Elements for improving COVID-19 or preventing SARS-COV-2 infection.

Abstract

Invention details;

Description

METHODS FOR TREATING OR PREVENTING SARS-CoV-2 INFECTIONS AND COVID-19 WITH ANTI -SARS-CoV-2 SPIKE GLYCOPROTEIN ANTIBODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 USC §119(e) of US Provisional Application Nos.: 63 / 034,348, filed June 3, 2020; 63 / 036,956, filed June 9, 2020; 63 / 038,274, filed June 12, 2020; 63 / 043,336, filed June 24, 2020; 63 / 060,592, filed August 3, 2020; 63 / 062,961, filed August 7, 2020; 63 / 065,799, filed August 14, 2020; 63 / 084,881, filed September 29, 2020; 63 / 085,066, filed September 29, 2020; 63 / 089,399, filed October 8, 2020; 63 / 090,690, filed October 12, 2020; 63 / 094,133, filed October 20, 2020; 63 / 105,779, filed October 26, 2020; 63 / 106,696, filed October 28, 2020; 63 / 112,140, filed November 10, 2020; 63 / 116,773, filed November 20, 2020; 63 / 119,593, filed November 30, 2020; 63 / 120,065, filed December 1, 2020; 63 / 124,980, filed December 14, 2020; 63 / 131,627, filed December 29, 2020; 63 / 141,423, filed January 25, 2021; 63 / 141,952, filed January 26, 2021; 63 / 142,471, filed January 27, 2021; 63 / 144,789, filed February 2, 2021; 63 / 150,978, filed February 18, 2021; 63 / 162,504, filed March 17, 2021; 63 / 162,996, filed March 18, 2021; 63 / 164,488, filed March 22, 2021; 63 / 165,654, filed March 24, 2021; 63 / 166,187, filed March 25, 2021; 63 / 173,468, filed April 11, 2021; 63 / 185,301, filed May 6, 2021; and 63 / 186,029, filed May 7, 2021, each of which is incorporated herein by reference in its entirety for all purposes.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under Agreement HHS0100201700020C, awarded by the U.S. Department of Health and Human Services. The Government has certain rights in the invention.REFERENCE TO A SEQUENCE LISTING

[0003] This application incorporates by reference the Sequence Listing submitted in Computer Readable Form as file 10807W001-Sequence, created on June 2, 2021, and containing 72,328 bytes.FIELD OF THE INVENTION

[0004] The present invention resides in the field of medicine, and relates to methods and pharmaceutical compositions for treating SARS-CoV-2 infections and COVID-19 via administration of antigen-binding molecules that bind a surface protein of SARS-CoV-2 (e.g., anti-SARS-CoV-2 spike glycoprotein antibodies and antigen-binding fragments thereof, or combinations of such antibodies or antigen-binding fragments).BACKGROUND

[0005] Coronaviruses are a family of enveloped, single-stranded RNA viruses. In recent decades, two highly pathogenic strains of coronavirus were identified in humans: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). These viruses were found to cause severe, and sometimes fatal, respiratory illness.

[0006] In December 2019, pneumonia of unknown cause was identified in clusters of patients in Wuhan City, China. A novel enveloped RNA betacoronavirus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - was identified in these patients, and the disease caused by SARS-CoV-2 infection was later designated coronavirus disease 2019 (COVID-19) by the World Health Organization. As of May 2020, more than 5.5 million confirmed cases of COVID-19 have been reported globally. The rapidly spreading, worldwide outbreak has prompted the World Health Organization to declare COVID-19 a pandemic and public health emergency of international concern.

[0007] Patients with COVID-19 are at risk for developing a variety of respiratory conditions, ranging from relatively mild respiratory symptoms to severe respiratory failure and death. Among hospitalized patients, intensive care and / or oxygen supplementation (e.g., mechanical ventilation) is often required, and reported fatality rates are high. In a report from the Chinese Center for Disease Control and Prevention that included 44,500 confirmed infections, nearly 20% of the patients presented with advanced respiratory symptoms (14% with dyspnea, hypoxia, or >50% lung involvement on imaging; 5% in respiratory failure, shock, or multiorgan failure). Another analysis of patients with COVID-19 in China found that, among 1,099 hospitalized patients, 5% had been admitted to an intensive care unit (ICU), 2.3% required invasive mechanical ventilation, and 1.4% died. Among patients with advanced disease on admission (defined as pneumonia, hypoxemia, and tachypnea) reported in China, these negative outcomes rose to 19%, 14.5%, and 8.1%, respectively. A report of 2,634 hospitalized patients with COVID-19 in the United States identified similar clinical outcomes: 14.2% were admitted to an ICU, 12.2% required invasive mechanical ventilation, and 21% died. Other reports have found that approximately 20% to 30% of hospitalized patients with COVID-19 and pneumonia require intensive care for respiratory support.

[0008] Coronaviruses have an RNA genome packaged in nucleocapsid (N) protein surrounded by an outer envelope. The envelope is comprised of membrane (M) protein and envelope (E) protein, which are involved in virus assembly, and spike (S) protein, which mediates entry into host cells. S proteins form large trimeric projections, providing the hallmark crown-like appearance of coronaviruses. S protein trimers bind to a host receptor and, after priming by cellular proteases, mediate host-virus membrane fusion. S protein appears to be central to viral infectivity by SARS-CoV-2. SARS-CoV-2 S protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) with high affinity, and in cell assays and animal models can utilize ACE2 as a functional receptor for host cell entry.

[0009] In light of the likely pivotal role of S protein in the pathogenesis of SARS-CoV-2, a number of efforts are underway to develop antibodies and vaccines that target this protein.BRIEF SUMMARY OF THE INVENTION

[0010] The present disclosure provides methods for improving one or more clinical parameters of COVID-19. In some cases, the method comprises administering a therapeutic composition to a subject in need thereof, wherein the therapeutic composition comprises at least one antigen-binding molecule that binds a surface protein of SARS-CoV-2. In some embodiments, the subject is a human patient with laboratory-confirmed SARS-CoV-2 and one or more COVID-19 symptom(s). In some cases, the one or more COVID-19 symptom(s) comprise fever, cough, or shortness of breath.

