to a method of treatment of the invention include the: Alpha (U.K./B.1.1.7), Beta (South African/B.1.351), Gamma (Brazil/P.1), Delta (India/B.1.617.2), B.1.617 (L452R/E484Q) and Epsilon (California/B.1.429/427).
  • SARS-CoV-2 variants that are responsive to a method of treatment of the invention include the CDC Variants of Interest, including the Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS-CoV-2, the Gamma (Brazilian/P.1) variant of SARS-CoV-2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Epsilon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV- 2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B.1.1.529) variant of SARS- CoV-2.
  • Alpha U.K./B.1.1.7
  • Beta
  • an effective amount of an antibody or antibody composition of the invention to prevent or treat SARS-CoV-2 infection does not result in complete protection from a SARS-CoV-2 disease but results in a lower titer or reduced number of SARS-CoV-2 viruses compared to an untreated subject.
  • the effective amount results in a 0.5-fold, 1-fold, 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, 15- fold, 20-fold, 25-fold, 50-fold, 75-fold, 100-fold, 125-fold, 150-fold, 175-fold, 200-fold, 300- fold, 400-fold, 500-fold, 750-fold, or 1,000-fold or greater reduction in titer of SARS-CoV-2 virus relative to an untreated subject.
  • the effective amount results in a reduction in titer of SARS-CoV-2 virus relative to an untreated subject of approximately 1 log or more, approximately 2 logs or more, approximately 3 logs or more, approximately 4 logs or more, approximately 5 logs or more, approximately 6 logs or more, approximately 7 logs or more, approximately 8 logs or more, approximately 9 logs or more, approximately 10 logs or more, 1 to 5 logs, 2 to 10 logs, 2 to 5 logs, or 2 to 10 logs.
  • Antibodies of the invention are typically monoclonal antibodies, meaning an antibody is produced by a single clonal B-lymphocyte population, a clonal hybridoma cell population, or a clonal population of cells into which the genes of a single antibody, or portions thereof, have been transfected.
  • Monoclonal antibodies are produced by methods known to those of skill in the art, for instance by making hybrid antibody-forming cells from a fusion of myeloma cells with immune lymphocyte cells.
  • An antibody of the invention may also be an "antigen-binding fragment".
  • An antigen-binding fragment refers to a polypeptide fragment of an immunoglobulin or antibody that binds antigen or competes with intact antibody (i.e., with the intact antibody from which they were derived) for antigen binding (i.e., specific binding to an epitope of SARS-CoV-2).
  • fragment of an antibody molecule includes antigen-binding fragments of antibodies, for example, an antibody light chain variable domain (VL), an antibody heavy chain variable domain (VH), a single chain antibody (scFv), a F(ab')2 fragment, a Fab fragment, an Fd fragment, an Fv fragment, and a single domain antibody fragment (DAb). Fragments can be obtained, e.g., via chemical or enzymatic treatment of an intact or complete antibody or antibody chain or by recombinant means.
  • VL antibody light chain variable domain
  • VH antibody heavy chain variable domain
  • scFv single chain antibody
  • F(ab')2 fragment fragment
  • Fab fragment fragment
  • Fd fragment fragment
  • Fv fragment single domain antibody fragment
  • DAb single domain antibody fragment
  • immunoglobulin variants that are considered antibodies according to the invention include single-domain antibodies (such as VH domain antibodies), Fab fragments, Fab' fragments, F(ab)'2 fragments, single chain Fv proteins ("scFv”), and disulfide stabilized Fv proteins ("dsFv").
  • a VH single-domain antibody is an immunoglobulin fragment consisting of a heavy chain variable domain.
  • An Fab fragment contains a monovalent antigen-binding immunoglobulin fragment, which can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain.
  • an Fab' fragment also contains a monovalent antigen-binding immunoglobulin fragment, which can be produced by digestion of whole antibody with the enzyme pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain. Two Fab' fragments are obtained per immunoglobulin molecule.
  • a (Fab')2 fragment is a dimer of two Fab' fragments, that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction, so Fab' monomers remain held together by two disulfide bonds.
  • An Fv fragment is a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains.
  • a single chain (“sc”) antibody such as scFv fragment
  • scFv fragment is a genetically engineered molecule containing the VL region of a light chain, the VH region of a heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.
  • a dimer of a single chain antibody such as a scFV2 antibody, is a dimer of a scFV, and may also be known as a "miniantibody”.
  • a dsFvs variant also contains a VL region of an immunoglobulin and a VH region, but the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains.
  • An antibody of the invention is typically a "human” antibody, which may also be referred to as a "fully human” antibody.
  • An antibody which possess a human framework regions and CDRs from a human immunoglobulin is generally be considered to be a human or humanized antibody.
  • a human or humanized antibody may contain the framework and the CDRs of an antibody from the same originating human heavy chain, or human light chain amino acid sequence, or both.
  • the framework regions may originate from one human antibody, and be engineered to include CDRs from a different human antibody.
  • An antibody according to the invention may also comprise a "tagged" immunoglobulin CH3 domain to facilitate detection of the biologic against a background of endogenous antibodies. More particularly, a tagged CH3 domain is a heterogeneous antibody epitope that has been incorporated into one or more of the AB, EF, or CD structural loops of a human IgG-derived CH3 domain.
  • CH3 tag may be incorporated into the structural context of an IgG1 subclass antibody, other human IgG subclasses, including IgG2, IgG3, and IgG4.
  • Epitope-tagged CH3 domains also referred to as "CH3 scaffolds” can be incorporated into any antibody of the invention having a heavy chain constant region, generally in the form of an immunoglobulin Fc portion. Examples of CH3 scaffold tags, and methods for incorporating them into antibodies are disclosed in International Patent Application No. PCT/US2019/032780.
  • Antibodies used to detect epitope tagged CH3 scaffolds, and antibodies of the invention, that comprise epitope tagged CH3 scaffolds are generally referred to herein as "detector antibodies”.
  • Some antibodies of the invention may be described as an "isolated” antibody or “isolated” antigen-binding fragment thereof.
  • An isolated antibody or antigen-binding fragment thereof has been substantially separated or purified away from other biological components environment, such as a cell, proteins and organelles.
  • an isolated antibody or antigen-binding fragment thereof is prepared by a process involving at least one purification step, although the term "isolated” is not intended to refer to a complete absence of such biological molecules or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes an antibody or antigen-binding fragment of the invention.
  • antibody or antigen-binding fragment thereof is specific for the Spike protein (S) of SARS-CoV-2.
  • an antibody or antigen- binding fragment thereof may, in one embodiment, bind the S1 subunit of the Spike protein, while in another embodiment, an antibody or antigen-binding fragment thereof binds the S2 subunit.
  • some antibodies or antigen-binding fragments thereof bind to the receptor-binding domain (RBD) of the S protein, while other antibodies of the invention bind to non-RBD epitopes of the S protein.
  • RBD-binding antibodies or antigen-binding fragments thereof of the invention may, in certain embodiments, bind a soluble form of the RBD of the S protein.
  • Some antibodies or antigen-binding fragments of the invention bind to sites on the RBD that are resistant to mutational drift.
  • an antibody or antigen-binding fragment thereof binds the RBD at, or in close proximity of such a site described by Greaney t al. (2021) as the “the E465 patch”.
  • Greaney t al. (2021) as the “the E465 patch”.
  • binding of an antibody or antigen-binding fragment of the invention to a highly-conserved site of the SARS-CoV-2 Spike protein is not affected by point mutations in the Spike protein associated with variants of SARS-Cov-2, Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS-CoV-2, the Gamma (Brazilian/P.1) variant of SARS-CoV- 2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Epsilon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B
  • an isolated antibody or antigen-binding fragment thereof contains a heavy chain variable region (HCVR) and a light chain variable region (LCVR) that is described in Table 1.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • an antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 of a heavy chain variable region (HCVR) and a light chain variable region (LCVR) that is described in Table 1.
  • an antibody comprising a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 set forth in Table 1.
  • the CDRs are determined using Kabat, Chothia, or contact systems. In some embodiments, the CDRs are determined using the system described in North et al. J.M.B 406(8):228-56 (2011) as set forth in Table 1. Table 1 Description SEQ Sequence Name Binds Amino acid sequence ID P _ ( I P _ ( IMM200184) ASWVFGGGTKLTVL Description SEQ Sequence Name Binds Amino acid sequence ID No.
  • CD-4I2X A WEIDGSERQNGKTT e b s C e C e b s C e C e b s C e C e b s C e C e b s C e C e b s C e C d e b s C d e C epitope with 233 Description SEQ Sequence Name Binds Amino acid sequence ID No.
  • an antibody that binds to a SARS-CoV- 2 Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55); a HCDR2 comprising the amino acid sequence TIREDGSEKYYVD (SEQ ID NO: 56); and a HCDR3 comprising the amino acid sequence ARSKWLRGSFDY (SEQ ID NO: 57); wherein the antibody comprises a LCDR1 comprising the amino acid sequence TRRSGSIASNYVQ (SEQ ID NO: 58); a LCDR2 comprising the amino acid sequence YEDNQRPS (SEQ ID NO: 59); and a LCDR3 comprising the amino acid sequence QSYDSSNPPGA
  • the CDRs are defined according to North et al.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 1.
  • the VL comprises the amino acid sequence set forth in SEQ ID NO: 2.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 1 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 2.
  • the antibody comprises a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 1, and a LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence is set forth in SEQ ID NO: 2.