[0011] In some embodiments, the subject is selected from the group consisting of: (a) a human COVID-19 patient requiring low-flow oxygen supplementation; (b) a human COVID-19 patient requiring high-intensity oxygen therapy but not on mechanical ventilation; and (c) a human COVID- 19 patient requiring mechanical ventilation. In some cases, the subject is hospitalized due to one or more COVID-19 symptom(s). In some cases, the subject is an outpatient (i.e., treated on an outpatient basis).

[0012] The present disclosure also provides methods for preventing a SARS-CoV-2 infection or COVID-19 in a subject. In some cases, the method comprises administering a prophylactic composition to the subject, wherein the prophylactic composition comprises at least one antigen binding molecule that binds a surface protein of SARS-CoV-2, e.g., SARS-CoV-2 spike protein.

[0013] In some embodiments, the subject is an uninfected individual at high risk of SARS-CoV-2 infection. In some embodiments, the subject at high risk of SARS-CoV-2 infection is a healthcare worker, a first responder, or a household member of an individual with a positive test for a SARS- CoV-2 infection.

[0014] In some embodiments, the therapeutic or prophylactic composition comprises a first antigen-binding molecule that binds a first epitope on a surface protein of SARS-CoV-2, and a second antigen-binding molecule that binds a second epitope on a surface protein of SARS-CoV-2, wherein the first epitope and the second epitope are structurally non-overlapping.

[0015] In some embodiments, the therapeutic or prophylactic composition further comprises a third antigen-binding molecule that binds a third epitope on a surface protein of SARS-CoV-2,wherein the third epitope is structurally non-overlapping with the first epitope and the second epitope.

[0016] In some embodiments, the therapeutic or prophylactic composition comprises a first antigen-binding molecule that binds a first epitope on a surface protein of SARS-CoV-2, and a second antigen-binding molecule that binds a second epitope on a surface protein of SARS-CoV-2, wherein the first antigen-binding molecule and the second antigen-binding molecule are capable of simultaneously binding the surface protein of SARS-CoV-2. In some embodiments, the therapeutic or prophylactic composition further comprises a third antigen-binding molecule that binds a third epitope on a surface protein of SARS-CoV-2, wherein the first antigen-binding molecule, the second antigen-binding molecule, and the third antigen-binding molecule are capable of simultaneously binding the surface protein of SARS-CoV-2. In some embodiments, a) the first antigen-binding molecule comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 2, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 10; b) the second antigen-binding molecule comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 22, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 30; and c) the third antigen-binding molecule comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 73, and three light chain complementarity determining regions (CDRs) (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 81.

[0017] In any of the various embodiments, the surface protein of SARS-CoV-2 is a spike (S) protein comprising a receptor binding domain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 59.

[0018] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2 / 10,22 / 30, 42 / 50, and 73 / 81. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises six complementarity determining regions, HCDR1-HCDR2- HCDR3-LCDR1-LCDR2-LCDR3, comprising the amino acid sequences, respectively, selected from the group consisting of SEQ ID NOs: 4-6-8-12-14-16, 24-26-28-32-34-36, 44-46-48-52-34-54, and 75-77-79-83-85-87. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen binding fragment comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a human IgG heavy chain constant region. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain constant region of lgG1 or lgG4 isotype. In some cases, the anti-SARS- CoV-2 spike glycoprotein antibody comprises a heavy chain and light chain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18 / 20, 38 / 40, 56 / 58, and 89 / 91.

[0019] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody that has the same binding and / or blocking properties as a reference antibody comprising a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody that has the same binding and / or blocking properties as a reference antibody comprising a heavy chain and light chain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18 / 20, 38 / 40, 56 / 58, and 89 / 91.

[0020] In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1- LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30. In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1- LCDR2-LCDR3, comprising the amino acid sequences, respectively, of SEQ ID NOs: 4-6-8-12-14- 16, and the second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, comprising the amino acid sequences, respectively, of SEQ ID NOs: 24-26-28-32-34-36.In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and the second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30. In some embodiments, the first and the second anti-SARS-CoV- 2 spike glycoprotein antibodies comprises human IgG heavy chain constant regions. In some cases, the first and the second anti-SARS-CoV-2 spike glycoprotein antibodies comprises heavy chain constant regions of lgG1 or lgG4 isotype. In some cases, the first anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and the second anti- SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid sequence of SEQ ID NO: 40.

[0021] In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof that has the same binding and / or blocking properties as a reference antibody comprising a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and the second antigen-binding molecule is a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof that has the same binding and / or blocking properties as a reference antibody comprising a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30. In some embodiments, the first antigen-binding molecule is a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof that has the same binding and / or blocking properties as a reference antibody comprising a heavy chain and a light chain pair comprising the amino acid sequences of SEQ ID NOs: 18 / 20, and the second antigen-binding molecule is a first anti-SARS- CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof that has the same binding and / or blocking properties as a reference antibody comprising a heavy chain and a light chain pair comprising the amino acid sequences of SEQ ID NOs: 38 / 40.

[0022] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising six complementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 42 and light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 50. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises sixcomplementarity determining regions, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, comprising the amino acid sequences, respectively, of SEQ ID NOs: 44-46-48-52-34-54. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and a LCVR comprising the amino acid sequence of SEQ ID NOs: 50. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a human IgG heavy chain constant region. In some cases, the anti-SARS- CoV-2 spike glycoprotein antibody comprises a heavy chain constant region of lgG1 or lgG4 isotype. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 56, and a light chain comprising the amino acid sequence of SEQ ID NO: 58.

[0023] In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody that has the same binding and / or blocking properties as a reference antibody comprising a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 42 / 50. In some embodiments, the antigen-binding molecule is an anti-SARS-CoV-2 spike glycoprotein antibody that has the same binding and / or blocking properties as a reference antibody comprising a heavy chain and light chain pair comprising the amino acid sequences of SEQ ID NOs: 56 / 58.