  • the antibody comprises one or more CDRs or variable region sequences of IMM20184 (PR193_00018_HC). In some embodiments, the antibody binds to an epitope on the Spike protein outside of the ACE2 binding site. In some embodiments, the antibody neutralizes SARS-CoV-2 through an ACE2-dependent mechanism. In some embodiments, IMM20184 contacts one or more amino acids in the Spike protein selected from the group consisting of N370, A372, F374, K378, S383, and P384. In some embodiments, IMM20184 binds to a conserved epitope.
  • IMM20184 binds to an epitope of the Spike protein comprising one or more of N370, A372, F374, K378, S383, and P384.
  • VH variable heavy chain
  • VL variable light chain
  • the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTVSSNYMS (SEQ ID NO: 61); a HCDR2 comprising the amino acid sequence VIYAGGSTF (SEQ ID NO: 62); and a HCDR3 comprising the amino acid sequence ARDRGGYLDY (SEQ ID NO: 63); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQGISNYLA (SEQ ID NO: 64); a LCDR2 comprising the amino acid sequence YAASTLQS (SEQ ID NO: 65); and a LCDR3 comprising the amino acid sequence
  • the CDRs are defined according to North et al.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 3.
  • the VL comprises the amino acid sequence set forth in SEQ ID NO: 4.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 3 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 4.
  • the antibody comprises a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 3, and a LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence is set forth in SEQ ID NO: 4.
  • the antibody comprises one or more CDRs or variable region sequences of IMM20190 (PR194_00232_HC). In some embodiments, the antibody binds to an epitope of the Spike protein in the ACE2 binding site and operates through an ACE2-dependent mechanism. In some embodiments, IMM20190 contacts one or more amino acids of the Spike protein selected from the group consisting of K417, D420, L455, F456, N460, Y473, N487, Y489, N501, and Y505. In some embodiments, IMM20190 binds to a non-conserved epitope.
  • IMM20190 binds to an epitope of the Spike protein comprising one or more of K417, D420, L455, F456, N460, Y473, N487, Y489, N501, and Y505.
  • an antibody that binds to a SARS-CoV- 2 Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence TASGFTFSTYGMH (SEQ ID NO: 67); a HCDR2 comprising the amino acid sequence VISYDGSSKH (SEQ ID NO: 68); and a HCDR3 comprising the amino acid sequence ARDGQPPGWGNYFDY (SEQ ID NO: 69); wherein the antibody comprises a LCDR1 comprising the amino acid sequence GGNGIGSKSVY (SEQ ID NO: 70); a LCDR2 comprising the amino acid sequence YDDSDRPS (SEQ ID NO: 71); and a LCDR3 comprising the amino acid sequence QVWDSSSDPWV (SEQ ID NO: 72).
  • VH variable heavy chain
  • VL variable light chain
  • the CDRs are defined according to North et al.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 5.
  • the VL comprises the amino acid sequence set forth in SEQ ID NO: 6.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 5 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 6.
  • the antibody comprises a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence is set forth in SEQ ID NO: 6.
  • the antibody comprises one or more CDR sequences or variable region sequences of IMM20253 (PR200_00622_HC).
  • the antibody binds to a Spike protein with a mutation in the protease cleavage site.
  • the antibody binds with high affinity to pre-cleaved Spike proteins (i.e. Spike proteins that are cleaved prior to binding to the host cell surface).
  • the antibody binds with high affinity to Spike proteins with mutations that make a protease site more readily cleavable.
  • the antibody binds to a Spike protein at an epitope outside of the ACE2 binding site and operates through an ACE2 independent mechanism.
  • the antibody causes a confirmation change in the Spike protein. In some embodiments, the antibody makes the Spike protein more susceptible to cleavage. In some embodiments IMM20253 contacts one or more amino acid of the Spike protein selected from the group consisting of K356 and R466. In some embodiments, IMM20253 binds to a conserved epitope. In some embodiments, IMM20253 binds to an epitope of the Spike protein comprising K356 and/or R466.
  • an antibody that binds to a SARS-CoV- 2 Spike protein comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTYGMH (SEQ ID NO: 109); a HCDR2 comprising the amino acid sequence VIWYNGINKH (SEQ ID NO: 110); and a HCDR3 comprising the amino acid sequence ARDWGTLTTLFDF (SEQ ID NO: 111); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQSISSHLN (SEQ ID NO: 112); a LCDR2 comprising the amino acid sequence YGASSLQS (SEQ ID NO: 113); and a LCDR3 comprising the amino acid sequence QQSYSTPPWT (SEQ ID NO: 114).
  • VH variable heavy chain
  • VL variable light chain
  • the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTY
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 19.
  • the CDRs are defined according to North et al.
  • the VL comprises the amino acid sequence set forth in SEQ ID NO: 20.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO: 19 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 20.
  • the antibody comprises a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 19, and a LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence is set forth in SEQ ID NO: 20.
  • the antibody comprises one or more CDR sequences or variable region sequences of IMM20279 (PR199_00255_HC).
  • the antibody binds to an epitope of the Spike protein outside of the ACE2 binding site.
  • the antibody comprising one or more CDR sequences or variable region sequences of IMM20279 cross-reacts with an antibody comprising one or more CDR sequences or variable region sequences of IMM20184.
  • an isolated antibody or antigen-binding fragment thereof binds a SARS-CoV-2 Spike protein, and contains one of the following combinations of a heavy chain variable region (HCVR) and a light chain variable region (LCVR): a HCVR comprising three heavy chain complementarity determining regions (CDRs), (HCDR1, HCDR2 and HCDR3), wherein the amino acid sequence of the HCVR is set forth in SEQ ID NO: 1, and a LCVR comprising three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3), wherein the amino acid sequence of the LCVR is set forth in SEQ ID NO: 2; a HCVR comprising three CDRs, (HCDR1, HCDR2 and HCDR3),
  • antibodies of the invention bind to highly-conserved epitopes, and, thus, are not affected by point mutations in the Spike protein associated with variants of SARS-Cov-2.
  • a nonlimiting list of examples of antibodies or antigen-binding fragments of the invention which bind equivalently to the SARS-CoV-2 reference isolate, USA/WA_CDC-WA1/2020, and each of the aforementioned variant isolates include: An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 1 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 2 or fragment thereof; An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 3 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 4 or fragment thereof; An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 5 or fragment thereof, and a LCVR
  • the foregoing antibodies of the invention neutralize SARS-CoV-2 and SARS- CoV-2 variants, including variants Alpha (U.K./B.1.1.7), Beta (South African/B.1.351), Gamma (Brazil/P.1), Delta (India/B.1.617.2), B.1.617 (L452R/E484Q) and Epsilon (California/B.1.429/427), either alone, or in combination.
  • the antibodies neutralize the Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS-CoV-2, the Gamma (Brazilian/P.1) variant of SARS-CoV- 2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Epsilon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B.1.1.529) variant of SARS-CoV-2.
  • certain antibodies of the invention bind the SARS-CoV-2 RBD at epitopes, which contain residues that are conserved among variants. In some embodiments, binding to such conserved residues prevents viral escape. In some embodiments, binding to such conserved residues allows binding across variants. Accordingly, a RBD amino acid substitution at a non-conserved or poorly-conserved residue position will have limited or no impact on binding of an antibody of the invention. Such non conserved or poorly-conserved substitutions in the RBD are commonly associated with SARS-CoV-2 variants.
  • an RBD epitope of some antibodies of the invention may contain at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more residues at RBD positions 356 (K), 370 (N), 372 (A), 374 (F), 378 (K), 384 (P), 417 (K), 420 (D), 455 (L), 456 (F), 460 (N), 466 (R), 473 (Y), 487 (N), 489 (Y), 501 (N), and 505 (Y).
  • an antibody of the invention may bind an RBD epitope in which the binding energy is relatively higher at residues at 417 (K), 420 (D), 455 (L), 456 (F), 460 (N), 473 (Y), 487 (N), 489 (Y), 501 (N), and 505 (Y).
  • another antibody of the invention may bind an RBD epitope in which the binding energy is relatively higher at residues at 370 (N), 372 (A), 374 (F), 378 (K), 384 (P).
  • yet another antibody of the invention may bind an RBD epitope in which the binding energy is relatively higher at residues at 356 (K) and 466 (R).
  • the antibody contacts one or more residues at RBD positions 356 (K), 370 (N), 372 (A), 374 (F), 378 (K), 384 (P), 417 (K), 420 (D), 455 (L), 456 (F), 460 (N), 466 (R), 473 (Y), 487 (N), 489 (Y), 501 (N), and 505 (Y).
  • the antibody contacts one or more of 417 (K), 420 (D), 455 (L), 456 (F), 460 (N), 473 (Y), 487 (N), 489 (Y), 501 (N), and 505 (Y).
  • the antibody contacts residues at 370 (N), 372 (A), 374 (F), 378 (K), 384 (P).
  • the epitope is identified using alanine scanning.
  • the antibody binds the SARS-CoV-2 RBD at epitopes, which contain residues that are not conserved.
  • a composition i.e., a mixture of two or more of: An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 1 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 2 or fragment thereof; An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 3 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 4 or fragment thereof; An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 5 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 6 or fragment thereof; An antibody with a HCVR based on the amino acid sequence set forth in SEQ ID NO: 19 or fragment thereof, and a LCVR based on the amino acid sequence set forth in SEQ ID NO: 20 or fragment thereof; and An antibody with a HCVR based on the amino acid sequence set forth in S
  • the antibodies neutralize the Omicron variant.
  • the antibodies neutralize Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS-CoV-2, the Gamma (Brazilian/P.1) variant of SARS-CoV-2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Epsilon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B.1.1.529) variant of SARS-CoV-2.