[0024] In any of the various embodiments of the methods discussed above or herein, the therapeutic or prophylactic composition comprises 1 mg to 10 g of the antigen-binding molecule(s). In some cases, the therapeutic or prophylactic composition comprises about 1.2 g of mAb10933 and about 1.2 g of mAb10987. In some cases, the therapeutic or prophylactic composition comprises about 1.2 g of mAb10985. In some cases, the therapeutic or prophylactic composition comprises about 4.0 g of mAb10933 and about 4.0 g of mAb10987. In some cases, the therapeutic or prophylactic composition comprises about 150 mg of mAb10933 and about 150 mg of mAb10987. In some cases, the therapeutic or prophylactic composition comprises about 150 mg of mAb10985. In some cases, the therapeutic or prophylactic composition comprises about 300 mg of mAb10933 and about 300 mg of mAb10987. In some cases, the therapeutic or prophylactic composition comprises about 300 mg of mAb10985. In some cases, the therapeutic or prophylactic composition comprises about 600 mg of mAb10933 and about 600 mg of mAb10987. In some cases, the therapeutic or prophylactic composition comprises about 600 mg of mAb10985. In some case, the therapeutic or prophylactic composition comprises from 150 mg to 1200 mg of mAb10933 and from 150 mg to 1200 mg of mAb10987. In some cases, the therapeutic or prophylactic composition further comprises from 150 mg to 1200 mg of mAb10985. In some cases, the therapeutic or prophylactic composition comprises about 1.2 g of mAb10989.

[0025] In some embodiments, the therapeutic or prophylactic composition is administered to the subject by intravenous infusion or subcutaneous injection. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 1.2 g of mAb10987 and 1.2 g of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 1.2 g of mAb10987 and 1.2 g of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 600 mg of mAb10987 and 600 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 600 mg of mAb10987 and 600 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 4 g of mAb10987 and 4 g of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 4 g of mAb10987 and 4 g of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 300 mg of mAb10987 and 300 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 300 mg of mAb10987 and 300 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 150 mg of mAb10987 and 150 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 150 mg of mAb10987 and 150 mg of mAb10933 via intravenous infusion. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS-CoV-2, comprising administering 600 mg of mAb10987 and 600 mg of mAb10933 via subcutaneous injection. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 600 mg of mAb10987 and 600 mg of mAb10933 via subcutaneous injection. In some embodiments, the present disclosure provides a method for treating a subject infected with SARS- CoV-2, comprising administering 300 mg of mAb10987 and 300 mg of mAb10933 via subcutaneous injection. In some embodiments, the present disclosure provides a method for treating a subject with COVID-19, comprising administering 300 mg of mAb10987 and 300 mg of mAb10933 via subcutaneous injection. In the above embodiments, mAb10987 and mAb10933 may be co administered simultaneously, e.g., by combining the antibodies in an IV bag prior to a singleinfusion, or by combining the antibodies into a syringe prior to a single injection. Alternatively, the two antibodies may be administered as two separate subcutaneous injections. In the above embodiments, the subject may be at high risk for clinical complications.

[0026] In any of the various embodiments, the subject exhibits one or more efficacy parameters, following administration of the therapeutic composition, selected from the group consisting of: (a) reduction from baseline in SARS-CoV-2 viral shedding; (b) at least 1 point improvement in clinical status using the 7-point ordinal scale; (c) reduction or elimination of need for oxygen supplementation; (d) reduction or elimination of need for mechanical ventilation; (e) prevention of COVID-19-related mortality; (f) prevention of all-cause mortality; and (g) change in serum concentration of one or more disease-related biomarkers. In some cases, the 7-point ordinal scale is: [1] Death; [2] Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; [3] Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; [4] Hospitalized, requiring supplemental oxygen; [5] Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19-related or otherwise); [6] Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; and [7] Not hospitalized. In some cases, the one or more efficacy parameters are measured 21 days after administration of a first dose of the therapeutic composition. In some cases, the reduction from baseline in SARS-CoV-2 viral shedding is determined by real-time quantitative PCR (RT-qPCR) in nasopharyngeal swab samples, nasal samples, or saliva samples. In some cases, the change in serum concentration of one or more disease-related biomarkers is a change in c-reactive protein, lactate dehydrogenase, D-dimer, or ferritin.

[0027] In any of the various embodiments, the subject exhibits less than 5 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions, following administration of the therapeutic composition. In some cases, the less than 5 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions are exhibited by the subject within 29 days following administration of a first dose of the therapeutic composition. In some cases, the subject exhibits less than 4, less than 3, less than 2, or less than 1 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions.

[0028] In some embodiments, the subject tests negative for SARS-CoV-2 within 2 days to 3 weeks following first administration of the therapeutic composition. In some cases, the negative test for SARS-CoV-2 is determined by RT-qPCR in nasopharyngeal swab samples, nasal samples, or saliva samples.

[0029] In some embodiments, the methods further comprise administering an additional therapeutic agent to the subject. In some cases, the additional therapeutic agent is an antiviral compound. In some embodiments, the antiviral compound is remdesivir. In some cases, the additional therapeutic agent is an IL-6 or IL-6R blocker. In some embodiments, the additional therapeutic agent is tocilizumab or sarilumab. In some cases, the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is administered prior to the therapeutic composition. In some embodiments, the additional therapeutic agent is administered after or concurrent with the therapeutic composition. In any of the various embodiments of the methods discussed above or herein, the subject may be seronegative for SARS-CoV-2 infection.

[0030] In one aspect, the present disclosure provides a method for improving one or more clinical parameters of a SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject with a SARS-CoV-2 infection, wherein the therapeutic composition comprises a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three HCDRs and three LCDRs contained within an HCVR and an LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30, wherein said therapeutic composition alleviates at least one symptom of SARS-CoV-2 infection more rapidly when administered to a population of seronegative subjects as compared to a comparable population of seronegative subjects administered a placebo.

[0031] In one aspect, the present disclosure provides a method for improving one or more clinical parameters of a SARS-CoV-2 infection, wherein the method comprises administering a therapeutic composition to a subject with a SARS-CoV-2 infection, wherein the therapeutic composition comprises a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three HCDRs and three LCDRs contained within an HCVR and an LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30, wherein said therapeutic composition alleviates at least one symptom of SARS-CoV-2infection more rapidly when administered to a population of seronegative subjects as compared to a comparable population of seropositive subjects.