  • an antibody of the invention alters the conformation of Spike protein upon binding of the antibody to the Spike protein. More particularly, in certain embodiments, an antibody of the invention binds a Spike protein epitope located on the outside face of the RBD domain of the SARS-CoV-2 RBD. In such embodiments, the epitope may be in close proximity to the N-terminal domain of a second Spike protein within the Spike trimer, and binding of the antibody inactivates the virus’ ability to bind cells. Consequently, certain antibodies of the invention neutralize SARS-CoV-2 by the foregoing mechanism.
  • binding of such antibodies to the outer face of the RBD imparts its intrinsic neutralization through induction of a conformational change in the Spike protein that prevents virus uptake into the cells without competing for ACE2 binding.
  • An example of an embodiment of the invention that alters conformation of the Spike protein upon binding is an antibody with a heavy chain variable region (HCVR) or fragment thereof and/or a light chain variable region (LCVR) or a fragment thereof derived from an antibody described herein as IMM20253, which contains HCVR and LCVR with amino acid sequences of SEQ ID NOS. 5 and 6, respectively.
  • an antibody of the invention that alters the conformation of Spike protein upon binding of the antibody to the Spike protein as part of its intrinsic neutralization activity acts additively, and more preferentially synergistically, with other antibodies that compete for ACE2 binding as part of their intrinsic neutralization mechanism.
  • An example of an embodiment of the invention that alters conformation of the Spike protein upon binding and acts additively, and more preferentially synergistically, with antibodies that block ACE2 binding is an antibody with a heavy chain variable region (HCVR) or fragment thereof and/or a light chain variable region (LCVR) or a fragment thereof derived from an antibody described herein as IMM20253, which contains HCVR and LCVR with amino acid sequences of SEQ ID NOS.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • an isolated antibody or antigen-binding fragment thereof of the invention may contain a CH3 scaffold "epitope tag", comprising at least one modification of the wild-type amino acid sequence of the CH3 domain derived from an immunoglobulin Fc region. Accordingly, any of the aforementioned antibodies may have been engineered to contain a CH3 scaffold.
  • the CH3 scaffold of such an isolated antibody or antigen-binding fragment thereof may possess at least one modification of the wild-type sequence occurs within the AB, EF, or CD loops of the CH3 scaffold, including an amino acid substitution, deletion or insertion, for example.
  • the epitope tag amino acid sequence contains a sequence derived from SIRP ⁇ or Sip.
  • he epitope tag amino acid sequence contains a sequence derived from a constant light chain of an antibody. More particularly, the antibody epitope amino acid sequence of an isolated antibody or antigen-binding fragment thereof that contains a CH3 scaffold with an amino acid sequence set forth in SEQ ID Nos. 3-30, SEQ ID Nos. 33-57, or SEQ ID Nos. 60-67 of International Patent Application No. PCT/US2019/032780.
  • Compositions [0145] Also provided herein are compositions comprising one or more antibodies provided herein. In some embodiments, provided herein a composition comprising two or more antibodies that bind to a Spike protein, wherein the antibodies bind to different epitopes.
  • the composition comprises an antibody that operates in an ACE2 independent mechanism and an antibody that operates through an ACE2 dependent mechanism.
  • the multiple antibodies in the composition act synergistically to treat a SARS-CoV-2 infection in a subject.
  • the presence of multiple antibodies binding to different epitopes of a SARS-CoV-2 protein allows treatment of variants with mutations in one or more SARS-CoV-2 proteins, such as the Spike protein.
  • a composition comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55); a HCDR2 comprising the amino acid sequence TIREDGSEKYYVD (SEQ ID NO: 56); and a HCDR3 comprising the amino acid sequence ARSKWLRGSFDY (SEQ ID NO: 57); wherein the antibody comprises a LCDR1 comprising the amino acid sequence TRRSGSIASNYVQ (SEQ ID NO: 58); a LCDR2 comprising the amino acid sequence YEDNQRPS (SEQ ID NO: 59); and a LCDR3 comprising the amino acid sequence QSYDSSNPPGASWV (SEQ ID NO: 60).
  • VH variable heavy chain
  • VL variable light chain
  • the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55); a HCDR2 compris
  • the CDRs are defined according to North et al.
  • a composition comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTVSSNYMS (SEQ ID NO: 61); a HCDR2 comprising the amino acid sequence VIYAGGSTF (SEQ ID NO: 62); and a HCDR3 comprising the amino acid sequence ARDRGGYLDY (SEQ ID NO: 63); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQGISNYLA (SEQ ID NO: 64); a LCDR2 comprising the amino acid sequence YAASTLQS (SEQ ID NO: 65); and a LCDR3 comprising the amino acid sequence QKYNSAPGLT (SEQ ID NO: 66).
  • VH variable heavy chain
  • VL variable light chain
  • the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTVSSNYMS (SEQ ID NO:
  • the CDRs are defined according to North et al.
  • a composition comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence TASGFTFSTYGMH (SEQ ID NO: 67); a HCDR2 comprising the amino acid sequence VISYDGSSKH (SEQ ID NO: 68); and a HCDR3 comprising the amino acid sequence ARDGQPPGWGNYFDY (SEQ ID NO: 69); wherein the antibody comprises a LCDR1 comprising the amino acid sequence GGNGIGSKSVY (SEQ ID NO: 70); a LCDR2 comprising the amino acid sequence YDDSDRPS (SEQ ID NO: 71); and a LCDR3 comprising the amino acid sequence QVWDSSSDPWV (SEQ ID NO: 72).
  • the CDRs are defined according to North et al.
  • a composition comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTYGMH (SEQ ID NO: 109); a HCDR2 comprising the amino acid sequence VIWYNGINKH (SEQ ID NO: 110); and a HCDR3 comprising the amino acid sequence ARDWGTLTTLFDF (SEQ ID NO: 111); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQSISSHLN (SEQ ID NO: 112); a LCDR2 comprising the amino acid sequence YGASSLQS (SEQ ID NO: 113); and a LCDR3 comprising the amino acid sequence QQSYSTPPWT (SEQ ID NO: 114).
  • VH variable heavy chain
  • VL variable light chain
  • the CDRs are defined according to North et al.
  • a composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67),
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 109),
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 109), a HCDR2 comprising the
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the amino acid sequence of VISYDGSSKH (SEQ ID NO: 68), and a HCDR3 comprising the amino acid sequence of ARDGQPPGWGNYFDY (SEQ ID NO: 69); and a VL comprising a LCDR1 comprising the amino acid sequence of GGNGIGSKSVY (SEQ ID NO: 70), a LCDR2 comprising the amino acid sequence of YDDSDRPS (SEQ ID NO: 71), and a LCDR3 comprising the amino acid sequence of QVWDSSSDPWV (SEQ ID NO: 72); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 109),
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HC
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF
  • composition comprising a first antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the amino acid sequence of VISYDGSSKH (SEQ ID NO: 67), a HCDR2 comprising the
  • composition comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF
  • compositions of the invention contain one or more isolated antibodies or antigen-binding fragments thereof of the invention and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition contains only one of the Spike-binding antibodies described herein.
  • Other pharmaceutical composition of the invention contain a mixture of different Spike-binding antibodies which are described herein, such as, for example, at least 2, at least 3, at least 4, or at least 5, or at least 6 or more Spike-binding antibodies.
  • the antibodies neutralize Alpha (U.K./B.1.1.7) variant of SARS-CoV-2, the Beta (South African/B.1.351) variant of SARS- CoV-2, the Gamma (Brazilian/P.1) variant of SARS-CoV-2, the Delta (India/B.1.617.2), B.1.617 (L452R/E484Q )), the Epsilon (California/B.1.429/427, New York/B.1.526/526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2, the lambda (C.37) variant of SARS-CoV-2, or the Omicron (B.1.1.529) variant of SARS-CoV-2.
  • a pharmaceutical composition of the invention further contains a second therapeutic agent.
  • a pharmaceutical composition of the invention may also contain an anti-inflammatory agent or an antiviral agent.
  • the second agent is an antibody.
  • the second agent is casirivimab (REGN10933).
  • the second agent is imdevimab (REGN10987).
  • the second agent is a combination of the neutralizing antibodies, casirivimab and imdevimab (REGEN-COV, previously known as REGN-COV-2) (ClinicalTrials.gov number, NCT04452318 and NCT04425629).
  • the two antibodies can simultaneously bind to two independent epitopes on the RBD (Hansen J. et.al., Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. 369(6506):1010-1014 (2020); Baum A. et.al, Antibody cocktail to SARS-CoV-2 Spike protein prevents rapid mutational escape seen with individual antibodies, Science 369(6506):1014-1018 (2020)).
  • the second agent is bamlanivimab (LY3819253).
  • the second agent is etesevimab (LY3832479).
  • the second agent is a combination of the neutralizing antibodies, bamlanivimab and etesevimab (ClinicalTrials.gov number, NCT04427501, Dougan M. et.al., Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J med 385(15):1382-1392 (2021) ).
  • the second agent is sotrovimab (ClinicalTrials.gov number, NCT04545060, Gupta A. et.al., Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing antibody sotrovimab. N Engl J med 385:1941-1950 (2021)).
  • kits for treating or preventing a SARS-CoV-2 infection in a subject comprising one or more antibodies provided herein.
  • the kit comprises instructions for use according to the methods provided herein.
  • the kit comprises instructions for treating an immunocompromised subject. In some embodiments, the kit provides instructions for treating a subject who is receiving an immunosuppressant. In some embodiments the subject has received a solid organ transplant or has a chronic inflammatory disease. In some embodiments, the kit provides instructions for administration of the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg . In some embodiments, the kit provides instructions for In some embodiments, the kit comprises two antibodies that bind to a Spike protein. In some embodiments, the kit comprises three or more antibodies that bind to a Spike protein. In some embodiments, the kit comprises four or more antibodies that bind to a Spike protein.
  • the anti-Spike antibodies are in different compositions in the kit. In some embodiments, the anti-Spike antibodies are in the same composition. [0165] In some embodiments, the kit comprises one or more of IMM20184, IMM20190, IMM20253, and/or IMM20279 and an additional agent. In some embodiments, the kit comprises one or more of IMM20184, IMM20190, IMM20253, and/or IMM20279 and an additional agent selected from the group consisting of casirivimab, imdevimab, bamlanivimab, etesevimab and sotrovimab.
  • the kit comprises an anti- Spike antibody comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55); a HCDR2 comprising the amino acid sequence TIREDGSEKYYVD (SEQ ID NO: 56); and a HCDR3 comprising the amino acid sequence ARSKWLRGSFDY (SEQ ID NO: 57); wherein the antibody comprises a LCDR1 comprising the amino acid sequence TRRSGSIASNYVQ (SEQ ID NO: 58); a LCDR2 comprising the amino acid sequence YEDNQRPS (SEQ ID NO: 59); and a LCDR3 comprising the amino acid sequence QSYDSSNPPGASWV (SEQ ID NO: 60).
  • VH variable heavy chain
  • VL variable light chain
  • the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTFSSFWMS (SEQ ID NO: 55);
  • the CDRs are defined according to North et al.
  • the kit comprises a composition comprising the antibody or antigen binding fragment for administration at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the kit comprises an anti-Spike antibody comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence SASGFTVSSNYMS (SEQ ID NO: 61); a HCDR2 comprising the amino acid sequence VIYAGGSTF (SEQ ID NO: 62); and a HCDR3 comprising the amino acid sequence ARDRGGYLDY (SEQ ID NO: 63); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQGISNYLA (SEQ ID NO: 64); a LCDR2 comprising the amino acid sequence YAASTLQS (SEQ ID NO: 65); and a LCDR3 comprising the
  • the CDRs are defined according to North et al.
  • the kit comprises a composition comprising the antibody or antigen binding fragment for administration at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the kit comprises an anti-Spike antibody comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence TASGFTFSTYGMH (SEQ ID NO: 67); a HCDR2 comprising the amino acid sequence VISYDGSSKH (SEQ ID NO: 68); and a HCDR3 comprising the amino acid sequence ARDGQPPGWGNYFDY (SEQ ID NO: 69); wherein the antibody comprises a LCDR1 comprising the amino acid sequence GGNGIGSKSVY (SEQ ID NO: 70); a LCDR2 comprising the amino acid sequence YDDSDRPS (SEQ ID NO: 71); and
  • the CDRs are defined according to North et al.
  • the kit comprises a composition comprising the antibody or antigen binding fragment for administration at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the kit comprises an anti-Spike antibody comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the antibody comprises a HCDR1 comprising the amino acid sequence AASGFTFSTYGMH (SEQ ID NO: 109); a HCDR2 comprising the amino acid sequence VIWYNGINKH (SEQ ID NO: 110); and a HCDR3 comprising the amino acid sequence ARDWGTLTTLFDF (SEQ ID NO: 111); wherein the antibody comprises a LCDR1 comprising the amino acid sequence RASQSISSHLN (SEQ ID NO: 112); a LCDR2 comprising the amino acid sequence YGASSLQS (SEQ ID NO: 113); and a
  • the CDRs are defined according to North et al.
  • the kit comprises a composition comprising the antibody or antigen binding fragment for administration at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • the kit comprises an anti-Spike antibody comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising
  • each antibody is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of two anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 55), a
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of two anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 55), a
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of two anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of two anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 109), a
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of two anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the amino acid sequence of VISYDGSSKH (SEQ ID NO: 68), and a HCDR3 comprising the amino acid sequence of ARDGQPPGWGNYFDY (SEQ ID NO: 69); and a VL comprising a LCDR1 comprising the amino acid sequence of GGNGIGSKSVY (SEQ ID NO: 70), a LCDR2 comprising the amino acid sequence of YDDSDRPS (SEQ ID NO: 71), and a LCDR3 comprising the amino acid sequence of QVWDSSSDPWV (SEQ ID NO: 72); and a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of AASGFTFSTYGMH (SEQ ID NO: 67),
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of three anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of three anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of three anti-Spike antibodies comprising a first antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid sequence of VIYAGGSTF (SEQ ID NO: 62), and a HCDR3 comprising the amino acid sequence of ARDRGGYLDY (SEQ ID NO: 63); and a VL comprising a LCDR1 comprising the amino acid sequence of RASQGISNYLA (SEQ ID NO: 64), a LCDR2 comprising the amino acid sequence of YAASTLQS (SEQ ID NO: 65), and a LCDR3 comprising the amino acid sequence of QKYNSAPGLT (SEQ ID NO: 66); a second antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of TASGFTFSTYGMH (SEQ ID NO: 67), a HCDR2 comprising the amino acid sequence of VISYDG
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition. In some embodiments, each antibody is provided in the same composition.
  • the kit comprises a combination of four anti-Spike antibodies comprising a first antibody comprising a VH comprising a HCDR1 comprising the amino acid sequence of SASGFTFSSFWMS (SEQ ID NO: 55), a HCDR2 comprising the amino acid sequence of TIREDGSEKYYVD (SEQ ID NO: 56), and a HCDR3 comprising the amino acid sequence of ARSKWLRGSFDY (SEQ ID NO: 57); and a VL comprising a LCDR1 comprising the amino acid sequence of TRRSGSIASNYVQ (SEQ ID NO: 58), a LCDR2 comprising the amino acid sequence of YEDNQRPS (SEQ ID NO: 59), and a LCDR3 comprising the amino acid sequence of QSYDSSNPPGASWV (SEQ ID NO: 60); a second antibody comprising the amino acid sequence of SASGFTVSSNYMS (SEQ ID NO: 61), a HCDR2 comprising the amino acid
  • the kit comprises a combination of casirivimab and imdevimab (REGEN-COV, previously known as REGN-COV-2).
  • the kit comprises a combination of bamlanivimab and etesevimab.
  • the kit comprises sotrovimab.
  • each antibody or antigen binding fragment thereof is provided in a composition suitable for administering the antibody or antigen binding fragment thereof at a dose of about 200 mg, about 400 mg, about 600 mg, or about 800 mg.
  • each antibody is provided in a separate composition.
  • each antibody is provided in the same composition.
  • a method of treating a SARS-CoV-2 infection in an immunocompromised subject comprising administering to the subject at least first and second antibodies or antigen binding fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the first antibody or antigen binding fragment thereof binds to an epitope in an ACE2 receptor binding site of the Spike protein and the second antibody or antigen binding fragment thereof binds to an epitope outside of the ACE2 receptor binding site of the Spike protein.
  • Embodiment 2 Embodiment 2.
  • a method of treating a SARS-CoV-2 infection in an immunocompromised subject comprising administering to the subject at least first and second antibodies or antigen binding fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the first antibody or antigen binding fragment thereof neutralizes SARS-CoV-2 via an ACE2 independent mechanism and the second antibody or antigen binding fragment thereof neutralizes SARS-CoV-2 via an ACE2 dependent mechanism.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject at least first and second antibodies or antigen binding fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the first antibody or antigen binding fragment thereof binds to an epitope in an ACE2 receptor binding site of the Spike protein and the second antibody or antigen binding fragment thereof binds to an epitope outside of the ACE2 receptor binding site of the Spike protein.
  • a method of treating a SARS-CoV-2 infection in a subject comprising administering to the subject at least first and second antibodies or antigen binding fragments thereof that specifically bind to distinct epitopes of a Spike protein of SARS-CoV-2, wherein the first antibody or antigen binding fragment thereof neutralizes SARS-CoV-2 via an ACE2 independent mechanism and the second antibody or antigen binding fragment thereof neutralizes SARS-CoV-2 via an ACE2 dependent mechanism.
  • Embodiment 5 The method of any one of embodiments 1-4, further comprising administering a third antibody or antigen binding fragment thereof that specifically binds to the Spike protein of SARS-CoV-2 at an epitope distinct from the first and second antibodies or antigen binding fragments thereof. 6.
  • Embodiment 3 wherein the third antibody or antigen binding fragment thereof binds to an epitope outside of the ACE2 receptor binding site of the Spike protein.
  • Embodiment 7 The method of embodiment 5 or embodiment 6, wherein the third antibody or antigen binding fragment thereof neutralizes SARS-CoV-2 via an ACE2 dependent mechanism.
  • Embodiment 8. The method of any one of embodiments 5-7, wherein each of the first, second, and third antibodies or antigen binding fragments thereof are administered at a total dose of about 600 mg to about 2400 mg.
  • Embodiment 9 The method of embodiment 8, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a total dose of about 600 mg.
  • Embodiment 11. The method of embodiment 8, wherein first, second, and third antibodies or antigen binding fragments thereof are administered at a total dose of about 1200 mg.
  • Embodiment 12. The method of embodiment 11, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a dose of about 400 mg each.
  • Embodiment 13 The method of embodiment 8, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a total dose of about 1800 mg.
  • Embodiment 14. The method of embodiment 13, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a dose of about 600 mg each.
  • Embodiment 15 The method of embodiment 8, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a total dose of about 2400 mg.
  • Embodiment 16 The method of embodiment 15, wherein the first, second, and third antibodies or antigen binding fragments thereof are administered at a dose of about 800 mg each.