[0032] In one aspect, the present disclosure provides a method for improving one or more clinical parameters of a SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject with a SARS-CoV-2 infection, wherein the therapeutic composition comprises a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three HCDRs and three LCDRs contained within an HCVR and an LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30, wherein said therapeutic composition reduces viral load through 7 days post administration (Day 7) to a population of subjects as compared to the day of administration (Day 0).

[0033] In some embodiments, the time-weighted-average change from baseline nasopharyngeal (NP) viral load through Day 7 in a seronegative population of subjects is at least 0.86 Iog10 copies / mL greater reduction (p<0.0001) in patients treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, as compared to a comparable population of subjects treated with a placebo.

[0034] In some embodiments, the change from baseline nasopharyngeal (NP) viral load through Day 7 in a seronegative population of subjects is at least 1.04 Iog10 copies / mL greater reduction (p<0.0001) in patients treated with 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, as compared to a comparable population of subjects treated with a placebo.

[0035] In some embodiments, the average change from baseline nasopharyngeal (NP) viral load through Day 7 in the population of subjects is at least 0.71 Iog10 copies / mL greater reduction (p<0.0001) in patients treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, as compared to a comparable population of subjects treated with a placebo.

[0036] In some embodiments, the average change from baseline nasopharyngeal (NP) viral load through Day 7 in the population of subjects is a 0.86 Iog10 copies / mL greater reduction (p<0.0001) in patients treated with 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, as compared to a comparable population of subjects treated with a placebo.

[0037] In one aspect, the present disclosure provides a method for improving one or more clinical parameters of a SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject with a SARS-CoV-2 infection, wherein the therapeutic composition comprises a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three HCDRs and three LCDRs contained within an HCVR and an LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 22 / 30, wherein said therapeutic composition reduces viral load in a population of subjects.

[0038] In some embodiments of the methods discussed above or herein, administration of said therapeutic composition comprises administering 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, and wherein said administering produces a mean reduction in viral load at day 7 post-administration compared to baseline viral load measured at day 0 pre-administration of at least 3.00 Iog10 copies / mL. In some cases, said reduction is at least 3.50 Iog10 copies / mL. In some cases, said reduction is at least 3.90 Iog10 copies / mL.

[0039] In some embodiments, administration of said therapeutic composition comprises administering 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, and wherein said administering produces a mean reduction in viral load at day 7 post-administration compared to baseline viral load measured at day 0 pre-administration of at least 3.50 Iog10 copies / mL. In some cases, said reduction is at least 3.75 Iog10 copies / mL. In some cases, said reduction is at least 4.09 Iog10 copies / mL.

[0040] In one aspect, the present disclosure provides a method for improving one or more clinical parameters of a SARS-CoV-2 infection, the method comprising administering a therapeutic composition to a subject with a SARS-CoV-2 infection, wherein the therapeutic composition comprises a first anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) amino acid sequence pair comprising the amino acid sequences of SEQ ID NOs: 2 / 10, and a second anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment thereof comprising three HCDRs and three LCDRs contained within an HCVR and an LCVR amino acid sequence pair comprising the amino acid sequences of SEQ IDNOs: 22 / 30, wherein said therapeutic composition reduces time to symptom alleviation (defined as symptoms becoming mild or absent) by a median of 4 days in a population of subjects treated with 0.6 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 0.6 g of the second anti-SARS- CoV-2 spike glycoprotein antibody or 1.2 g of the first anti-SARS-CoV-2 spike glycoprotein antibody and 1.2 g of the second anti-SARS-CoV-2 spike glycoprotein antibody, as compared to a comparable population of subjects treated with a placebo. In some embodiments, the subjects and / or population of subjects comprises subjects not hospitalized for COVID-19.

[0041] Any of the various methods discussed above or herein can be reformatted as (i) antigen binding molecules or antibodies (and antigen-binding fragments) for use in a method of treating and / or preventing SARS-CoV-2 infections and / or COVID-19, and / or for treating, preventing and reducing the severity or progression of a SARS-CoV-2 infection and / or COVID-19, or symptoms thereof, or (ii) use of the antigen-binding molecules or antibodies (and antigen-binding fragments) in the manufacture of a medicament for treating and / or preventing SARS-CoV-2 infections and / or COVID-19, and / or for treating, preventing and reducing the severity or progression of a SARS-CoV- 2 infection and / or COVID-19, or symptoms thereof. In particular, the present disclosure includes use of antigen-binding molecules that bind a surface protein of SARS-CoV-2, including the anti- SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein, for preventing and treating SARS-CoV-2 infections and COVID-19 and / or for treating, preventing and reducing the severity or progression of a SARS-CoV-2 infection and / or COVID-19, or symptoms thereof. The present disclosure also includes use of antigen-binding molecules that bind a surface protein of SARS-Co-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein, in the manufacture of a medicament for preventing and treating SARS-CoV-2 infections and COVID-19 and / or for treating, preventing and reducing the severity or progression of a SARS-CoV-2 infection and / or COVID-19. Where methods are discussed herein with reference to a combination of two anti-SARS-CoV-2 spike protein antibodies, such combinations include use of a first such antibody or antigen-binding fragment thereof in the manufacture of a medicament for use in combination with a second such antibody or antigen-binding fragment thereof (or a third or fourth, etc. such antibody or antigen-binding fragment), as well as use of the second such antibody or antigen-binding fragment thereof (or a third or fourth, etc. such antibody or antigen-binding fragment) in the manufacture of a medicament for use in combination with the first such antibody.

[0042] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined withanother related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.

[0043] Other embodiments will become apparent from a review of the ensuing detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1A and FIG. 1B illustrate the overview of a study design evaluating the prophylactic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a rhesus macaque model of SARS- CoV-2 infection (FIG. 1A), and the impact of anti-SARS-CoV-2 spike glycoprotein antibody prophylaxis on viral genomic RNA (gRNA) and subgenomic RNA (sgRNA) in nasopharyngeal swabs and bronchioalveolar lavage (BAL) fluid (FIG. 1B).

[0045] FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D illustrate the overview of a study design evaluating prophylactic and therapeutic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a rhesus macaque model of SARS-CoV-2 infection (FIG. 2k), the impact of anti-SARS-CoV-2 spike glycoprotein antibody prophylaxis on viral gRNA and sgRNA in nasopharyngeal swabs and oral swabs (FIG. 2B), the impact of anti-SARS-CoV-2 spike glycoprotein antibody treatment on viral gRNA and sgRNA in nasopharyngeal swabs and oral swabs (FIG. 2C), and representative images of histopathology in lungs of treated and placebo animals (FIG. 2D).

[0046] FIG. 3A and FIG. 3B illustrate the results of RNA sequence analysis of viral RNA from the study illustrated in FIGs. 2A-2D. FIG. 3A shows the frequencies of all amino acid changes identified in the spike protein across all virus sequences; each dot represents the frequency of the corresponding amino acid change in a specific virus sample, and samples are grouped based on treatment regimen: isotype control (placebo), therapeutic antibodies administered prior (prophylactic) or following (treatment) viral challenge. FIG. 3B shows detailed genomic information on all amino acid changes identified within the spike protein sequence across all samples; for each sample, the frequency of all mutations has been calculated, and these frequencies are shown as percentage of the virus population with the amino acid change in the input virus or as range of frequency percentages (lowest to highest %) in the virus populations isolated from the placebo, prophylactic and therapeutic groups.

[0047] FIG. 4A, FIG. 4B and FIG. 4C illustrate the overview of a study design evaluating the therapeutic and prophylactic efficacy of anti-SARS-CoV-2 spike glycoprotein antibodies in a golden Syrian hamster model of SARS-CoV-2 infection (FIG. 4A), the impact of anti-SARS-CoV-2 spikeglycoprotein antibody treatment or prophylaxis on weight loss (FIG. 4B), and the impact of anti- SARS-CoV-2 spike glycoprotein antibody therapy on levels of gRNA and sgRNA in lungs.

[0048] FIG. 5 is a schematic overview of the study design discussed in Example 2.

[0049] FIG. 6 illustrates a CONSORT diagram showing the screening, randomization and treatment of subjects in the study discussed in Example 2.

[0050] FIG. 7 illustrates the relationship between baseline serum antibody status and baseline viral load in the placebo arm of the study discussed in Example 2.

[0051] FIG. 8 illustrates viral load over time in the placebo arm by baseline serum antibody status in the study discussed in Example 2.

[0052] FIG. 9 illustrates the proportion of patients in the placebo arm with ≥1 Covid-19-related medically-attended visit (MAV) through day 29 in the study discussed in Example 2.

[0053] FIG. 10A and FIG. 10B illustrate time-weighted-average (TWA) daily change from baseline in viral load (log10copies / mL) with REGEN-COV treatment (forest plots) in the study discussed in Example 2.

[0054] FIG. 11 illustrates TWA daily change from baseline in viral load (log10copies / mL) with REGEN-COV treatment (graphs) in the study discussed in Example 2. Shown is the change in mean viral load (in Iog10 copies per milliliter) from baseline at each visit through day 7 in the overall population (modified full analysis set, which excluded patients who tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by qualitative reverse-transcriptase polymerase chain reaction at baseline) and in groups defined according to baseline antibody status and baseline viral load. I bars in Panel C indicate the standard error. The lower limit of detection (dashed line) is 714 copies per milliliter (2.85 Iog10 copies per milliliter). IV, intravenous(ly); SE, standard error.

[0055] FIG. 12 illustrates time to sustained negative RT-qPCR by baseline viral load category in the study discussed in Example 2.

[0056] FIG. 13 illustrates the proportion of patients with high viral load at each visit in the study discussed in Example 2.

[0057] FIG. 14A, FIG. 14B, and FIG. 14C illustrate the proportion of patients with Covid-19- related MAVs in the study discussed in Example 2.

[0058] FIG. 15A, FIG. 15B and FIG. 15C illustrate the viral load through day 29 in patients with and without ≥1 Covid- 19- related MAVs in the study discussed in Example 2.

[0059] FIG. 16 illustrates that seronegative patients (n=217) had much higher viral loads than those who had already developed their own antibodies (seropositive) to SARS-CoV-2 at the time of randomization.

[0060] FIG. 17 illustrates that, among hospitalized patients with COVID-19 on low flow supplemental oxygen, seropositive patients had lower cumulative incidence of death or mechanical ventilation compared to seronegative patients

[0061] FIG. 18 illustrates clinical outcomes in Cohort 1, by serostatus and viral load. Clinical outcomes were worse in patients who were seronegative at baseline or who had high viral load at baseline.

[0062] FIG. 19 illustrates a seamless phase 1 / 2 / 3 study design in hospitalized patients with COVID-19.

[0063] FIG. 20 illustrates the number of patients that are seronegative, seropositive, or having borderline results or missing data (“other”), in the full analysis set (FAS), modified full analysis set (mFAS), having viral loads > 106, or having viral loads >107.

[0064] FIG. 21 illustrates the mean viral load in seronegative patients (circles), seropositive patients (squares), and other patients (borderline results or missing data; triangles). TWA, time- weighted average; Cl, confidence interval.

[0065] FIG. 22 illustrates the mean viral load in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles).

[0066] FIG. 23 illustrates change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by viral load: >104copies / ml, >105copies / ml, >106copies / ml, and >107copies / ml.

[0067] FIG. 24 illustrates mean viral load over time in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by baseline viral load: >104copies / ml, >105copies / ml, >106copies / ml, and >107copies / ml.

[0068] FIG. 25 illustrates mean viral load over time in seronegative or seropositive patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by serostatus and clinical trial: 2066 (hospitalized study; Example 1) and 2067 (ambulatory / outpatient study; Example 2).

[0069] FIG. 26 illustrates change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by serostatus and clinical trial: 2066 (hospitalized study; Example 1) and 2067 (ambulatory / outpatient study; Example 2).

[0070] FIG. 27 illustrates mean viral load over time in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by baseline viral load and clinical trial: 2066 (hospitalized study; Example 1) and 2067 (ambulatory / outpatient study; Example 2).

[0071] FIG. 28 illustrates change in mean viral load from baseline in patients treated intravenously with placebo (circles), 1.2 g mAb10933 + 1.2 mAb10987 (2.4 g total; squares), or 4 g mAb10933 + 4 mAb10987 (8 g total; triangles). Graphs divide patients by baseline viral load and clinical trial: 2066 (hospitalized study; Example 1) and 2067 (ambulatory / outpatient study; Example 2).