  • Embodiment 17. The method of any one of embodiments 5-8, wherein the first, second and third antibodies or antigen binding fragments thereof are administered at a dose of about 3 mg/kg, or about 6 mg/kg each.
  • a method of treating a SARS-CoV-2 infection in an immunocompromised subject comprising administering to the subject an antibody or antigen binding fragment that binds to the Spike protein of SARS-CoV-2, wherein the antibody or antigen binding fragment comprises a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 1, and a LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence is set forth in SEQ ID NO: 2; a HCDR1, HCDR2, and HCDR3 of a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 3, and a LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 4; a HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 5, and
  • Embodiment 19 The method of embodiment 18, wherein the antibody or antigen binding fragment thereof comprises a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, and a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 2; a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 3, and a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 4; a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 6; a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, and a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 8; a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 9, and a LCVR comprising the amino acid sequence is set forth in SEQ ID NO: 10; a HCVR comprising the amino acid sequence set forth in SEQ ID NO
  • Embodiment 20 The method of embodiment 18, wherein the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60; a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 comprising the amino acid sequence of SEQ ID NO:62, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:63; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:64 a LCDR2 comprising the amino
  • Embodiment 21 The method of any one of embodiments 18-20, comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, and a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 comprising the amino acid sequence of SEQ ID NO:62, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:63; and a V
  • Embodiment 22 The method of any one of embodiments 5-20 comprising administering to the subject a) a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 comprising the amino acid sequence of SEQ ID NO:62, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:63; and a VL compris
  • Embodiment 23 The method of embodiment 18 comprising administering to the subject a first antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:55, a HCDR2 comprising the amino acid sequence of SEQ ID NO:56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:57; and a VL comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO:58, a LCDR2 comprising the amino acid sequence of SEQ ID NO:59, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:60, a second antibody or antigen binding fragment thereof comprising a VH comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO:61, a HCDR2 comprising the amino acid sequence of SEQ ID NO:62, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:63; and a VL comprising a LCDR1 comprising
  • Embodiment 24 The method of any one of embodiments 1-23, wherein the subject has a high risk for contracting SARS-CoV-2.
  • Embodiment 25 The method of any one of embodiments 1-24, wherein the subject is being treated with an immunosuppressant.
  • Embodiment 26 The method of embodiment 25, wherein the immunosuppressant is a corticosteroid.
  • Embodiment 27 The method of any one of embodiments 1-26, wherein the subject has received a solid organ transplant or has a chronic inflammatory disease.
  • Embodiment 28 The method of embodiment 27, wherein the subject has a chronic inflammatory disease selected from the group consisting of rheumatoid arthritis, psoriasis, and Crohn’s disease.
  • Embodiment 29 The method of any one of embodiments 1-24, wherein the subject is being treated with a chemotherapeutic agent or radiation.
  • Embodiment 30 The method of any one of embodiments 1-29, wherein the subject is at risk for developing severe COVID-19.
  • Embodiment 31 The method of any one of embodiments 1-24 or 30, wherein the subject has diabetes, a chronic pulmonary condition, a chronic cardiovascular condition, obesity, or is pregnant.
  • Embodiment 32 The method of any one of embodiments 1-31, wherein the viral load in the subject is decreased upon treatment.
  • Embodiment 33 The method of any one of embodiments 1-32, wherein administration of the antibody or antigen-binding fragment thereof results in viral clearance in the subject.
  • Embodiment 34 The method of any one of embodiments 1-32, wherein administration of the antibody or antigen-binding fragment thereof results in viral clearance in the subject.
  • Embodiment 35 The method of any one of embodiments 1-17 and 21-34, wherein the ratio between the first and the second antibodies or antigen binding fragments thereof is about 1 : 1.
  • Embodiment 36 The method of any one of embodiments 1-17 and 22-34, wherein the ratios between the first, second, and third antibodies or antigen binding fragments thereof are about 1 : 1 : 1.
  • Embodiment 37 The method of embodiment 23, wherein the ratio between the first, second, third, and fourth antibodies or antigen binding fragments thereof is about 1 : 1 : 1: 1.
  • Embodiment 38 The method of embodiment 38.
  • the antibody or antigen binding fragment therefor is an Fc IgG1, IgG2, IgG3, IgG4, IgM, IgD, IgA1, IgA2 or IgE isotype.
  • Embodiment 39. The method of embodiment 38, wherein the antibody is an IgG1 isotype.
  • Embodiment 40 The method of embodiment 39, wherein the IgG1 is a G1m1 or nG1m1 allotype.
  • Embodiment 41 The method of any one of embodiment 1-40, wherein the antibody is a fully human antibody.
  • Embodiment 42. The method of any one of embodiments 1-41, wherein the antibody is a full length antibody.
  • Embodiment 46 The method of embodiment 45, wherein the SARS-CoV-2 variant is the U.K. (B.1.1.7) variant of SARS-CoV-2, the South African (B.1.351) variant of SARS-CoV-2, the California (B.1.429) variant of SARS-CoV-2, the California (B.1.427) variant of SARS- CoV-2, the Brazilian (P.1) variant of SARS-CoV-2, the New York (B.1.526) variant of SARS-CoV-2, the New York (B.1.526.1) variant of SARS-CoV-2, the UK/Nigeria (B.1.525) variant of SARS-CoV-2, the Brazilian (P.2) variant of SARS-CoV-2 or the Omicron (B.1.1.529) variant.
  • the SARS-CoV-2 variant is the U.K. (B.1.1.7) variant of SARS-CoV-2, the South African (B.1.351) variant of SARS-CoV-2, the California (B.1.429) variant
  • Embodiment 47 The method of any one of embodiments 1-46, wherein the antibody or antigen binding fragment thereof treats SARS-CoV-2 variant and nonvariant infections with about equivalent efficacies.
  • Embodiment 48 The method of any one of embodiments 1-47, wherein the administering of the antibody or antigen binding fragment thereof is intravenous.
  • Embodiment 49 The method of any one of embodiments 1-17 and 22-48, wherein the first, second, and third antibodies or antigen binding fragments are administered sequentially or simultaneously.
  • Embodiment 50 The method of any one of embodiments 1-17 and 22-48, wherein the first, second, and third antibodies or antigen binding fragments are administered sequentially or simultaneously.
  • Example 1 Evaluation of the breadth of patients’ humoral responses against SARS-CoV-2. The overall spectrum of the productive antibody response to SARS-CoV-2 was examined using an automated, high-throughput hybridoma library generation and screening platform [Puligedda et al.
  • Hybridomas stably expressing human mAbs were generated by electrofusion of expanded B-cells to the B5-6T myeloma cell line, which expresses an ectopic human telomerase gene that stabilizes human chromosomes in the hybrid cells created.
  • Fused hybridomas were plated into 96-well plates in growth medium with HAT selection of stable hybridomas for 7 days. After 7 days, growth media were switched to media with HT for stable selected hybridoma growth.
  • Hybridomas were cultured in a 37°C incubator for 14-21 days during which time they were imaged for monoclonality and monitored for isotype-and sub-class-specific Ig secretion. Supernatants from monoclonal wells expressing measurable levels of Ig were cherry-picked and submitted for target-based screening. [0182] Screening Assays For Antiviral Antibodies. The naturally occurring human antibodies (IgM, IgG, and IgA isotypes) secreted by those hybridomas were screened for reactivity against a panel of SARS-CoV-2 proteins. Antibody screening assays were developed for three SARS-CoV-2 structural proteins (S, N, M) and a panel of accessory ORF proteins of SARS-CoV-2.
  • the screening assays included a rapid and sensitive homogeneous time resolved fluorescence (hTRF) assay that used soluble recombinant viral proteins, as well as a selective, cell-based flow cytometry assay that allowed probing of antibodies to transiently transfected viral antigens expressed within the context of human cells.
  • hTRF homogeneous time resolved fluorescence
  • Viral protein expression in the cell-based assay was additionally confirmed by Western blot.
  • the localization of the C-terminus truncated Spike protein (S ⁇ 19aa) was confirmed to be on the surface of the transfected cells.
  • terbium labeled anti-human IgG (H+L) (Cisbio, custom label) donor and AF488-labeled anti-HIS (Cell Signaling, Cat # 14930S) acceptor antibodies was used to screen patient-derived antibodies for their binding to recombinantly produced SARS-CoV-2 antigens, and more specifically to the SARS-CoV-2 Spike protein.
  • This recombinant target panel consisted of a full-length S (FL, trimer-stabilized, LakePharma) and two truncated S protein domains, S1 (GenScript, Cat # Z03485-1) and RBD (aa 319-591, LakePharma).
  • S1 GenScript, Cat # Z03485-1
  • RBD aa 319-591, LakePharma
  • Commercially available antibodies specific for the individual structural viral proteins SARS-CoV/SARS-CoV-2 Spike S1 (RBD) chimeric mAb (Sino Biological, Cat # 40150-D001), SARS CoV-2 Nucleocapsid human chimeric mAb (GenScript, Cat # A02039-100 served as controls.
  • Assay background was determined by averaging the signal of wells containing only the donor and acceptor cocktail.
  • Hybridoma supernatants exhibiting signals greater than 2-fold over background were reported as positive HITs and are submitted for Ig sequence analysis.
  • Flow cytometry-based cellular screens for antiviral antibodies SARS-CoV-2 antigen sequences were cloned into pcDNA3.4 plasmids and transfected into 293F cells utilizing the Expi293 Expression System (Life Technologies, Inc.) per manufacturer’s instructions. Cells transiently expressing SARS-CoV-2 S (S ⁇ 19aa) were used for screening. Optimal protein expression was achieved three days post-transfection for S proteins.