[0072] FIG. 29 illustrates % neutralization of a pseudotyped VSV expressing the B.1.1.7 SARS- CoV-2 variant (also called the “UK variant”) by mAb10933 (REGN10933) alone, mAb10987 (REGN 10987) alone, and the combination of mAb10933 + mAb10987 (REGN 10933 +REGN 10987). The antibodies both alone and in combination neutralize the virus.

[0073] FIG. 30 illustrates the weekly viral load for individual symptomatic subjects (filled symbol) and asymptomatic subjects (open symbol) in the two treatment groups, placebo and mAb10933 + mAb10987 (also collectively called REGEN-COV™). Infections in the REGEN-COV™ group lasted no more than 1 week, while approximately 40% of infections in the placebo group lasted 3-4 weeks, as assessed by measuring viral load.

[0074] FIG. 31 illustrates the phase 3 study schematic for non-hospitalized patients treated with REGEN-COV or placebo.

[0075] FIG. 32 illustrates an amendment to the phase 3 cohort enrollment, modifying the trial to include 2400 mg and 1200 mg doses.

[0076] FIG. 33 illustrates the clinical efficacy of REGEN-COV, comparing treatment effects in placebo, 2400 mg, and 1200 mg intravenous treatment groups. Treatment significantly reduced COVID-19-related hospitalization or all-cause death and duration of symptoms, and there was a similar treatment effect in the two dose levels (higher confidence in point estimates for 2400 mg dose due to larger event size).

[0077] FIG. 34 illustrates balanced baseline demographics in the phase 3 cohort 1 mFAS (patients ≥18 years who are SARS-CoV-2 PCR-positive at baseline and have ≥1 risk factor for severe covid-19) for outpatients treated with 8000 mg REGEN-COV, 2400 mg REGEN-COV, 1200 mg REGEN-COV, or placebo (PBO). Phase 3 patients had higher baseline viral load and higher baseline seronegativity than high-risk patients in phase 1 / 2.

[0078] FIG. 35 illustrates a Kaplan-Meier curve for time to COVID-19 related hospitalization or all cause death through day 29 post-administration of 1200 mg mAb10933 +_1200 mg mAb10987(intravenously) in subjects with ≥ 1 risk factor for severe COVID-19. The risk for COVID-19 hospitalization or all-cause death was reduced by 71% in the overall modified full analysis set (mFAS) population compared to placebo.

[0079] FIG. 36 illustrates a Kaplan-Meier curve for time to COVID-19 related hospitalization or all cause death through day 29 post-administration of 600 mg mAb10933 +_600 mg mAb10987 (intravenously) in subjects with ≥ 1 risk factor for severe COVID-19. The risk for COVID-19 hospitalization or all-cause death was reduced by 71% in the overall modified full analysis set (mFAS) population compared to placebo.

[0080] FIG. 37 illustrates the number of COVID-19 related hospitalization or all-cause death through day 29 post-administration of 1200 mg mAb10933 +_1200 mg mAb10987 (intravenously) or 600 mg mAb10933 +_600 mg mAb10987 (intravenously) in subjects with ≥ 1 risk factor for severe COVID-19. Results were consistent between the two treatment groups.

[0081] FIG. 38 illustrates a Kaplan-Meier curve for time to resolution of symptoms consistent with COVID-19 among patients with ≥ 1 risk factor for severe COVID-19. HR: hazard ratio. Median time to symptom resolution was 14 days in the placebo group and 10 days in each of the 1.2 g and 2.4 g treatment groups.

[0082] FIG. 39 illustrates time to symptom resolution in outpatients with ≥ 1 risk factor for severe COVID-19. Symptom resolution improvement was consistent between the modified full analysis set (mFAS) population and those with high viral load or seronegativity at baseline.

[0083] FIG. 40 illustrates serious adverse events (SAEs) and adverse events of special interest (SAEIs) in Phase 3 cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO). Safety among all treatment arms was acceptable and no serious safety concerns were identified. In particular, SAEs and AESIs occurred more frequently in the placebo group compared to any REGEN-COV treatment group, no imbalance in safety was found between the different REGEN-COV dose groups, no safety signal was observed in safety labs (chemistry, hematology), more patients had treatment-emergent adverse events (TEAEs) with fatal outcome in the placebo group as compared to any REGEN-COV treatment group, and very few patients experienced AESIs of infusion-related reactions (IRRs) and hypersensitivity reactions in REGEN-COV dose groups.

[0084] FIG. 41 illustrates serious adverse events (SAEs) in Phase 3 cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO) that occurred in >1 patient in any treatment group. SAEs occurred more frequently in the placebo group as compared to any REGEN-COV dose groups, the more frequently reportedevents were consistent with COVID-19 and associated complications, and a lower frequency of events in the REGEN-COV dose groups was consistent with treatment benefit.

[0085] FIG. 42 illustrates adverse events of special interest (AESIs) (e.g., infusion-related reactions or hypersensitivity reactions) in Phase 3 cohort 1 outpatients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo (PBO) that occurred in >1 patient in any treatment group. There were low rates of infusion-related reactions or hypersensitivity reactions across all dose groups.

[0086] FIG. 43 illustrates the change from baseline in viral load (Iog10 copies / mL) at Day 7 post treatment with mAb10933 and mAb10987 in outpatients with 1 or more risk factors for severe COVID-19.

[0087] FIG. 44 illustrates the change from baseline in viral load (Iog10 copies / mL) at Day 7 post treatment with mAb10933 and mAb10987 in outpatients with 1 or more risk factors for severe COVID-19. N: number of subjects; SD: standard deviation; D7: day 7; mFAS: modified full analysis set; PA6: protocol amendment 6, which modified the clinical trial protocol to remove the 8 g dose and introduce the 1.2 g dose.

[0088] FIG. 45 illustrates the demographics and baseline characteristics for seronegative IV patients (seronegative mFAS). The groups were well balanced.

[0089] FIG. 46 illustrates the demographics and baseline characteristics for seronegative subcutaneous patients (seronegative mFAS). The groups were well balanced.

[0090] FIG. 47 illustrates the least squares mean of change from baseline viral load in patients treated with mAb10933 + mAb10987 either intravenously (IV) or subcutaneously (SC), over time.