  • the cell suspensions were dispensed into 384-well plates, followed by the addition of hybridoma supernatant at a 1:10 final dilution. The reaction was allowed to incubate for 90 minutes at room temperature. Cells for each assay were fixed with a final concentration of 1% paraformaldehyde and analyzed with IntelliCyte iQue Screener (IntelliCyte Corporation). Positive binding gates for detection of each secondary antibody were established using cells plus secondary antibody cocktail as a negative control. Binding of hybridoma supernatant antibodies to specific SARS-CoV-2 proteins, and more specifically the S ⁇ 19a, were quantified as percent positive relative to the secondary only control.
  • Example 2 Immunoglobulin gene usage in convalescent COVID-19 patients. Ig gene usage in memory B cells of six COVID-19 patients was evaluated using an NGS analysis of identified and sequenced 134 hybridoma hits. RNA isolation and Next Generation Sequencing (NGS). Hybridoma RNA was isolated using Invitrogen RNAqueous-96 Total RNA Isolation Kit (Cat. #AM1920). Isolated RNA samples were submitted to iRepertoire (Huntsville, AL) for NGS. Hybridoma-derived RNA samples were sequenced using the Illumina MiSeq system at iRepertoire (Huntsville, AL).
  • Immunoglobulin sequences containing CDR1, 2 and 3 and framework regions were amplified using IgG and IgA-specific mixes for IgH, and kappa and lambda- specific primers for IgL.
  • IgM-expressing hybridoma samples, from which IgG or IgA heavy chains were not amplified using this approach, were sequenced using the iRepertoire iPair system. Final sequences were exported using iPair software.
  • Immunoglobulin sequences were analyzed for predicted CDR sequences, % identity to appropriate germlines, isotype of the constant regions and read counts.
  • Antibody- containing supernatants or purified antibodies were advanced to downstream assays. If multiple heavy or light chain sequences were detected within one well, their CDRs were aligned and compared for potential PCR errors. In cases where multiple sequences within a well were different, i.e., originated from separate clones, all potential combinations of light and heavy chains were recombinantly produced and tested in downstream assays. Wells that yielded a single HC/LC pair were advanced to recombinant expression and downstream assays. 5’ fragments of the constant regions were sequenced to identify the isotype of the antibody and compared to the experimentally identified isotype of hybridoma supernatants.
  • the resulting isotype of the heavy or light chain was assigned based on two or more positive readings from experimental (ex. ELISA and FACS) assays and sequencing.
  • a combined analysis of Ig isotype and their level of SHM of virus-specific antibodies revealed several key properties of the productive antiviral response.
  • Purified recombinant antibodies were assessed, in the HTRF assay described above, using either soluble RBD or S1 domains containing mutations found in naturally occurring viral variants, as well as mutations predicted to decrease binding of neutralizing antibodies.
  • Table 3 depicts the binding of identified anti-Spike antibodies, expressed as fold-binding over background. As anticipated, binding of some antibodies, such as PR201_00151 and PR194_00232, are negatively affected by specific mutations within the Spike domain (e.g. K417N).
  • binding by antibodies like PR199_00255, PR193_00018, and PR200_00622 are unaffected by the range of mutations analyzed, including variants containing single point mutations, as well as multiple point mutations that mimic the naturally occurring Spike proteins found on the B.1.1.7 and B.1.351 virus isolates.
  • a subset of antibodies, such as PR199_00255 and PR200_00622 also bind to Spike protein found on SARS-CoV-1, suggesting that they bind to a highly conserved epitope.
  • Binding of the antibodies PR913_00018, PR194_00232, and PR200_00622 were further characterized in the HTRF assay to determine EC50 of binding to a wide range of single and multi-point mutations, including to the B.1.1.7, B.1.429, P.1, and B.1.351 variants.
  • PR194_00232 is the most sensitive of the three antibodies to mutational drift within the Spike protein. Mutations, such as K417N and N501Y, mutations known to exist in naturally occurring variants, and consistent with the alanine scanning data, significantly decrease the ability of PR194_00232 to bind the Spike protein. Whereas other naturally occurring mutations, such as L452R, E484Q, or D614G do not impact binding relative to binding to the Washington reference Spike protein. In contrast, binding of PR193_0018 and PR200_00622 are not significantly impacted by any of the single point mutations tested.
  • binding by PR193_0018 and PR200_00622 to specific variant Spike proteins appears to be modestly enhanced over the reference Spike.
  • Similar observations were made when binding of PR193_0018, PR194_00232, and PR200_00622 was tested against RBD domain proteins containing the full complement of mutations known to exist in four different variants. Of particular interest is the binding to RBDs corresponding to the South African (B.1.351) and U.K. (B.1.1.7) variants. As predicted by the K417N and N501Y single point mutation data, binding of PR194_00232 to both the U.K. and S.A. variants is weaker than observed against the reference strain Spike protein.
  • Identified anti-Spike antibodies bind to non-overlapping epitopes within the RBD of SARS-Co-V-2 Spike.
  • Purified recombinant forms of the PR193_00018, PR194_00232, and PR200_00622 failed to compete with each other for binding to the SARS-CoV-2 RBD when assessed via biolayer interferometry on an Octet QKe instrument.
  • These data suggested the three antibodies bind to non-overlapping epitopes on the SARS- CoV-2 RBD.
  • Alanine scanning of the RBD was performed to identify residues critical for binding of each of the antibodies. Consistent with each of the antibodies binding to non- overlapping epitopes, non-overlapping sets of residues were identified as being critical for binding of the antibodies (Table 5).
  • Identified anti-Spike antibodies neutralize SARS-CoV-2 pseudovirus.
  • the functional consequence of antibodies binding to Spike was assessed in assays using pseudotyped replication-incompetent lentivirus which were used to infect HEK293 cells overexpressing Angiotensin converting enzyme 2 (ACE2).
  • Spike-expressing pseudovirus was generated with System Bioscience’s pPACK-SPIKE packaging system (System Biosciences, Cat #CVD19-500A-1) as per manufacturer’s protocol. Briefly, 8 x 10 6 293TN Producer cells (System Biosciences, LV900A-1) were plated in T150 flasks overnight.
  • Plasmids encoding lentiviral packaging proteins and Spike were added 1 mL of plain DMEM for each T150 being transfected.
  • 55 mL of PureFection reagent (System Biosciences; Cat #LV750A-1) was added to each 1 mL tube, vortexed for 10 seconds, and incubated at room temperature for 15 minutes.
  • the plasmid and PureFection mixture were added to a T150 flask containing 293TN cells and placed in a 37°C incubator containing 5% CO 2 for 48 hours.
  • Pseudovirus-containing supernatants were harvested at 48 hours and passed through a 0.45 micron PVDF filter to remove cellular debris.
  • Pseudoviruses were produced with the pPACK-SPIKE packaging kit, 10 4 ACE2- 293T cells were plated in the inner 60 wells of a white opaque 96 well flat bottom plate (Corning; Cat #3917) in 100 ⁇ L of ACE2-293T media overnight in a 37°C incubator containing 5% CO2. To determine infectivity of each lot of pseudovirus, pseudovirus- containing supernatants were thawed from -80°C and two-fold dilutions were performed. 100 mL of pseudovirus at various dilutions was added to ACE2-293T cells.
  • RVP right atrial pressure
  • 384 well plate 384 well plate
  • Media containing the indicated amount of antibody was added to each well, resulting in a final volume of 100 mL per well (96 well plate) or 25 mL per well (384 well plate).
  • the antibody/RVP mixture was pre-incubated for 1 hour in a 37°C incubator containing 5% CO 2 .
  • ACE2-293T target cells were added to each well (2 x 10 4 cells in 100 mL for a 96 well plate or 0.9 x 10 4 cells for a 384 well plate) and incubated for 72 hours.
  • PR194_00232 antibody that exhibited potent neutralization against pseudovirus expressing both the reference (SARS-CoV-2/human/USA/WA_CDC- WA1/2020) and D614G (SARS-CoV-2/human/Germany/BavPat 1/2020) were also assessed in neutralization assays using live virus of each of the isolates (FIGSs 4A and 4B).
  • Full dose response of purified antibodies confirmed strong neutralizing activity by antibodies such as PR194_00232.
  • the D614G variant is a widespread mutation [Plante et al. 2020] found in a number of different isolates.
  • Pseudovirus particles expressing Spike proteins that mimic the U.K. (B.1.1.7) and South African (B.1.351) isolates are neutralized by antibodies which retain binding to the mutated Spikes (Tables 3 &4). This is exemplified by the antibodies PR193_00018 and PR200_00622 (FIGS. 5A-5C).
  • Example 7 A cocktail of three anti-SARS-CoV-2 anti-Spike antibodies elicit combinatorial effects.
  • antibodies selective for non-overlapping epitopes on the SARS-CoV-2 Spike protein were assessed in pair-wise, and three-way combinations to identify additive, or preferably synergistic, neutralization.
  • the antibodies PR194_00232 (IMM20190), PR193_00018 (IMM20184), and PR200_00622 (IMM20253) were assessed in combinations to evaluate the combinatorial impact on neutralization of pseudovirus expressing a range of different variations of the Spike protein (FIGS. 6A-6C).
  • IC50 values for the triple combination and double combination comprising IMM20184 and IMM20253 were determined using RVPs, as described above.
  • 6AA-6C the triple combination of antibodies neutralized pseudoviruses corresponding to the USA/WA_CDC-WA1/2020 (reference sequence) and the CDC variants of concern (alpha/U.K./B.1.1.7, beta/South African/B.1.351, gamma/Brazil/P.1 and epsilon/California/B.1.429/427).
  • the IC 50 s for neutralization of the reference and California variants were not determined due to the potency exhibited against those variants; concentrations sufficiently low enough to obtain below 50% neutralization were not tested.
  • the observed combination response matrix of pseudovirus neutralization was used as input for the online SynergyFinder platform (4), where quadruplicate data points were input separately.
  • the highest single agent (HSA) reference model was applied, which quantifies synergy as the excess over the maximum response of a single drug in the combination.
  • Synergy between antibodies in each combination is reported as an overall synergy score (the average of observed synergy across the dose combination matrix) as well as a peak HSA score (the highest synergy score calculated across the dose combination matrix).
  • Synergy scores of less than -10, between -10 and 10, and greater than 10 indicate antagonistic, additive, and synergistic antibody combinations, respectively.
  • the residues critical for binding of IMM20184, IMM20190, and IMM20253 are spatially distinct from the residues mutated in the RBD of the B.1.617.2 (delta), B.1.617.3 (kappa), and C.37 (lambda) variants.
  • B.1.617.2 delta
  • B.1.617.3 kappa
  • C.37 lambda
  • IMM20190 binds to a large epitope that encompasses two distinct regions on the RBD (FIG. 2).
  • K417 and N501 residues known to be mutated in different variants, represent residues in each of the two binding sites. Mutation of one of those sites (N501Y), as observed in the alpha/B.1.1.7 variant, is sufficient to maintain IMM20190 activity (FIGS. 5A-5C) and provides for improved synergy with IMM20184/IMM20253.
  • the delta plus/B.1.617.2.ay1/2 variant contains a K417N mutation.
  • Example 9 Triple combination is active against live virus
  • neutralization assays on four different live virus variants under BSL3 conditions: USA/WA_CDC-WA1/2020 (reference sequence), Germany/BavPat 1/2020 (D614G), UK (B.1.1.7), and South African (B.1.351).
  • PRA pseudovirus neutralization assays
  • Assays using the Germany/BavPat1/2020 strain were performed in a manner sufficient to assess combinatorial effects via the HSA algorithm. Data demonstrated an overall additive effect, with peak HSA scores reaching levels of synergy (FIG. 7B)
  • Example 10 Example 10.
  • Abs neutralize virus in a hamster model of SARS-CoV-2 Antibodies capable of neutralizing live virus in vitro were assessed for the ability to neutralize virus in vivo using a hamster model of SARS-CoV-2 infection.
  • Hamsters treated with increasing doses of PR194_00232 were infected with SARS-CoV-2 (SARS-CoV- 2/human/USA/WA_CDC-WA1/2020) and viral load in the lungs were assessed at Day 4 post inoculation of the virus using standard tissue culture infectivity assays and plaque counting.
  • PR194_00232 was able to neutralize virus, relative to no-treatment controls, in a dose- dependent manner when dosed in the prophylactic setting (FIG. 12).
  • IMM-BCP-01 is able to clear virus from the lungs of hamsters infected with variants of concern. Hamsters were dosed prophylactically with IMM-BCP-01 one day prior to inoculation with either the Alpha (FIG. 16A) or Beta (FIG.
  • IMM-BCP-01 at the lowest doses tested provided levels of viral clearance that match, or exceed, those obtained by antibodies with demonstrated clinical efficacy.
  • increased doses of IMM-BCP-01 led to a dose- dependent improvement in viral clearance, with > four-log clearance of WA1/2020 and 2.5 log clearance of Beta at the highest doses tested. All doses tested represent clinically relevant doses.
  • Robust activity of the cocktail was observed regardless of inoculation titer used (FIG. 17).
  • IMM20184, IMM20190, and IMM20253 bind to both isolated RBD and Spike trimer when assessed by surface plasmon resonance (FIGS. 18A-18C).
  • IMM20184 can bind avidly to the Spike trimer, as signified by the decrease off-rate (Table 7), and crosslink two Spike monomers.
  • IMM20190 Consistent with its epitope overlapping with the ACE2 binding site, IMM20190 is able to compete binding of ACE2 to isolated RBD protein from the REF and Alpha variant (FIG. 19A and FIG. 19B), but its ability to compete ACE2 binding to the Beta variant is decreased (FIG.
  • IMM20184 effectively competes binding of ACE2 to all three isolated RBD (FIGS. 19A – 19C), despite binding to an epitope that is outside of known ACE2 binding site (FIG. 2). Despite exhibiting neutralization activity against both pseudovirus and live virus, IMM20253 is unable to effectively compete for ACE2 binding (FIGS. 19A-19C). This suggests the neutralization is due to a mechanism distinct from direct ACE2 competition. [0223] IMM20184, IMM20190 and IMM20253 were assessed for the ability to fix complement using standard assays [Nikitin et al., 2019]. As depicted in FIGS.
  • IMM-BCP-01 exhibited enhanced activity, over a wider concentration range, as compared to any of the individual antibodies and the IMM20184/IMM20253 two antibody combination.
  • IMM-BCP-01 induces a more robust antibody-dependent cellular cytotoxicity than any of the individual component antibodies when assessed in vitro using Promega’s ADCC Reporter Bioassay and S-expressing CHO-K1 target cells at a 2:1 effector:target cell ratio and manufacturer protocols.
  • the IMM-BCP-01 cocktail robustly induces multiple effector functions in a manner that is enhanced by the presence of two or more of its constituent antibodies as compared to the individual antibodies alone.
  • IMM20253 may neutralize SARS-CoV-2 through a mechanism that alters Spike protein conformation. As depicted in FIG. 2, IMM20253 binds to an epitope that is on the outside face of the RBD domain of the SARS-CoV-2 RBD. When in the closed conformation, the epitope is in close proximity to the N-terminal domain of a second Spike protein within the Spike trimer.
  • Nb nanobodies
  • Biochemical characterization the Class III Nb demonstrates that binding of the Nb to the Spike protein induces a conformational change to the post-fusion conformation. This presumably inactivates the virus’ ability to bind cells and provides a mechanism for the neutralization observed in vitro.
  • IMM20253 is unable to directly compete for ACE2 binding (FIGS. 20A-20C), but is able to neutralize both reference and alpha variant live virus as a single agent when measured as a function of virus internalization (Table 9). Together, these data suggest that IMM20253 binding to the outer face of the RBD may impart its intrinsic neutralization through induction of a conformational change in the Spike protein that prevents virus uptake into the cells without competing for ACE2 binding.
  • IMM20253 appears to be approximately 30-times more potent against the alpha strain than the delta strain. This may be a function of the internalization kinetics of the two different variants. This difference may also underlie the strong synergy observed between the IMM20184/IMM20190/IMM20253 in the context of neutralizing the alpha variant (FIGS. 7A-7C). It should be noted that like Greaney et al [Greany e al], Sun et al describe the region around the IMM20253 epitope as being of therapeutic interest, one to which antibodies are not known to exist [Greany et al] and one that is going to be difficult for antibodies to access [Sun et al].
  • IMM20190/Spike trimer complex maintains a similar hydrodynamic radius throughout the two hour incubation.
  • Binding of either IMM20253, IMM20184, or the combination of the two antibodies (IMM20253/IMM20184) induces combinatorial effects, preferably synergy, when combined with the ACE2-competitive antibody IMM20190.
  • Combinations of IMM20253, IMM20184, or IMM20253/IMM20184 induces synergy with other ACE2-competing enzymes.
  • IMM20253, IMM20184, or IMM20253/IMM20184 combines with one or more of the following antibodies to induce combinatorial, preferably synergistic, viral neutralization in vitro and promote in vivo viral clearance.
  • Examples of antibodies that combine to induce the combinatorial effect with IMM20253, IMM20184 or IMM20253/IMM20184 include, but are not limited to, sotrovimab, casirivimab, imdevimab, bamlanivimab, etesevimab, tixagevimab, cilgavimab, ADG2, ADG10, ADG20, ADG30, and CR3022.
  • IMM20253 works in combination with IMM20184, as well as in-house generated versions of REGN987 (imdevimab) and REGN933 (casirivimab) when assayed against B.1.617.2 ay2 pseudovirus.
  • Example 14 IMM20253 and IMM20279 and exhibit potent binding to the Spike protein of the Omicron variant. Individual antibodies were assessed, in the HTRF assay described above, using the full length Spike protein and soluble RBD domains of the Spike protein containing mutations found in the Omicron variant. FIGS.
  • FIG. 27A-27D depict the binding of the individual antibodies to the Spike-RBD of the Omicron variant, expressed as percentage binding, relative to the binding to the reference strain.
  • Binding of the antibodies IMM20190 and IMM20184 are negatively affected by the mutations within the Spike domain of the Omicron variant.
  • binding by the IMM20253 (FIG. 27C) and IMM20279 (FIG. 27D) antibodies are unaffected by the range of mutations within the Spike protein of the Omicron variant.
  • the binding affinity of the IMM20279 antibody to the RBD as well as the full-length Spike protein is comparable to that of the reference strain (FIG. 27D).
  • IMM20253 antibody neutralizes SARS-CoV-2 pseudovirus expressing the Omicron variant.
  • the functional consequence of the IMM20253 antibody binding to Spike was assessed. Pseudovirus infection and neutralization assays were performed by using standard methods described above.
  • the IMM20253 antibody exhibited potent neutralization against pseudovirus expressing the Spike protein from the B.1.1.529 (Omicron) variant (FIG. 28).
  • the neutralization activity was comparable to the activity against pseudovirus expressing the Spike protein from the reference strain (SARS-CoV- 2/human/USA/WA_CDC-WA1/2020), D614G (SARS-CoV-2/human/Germany/BavPat 1/2020), B.1.351 (beta/S.