[0091] FIG. 48 illustrates the change from baseline viral load in the 2067 (Example 2; outpatient) phase 1 / 2 and phase 3 trials, and the 20145 (Example 7; dose range-finding) trial among seronegative patients. The change from baseline viral load was comparable between the studies.

[0092] FIG. 49 illustrates safety data for the clinical trial described in Example 7. All treatment groups were well tolerated, with no safety signal identified.

[0093] FIG. 50 illustrates the treatment emergent adverse events among the patients treated subcutaneously in the clinical trial described in Example 7. All doses were well tolerated with few treatment emergent adverse events. Among those events observed, the events were not serious.

[0094] FIG. 51 illustrates a comparison between the clinical trial described in Example 2 (“2067 analysis set”) and the clinical trial described in Example 7 (“20145 analysis set”). 2067 data is presented both before and after the amendment that changed the dosage groups from 2400 mg and 8000 mg to 1200 mg and 2400 mg (original Ph3 and amended Ph3, respectively). Theanalysis of change from baseline to day 7 in viral load (Iog10 copies / mL) showed similar viral load reduction before and after amendment change and across all doses.

[0095] FIG. 52 illustrates the mean viral load for patients with outcomes of hospitalization / death and without outcomes of hospitalization / death. Prior to PA 6 shows viral load in patients treated with placebo (PBO), 2.4 g of REGEN-COV, or 8.0 g of REGEN-COV. PA 6 or later shows viral load in patients treated with PBO, 1.2 g of REGEN-COV, or 2.4 g of REGEN-COV.

[0096] FIG. 53 illustrates spaghetti plots of viral load for individual patients with outcomes of hospitalization / death and without outcomes of hospitalization / death (placebo, 1.2 g REGEN-COV, and 2.4 g REGEN-COV).

[0097] FIG. 54 illustrates spaghetti plots of viral load for individual patients with outcomes of hospitalization / death and without outcomes of hospitalization / death (placebo, 2.4 g REGEN-COV, and 8.0 g REGEN-COV).

[0098] FIG. 55 illustrates boxplots of viral load at baseline and Day 7 post-treatment for patients with outcomes of hospitalization / death and without outcomes of hospitalization / death (placebo, 1.2 g REGEN-COV, and 2.4 g REGEN-COV).

[0099] FIG. 56 illustrates boxplots of viral load at baseline and Day 7 post-treatment for patients with outcomes of hospitalization / death and without outcomes of hospitalization / death (placebo, 2.4 g REGEN-COV, and 8.0 g REGEN-COV).

[0100] FIG. 57 illustrates an overview of the clinical trial described in Example 7.

[0101] FIG. 58 illustrates change in Day 7 post-treatment viral load in all patients, seronegative patients, and seropositive patients, divided between patients with and without COVID-19 related events. Patients on placebo with an event had higher baseline virus and cleared the virus more slowly, while seropositive patients who had events had similarly high baseline viral levels and delayed clearance, indicating that they may have had an ineffective antibody response.

[0102] FIG. 59 illustrates the hierarchy for hypothesis testing in the Phase 3 prevention trial described in Example 4, and the treatment effect for each endpoint. REGEN-COV significantly prevented infection, modified disease progression, and reduced viral burden.

[0103] FIG. 60 illustrates the symptomatic infection endpoints in the Phase 3 prevention trial described in Example 4. REGEN-COV significantly reduced symptomatic COVID-19 by all three definitions.

[0104] FIG. 61 illustrates the cumulative incidence of symptomatic infection in the Phase 3 prevention trial described in Example 4. REGEN-COV prevented the onset of symptomatic infection starting 1 day after dosing.

[0105] FIG. 62 illustrates the onset of symptomatic infection by week in the Phase 3 prevention trial described in Example 4. REGEN-COV reduced the risk of symptomatic infections by 81% overall, 72% in the first week, and 93% in weeks 2-4.

[0106] FIG. 63 illustrates that the number of weeks of symptomatic infection was significantly reduced by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[0107] FIG. 64 illustrates that the number of weeks of symptomatic infection was significantly reduced by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[0108] FIG. 65 illustrates that the number of weeks of overall infection was significantly reduced by REGEN-COV in the Phase 3 prevention trial described in Example 4.

[0109] FIG. 66 illustrates the hierarchy for hypothesis testing in the Phase 3 pre-emptive therapy trial described in Example 4. REGEN-COV significantly prevented the progression of asymptomatic infection to disease and reduced viral burden. The treatment effect was stronger after the first three days.

[0110] FIG. 67 illustrates the mean of viral load over time in asymptomatic patients in the Phase 3 pre-emptive therapy trial described in Example 4 (2069) as compared to symptomatic patients in the amended phase 3 trial of Example 2 (2067). Early treatment with REGEN-COV provided greater viral load reduction over time.

[0111] FIG. 68 illustrates the mean concentrations of mAb10933 and mAb10987 in serum over time for sentinel and safety cohorts after a single 1200 mg dose in the Phase 3 pre-emptive therapy trial described in Example 4.

[0112] FIG. 69 illustrates that REGEN-COV had an acceptable and well-tolerated safety profile with no serious or severe safety concerns in the Phase 3 trial of Example 4.

[0113] FIG. 70 illustrates the treatment emergent adverse events that occurred in ≥2% of any treatment group in the Phase 3 trial of Example 4.

[0114] FIG. 71 illustrates that serious adverse events are rare, with no COVID-related serious adverse events in REGEN-COV treated patients.

[0115] FIG. 72 illustrates the cumulative incidence of symptomatic infection by study day in a clinical trial assessing the ability of REGEN-COV to prevent COVID-19 symptoms. There was an 81.4% reduced risk of symptomatic SARS-CoV-2 infections with subcutaneous administration of REGEN-COV.

[0116] FIG. 73 illustrates the cumulative incidence of symptomatic infection by study day in a clinical trial assessing the ability of REGEN-COV to prevent COVID-19 symptoms. Treatment with REGEN-COV 1200mg subcutaneous (SC) resulted in a 31.5% relative risk reduction in progression from asymptomatic to symptomatic infection during the efficacy assessment period (29 / 100 [29.0%]vs 44 / 104 [42.3%] for placebo; p=0.0380), with a more pronounced effect 3 days or longer following REGEN-COV administration (76.4% relative risk reduction).