  • IMM20253 exhibited equivalent neutralization of psuedovirus expressing the spike of either the BA.1 or BA.2 sub-lineage of the Omicron variant (FIG. 29).
  • IMM20184 and IMM20279 act to enhance IMM20253 activity in vivo. Hamsters were dosed prophylactically with IMM20253 (0.3 mg, 1 mg, or 3 mg), IMM20253/IMM20184 (0.5 mg each or 1.5 mg each), or IMM20253/IMM20279 (1.5 mg each) one day prior to inoculation with the Omicron BA.1 (FIG.
  • IMM20253 exhibited a dose-dependent decrease in lung titer. While IMM20184 showed a substantial decrease in in vitro binding of omicron Spike protein relative to REF (FIG. 27A) and IMM20279 also showed decreased binding of omicron Spike protein relative to REF (FIG. 27D), the combinations of the combination of IMM20253/IMM20184 and IMM20253/IMM20279 exhibits more robust clearance of Omicron BA.1 in vivo.
  • Example 17 CryoEM structures of IMM20184, IMM20290, IMM20253, and IMM20279 in complex with the SARS-CoV-2 spike protein.
  • the structures of antibodies in complex with the intact trimer of the SARS-CoV-2 trimer were solved by cryoEM to a resolution of approximately 7 Angstroms (FIGS 30A-30B, FIGS. 31A-31B, FIGS. 32A-32B, and FIGS. 34A-34B).
  • IMM20279 binds to a site that appears to overlap with the binding site of IMM20184.
  • Three Fabs of IMM20190 bind simultaneously to the trimer in a manner consistent with the Class 1 binders as defined by the CoVIC consortium and induce all three RBDs to adopt the up conformation (FIGS. 30A-30B).
  • Three Fabs of IMM20184 bind simultaneously to the spike trimer, perpendicular to the vertical axis of the spike. Binding appears to induce a large conformational change in the spike trimer, particularly in the RBD domains.
  • IMM20279 binds to similar regions on RBD as compared to IMM20184, but does so by binding from a different angle of attack. It binds at approximately a 45 degree angle to the vertical axis of the spike as compared to the 90 degree angle adopted by IMM20184. [0236] Only a single FAb of IMM20253 is ever observed to bind to the intact trimer (FIGS. 32A-32B). Binding results in loss of density in the cryoEM structure associated with the RBD and N-terminal domain of spike monomer that is not bound by the Fab fragment.
  • the structures of the ternary complex are in agreement with those obtained with the intact trimer. Residues within 4 Angstroms of the variable domains of each Fab are depicted in spheres. Those residues include all residues identified by alanine scanning. Residues buried by IMM20253 interaction with the RBD are conserved in the Omicron variant and provide additional basis for continued activity of this antibody against the variant.
  • Example 18 Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Viral Clearance of Single Ascending Doses of IMM-BCP-01 Administered Intravenously in Adults with Mild to Moderate COVID
  • This is a randomized, double-blind, placebo-controlled Phase 1 study to evaluate the safety, PK, and viral clearance of single ascending doses of IV IMM-BCP-01 in subjects with mild to moderate COVID-19 caused by infection with SARS-CoV-2 and/or its variants.
  • the primary objective of this study is to evaluate the safety and tolerability of intravenous (IV) IMM-BCP-01 in subjects with mild to moderate COVID-19 through Day 28.
  • the secondary objectives of the study are to: Determine PK and evaluate viral clearance after single ascending doses of IV IMM-BCP-01 in subjects with mild to moderate COVID-19 through Day 28. Evaluate the safety and tolerability, determine PK, and evaluate viral clearance of single ascending doses of IV IMM-BCP-01 in subjects with mild to moderate COVID-19 through Week 12.
  • the study consists of a screening period of up to 36 hours, a treatment period of one day, two further clinic visits, four visits that take place either in the clinic or at the subject's home, six virtual visits (telephone or video), and an end-of-study visit 12 weeks (+/- 5 days) after study drug dosing. The total duration of a subject's participation is approximately 90 days.
  • Subjects presenting at the clinic with signs and symptoms of mild to moderate COVID-19 and agreeing to participate in the study are screened, and if deemed eligible for the study, are randomized (2:1) to receive a single IV dose of IMM-BCP-01 or placebo on Day 1.
  • Subjects at risk of severe disease and those who have been vaccinated against COVID-19 within 6 weeks prior to screening or who have received monoclonal antibodies against SARS-CoV-2 and/or COVID-19 convalescent plasma at any time are not eligible.
  • Subjects are randomized to receive IMM-BCP-01 or placebo.
  • Table 10 Phase 1 Trial Design - - Drug: Placebo Placebo matching single dose of IMM-BCP- - Primary Outcome Measure is: 1.
  • TEAEs Treatment Emergent Adverse Events
  • TEAEs include clinical laboratory values, standard 12-lead ECGs, vital signs, pulse oximetry Secondary Outcome Measures are: 1. Incidence and severity of Treatment Emergent Adverse Events (TEAEs) (Time Frame: up to 12 weeks) 2. PK parameters measured by maximum observed concentration, time to maximum observed concentration, terminal elimination half-life, clearance, volume of distribution (Time frame: up to 28 days) 3. PK parameters measured by maximum observed concentration, time to maximum observed concentration, terminal elimination half-life, clearance, volume of distribution (Time frame: up to 12 weeks) 4. Anti-drug antibody change from baseline (Time frame: 28 days) 5.
  • Anti-drug antibody change from baseline (Time frame: 12 weeks) 6. Viral clearance change from baseline (Time frame: 28 days) 7. Viral clearance change from baseline (Time frame: 12 weeks)
  • Inclusion Criteria are: 1. Male or female 18 to 50 years of age, inclusive, at the time of signing the informed consent. 2. Subjects must have mild to moderate COVID-19 with symptom onset within 5 days prior to study drug administration (see Appendix Error! Reference source not found. for Food and Drug Administration [FDA] severity guidance). Subjects whose symptoms began >5 days (i.e. ⁇ 120 hours) prior to dosing or whose time of symptom onset cannot be accurately assessed are not eligible. 3.
  • Subjects must have at least 2 of the following COVID-19 symptoms: fever, cough, sore throat, rhinorrhea, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste or smell, or other symptoms that the Principal Investigator judges to be referrable to COVID-19. 4. Subjects must be able to maintain oxygen saturation (SpO 2 ) ⁇ 94% on room air (no supplemental oxygen). 5. Body mass index ⁇ 18.0 and ⁇ 30.0 kg/m 2 . 6. Body weight ⁇ 40 kg at screening. 7. Sexually active subjects of reproductive potential must agree to use highly effective contraception from signing of the informed consent through 90 days after infusion of the study drug (see Section Error! Reference source not found.). 8.
  • Subjects must have been in generally good health, as judged by the Principal Investigator, prior to onset of current COVID-19 illness, with no clinically significant medical history. 10. Subjects must be without clinically significant abnormalities as assessed by review of medical and surgical history, physical examination, vital signs measurement, ECG, and laboratory evaluations conducted at screening. Exclusion criteria are: 1. Has one or more symptoms suggestive of more severe illness with COVID-19 (see Appendix Error! Reference source not found. for FDA severity guidance) and/or requires hospitalization. 2. Is asymptomatic at screening or randomization, regardless of a positive COVID- 19 test. 3.
  • Is at increased risk of severe COVID-19 for any reason including but not limited to: cancer (basal cell carcinoma and prostate carcinoma in situ [Gleason ⁇ 6] are acceptable), chronic kidney disease, chronic obstructive pulmonary disease, heart condition (congestive heart failure II, III and IV as per New York Heart Association: coronary disease and any other cardiac condition that imposes high risk of developing severe COVID-19), immunocompromised state from solid organ transplant, sickle cell disease, or other condition, autoimmune disease, use of immunosuppressants (including high doses of systemic corticosteroids), type 1 or type 2 diabetes mellitus,current or prior history of smoking or vaping any product, including nicotine or THC. 4. Has any active infection, other than the underlying COVID-19. 5.
  • cancer basic cell carcinoma and prostate carcinoma in situ [Gleason ⁇ 6] are acceptable
  • chronic kidney disease chronic obstructive pulmonary disease
  • heart condition congestive heart failure II, III and IV as per New York Heart Association: coronary disease and any other cardiac condition
  • History or suspicion of excessive alcohol use (defined as drinking on average 14 drinks a week for males and 7 drinks a week for females) or of binge drinking (defined as 4 drinks on any day for males and 3 drinks on any day for females, for 5 or more days in the past month) 13. History of substance abuse or current use of any drugs of abuse 14.
  • Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family.
  • the coronavirus is mutating — does it matter? Nature.2020;585.
  • Puligedda R.D., Kouiavskaia, D., Adekar, S.P., Sharma, R., Devi Kattala, C., Rezapkin, G., Bidzhieva, B., Dessain, S.K, and Chumakov, K. Human monoclonal antibodies that neutralize vaccine and wild-type poliovirus strains. Antiviral Res. 2014;108: 36–43.
  • TNT003 an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins.

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Abstract

L'invention concerne des méthodes d'administration d'anticorps pour traiter des infections à SARS-CoV-2 chez un sujet. L'invention concerne également des compositions comprenant un ou plusieurs anticorps, des méthodes de traitement comprenant l'administration d'un ou de plusieurs anticorps, ainsi que des kits comprenant un ou plusieurs anticorps.
PCT/US2022/071875 2021-04-23 2022-04-22 Méthodes d'administration d'anticorps contre la protéine de spicule du sars-cov-2 WO2022226539A1 (fr)

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