[0117] FIG. 74 illustrates the mean viral load over time in patients that were PCR-positive and seronegative at baseline in the clinical trial described in Example 7.

[0118] FIG. 75 illustrates the mean concentrations of total REGEN-COV in serum after single intravenous (IV) and subcutaneous (SC) in ambulatory PCR-positive patients enrolled in the clinical trial described in Example 7.

[0119] FIG. 76 illustrates the number of patients assigned to different treatment groups in a clinical trial designed to study REGEN-COV treatment in nonhospitalized patients.

[0120] FIG. 77 , FIG. 77B, and FIG. 77C: FIG. 77 illustrates the clinical efficacy of a 1200 mg IV dose of REGEN-COV on hospitalization or all-cause death. Treatment significantly reduced hospitalization or all-cause death. FIG. 77B illustrates the clinical efficacy of a 2400 mg IV dose of REGEN-COV on hospitalization or all-cause death. Treatment significantly reduced hospitalization or all-cause death. FIG. 77C illustrates the clinical efficacy of a 1200 mg IV dose and a 2400 mg IV dose of REGEN-COV on time to resolution of symptoms. Treatment reduced the median days to symptom resolution by 4 days.

[0121] FIG. 78 illustrates the demographic and baseline medical characteristics of patients assigned to different treatment groups in a clinical trial designed to study REGEN-COV treatment in nonhospitalized patients.

[0122] FIG. 79 illustrates the effect of different treatment groups across each of the phase 3 clinical trial endpoints in nonhospitalized adult patients with COVID-19.

[0123] FIG. 80 illustrates an overview of serious adverse events and adverse events of special interest among patients treated intravenously with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo.

[0124] FIG. 81 illustrates a schematic overview of the study design to evaluate treatment with REGEN-COV in adult nonhospitalized patients with COVID-19.

[0125] FIG. 82 illustrates viral load over time in the placebo arm by baseline serum antibody status.

[0126] FIG. 83A, FIG. 83B and FIG. 83C: FIG. 83A illustrates a Forest Plot showing COVID-19 related hospitalization or all-cause death through Day 29 in adult nonhospitalized adults with one or more risk factors for severe COVID-19. FIG. 83B breaks down those data by protocol-defined risk factor, and FIG. 83C breaks down the data by other risk factor combinations.

[0127] FIG. 84A and FIG. 84B: FIG. 84A illustrates the proportion of patients with COVID-19 related hospitalization or all-cause death from Day 4 to Day 29 among patients treated with a singleintravenous dose of 1200 mg REGEN-COV. FIG. 84B illustrates the proportion of patients with COVID-19 related hospitalization or all-cause death from Day 4 to Day 29 among patients treated with a single intravenous dose of 2400 mg REGEN-COV.

[0128] FIG. 85 illustrates the time to symptom resolution in outpatients with 1 or more risk factors for severe COVID-19 treated intravenously with 1200 mg REGEN-COV or 2400 mg REGEN-COV.

[0129] FIG. 86A, FIG. 86B, and FIG 86C: FIG. 86A illustrates viral load over time in outpatients with 1 or more risk factors for severe COVID-19 treated intravenously with 1200 mg REGEN-COV or 2400 mg REGEN-COV. Both doses significantly reduced viral load compared to placebo. FIG. 86B illustrates viral load over time in those patients, broken down by baseline serum antibody status (seronegative vs. seropositive). FIG. 86C illustrates viral load over time in those patients, broken down by baseline viral load category (>104copies / mL, >105copies / mL, >106copies / mL, and >107copies / mL).

[0130] FIG. 87 illustrates change from baseline in viral load (Iog10 copies / mL) at Day 7 in outpatients with 1 or more risk factors for severe COVID-19 treated intravenously with 1200 mg REGEN-COV or 2400 mg REGEN-COV.

[0131] FIG. 88A, FIG. 88B, and FIG 88C: FIG. 88A illustrates viral load over time in outpatients with 1 or more risk factors for severe COVID-19 treated intravenously with 2400 mg REGEN-COV or 8000 mg REGEN-COV. Both doses significantly reduced viral load compared to placebo. FIG. 88B illustrates viral load over time in those patients, broken down by baseline serum antibody status (seronegative vs. seropositive). FIG. 88C illustrates viral load over time in those patients, broken down by baseline viral load category (>104copies / mL, >105copies / mL, >106copies / mL, and >107copies / mL).

[0132] FIG. 89 illustrates a primary hierarchical analysis testing order indicating in what order primary and secondary endpoints were assessed.

[0133] FIG. 90 illustrates the protocol-defined risk factors for severe COVID-19 in a clinical trial to assess REGEN-COV in nonhospitalized patients.

[0134] FIG. 91 illustrates demographic and baseline medical characteristics of patients receiving 8000 mg of REGEN-COV or placebo.

[0135] FIG. 92 illustrates the proportion of patients in the placebo arm with at least 1 COVID-19 related hospitalization or all-cause death by baseline viral load category.

[0136] FIG. 93 illustrates viral load in the placebo arm (with hospitalization / death, without hospitalization / death, and by baseline serum antibody status).

[0137] FIG. 94 illustrates the proportion of patients with one or more COVID-19 related hospitalization and / or all-cause death.

[0138] FIG. 95 illustrates the proportion of patients that had one or more medically attended visits, or all-cause death, after treatment with REGEN-COV.

[0139] FIG. 96 illustrates the outcomes for patients hospitalized during the course of the clinical trial in outpatients with 1 or more risk factors for severe COVID-19.

[0140] FIG. 97 illustrates the proportion of patients with one or more COVID-19 related hospitalization, emergency room visits, or all-cause death in patients treated with 1200 mg REGEN- COV, 2400 mg REGEN-COV, or placebo.

[0141] FIG. 98 illustrates the proportion of patients with one or more COVID-19 related hospitalization or all-cause death in patients treated with 8000 mg REGEN-COV or placebo.

[0142] FIG. 99 illustrates the proportion of patients with one or more COVID-19 related medically attended visit or all-cause death in patients treated with 8000 mg REGEN-COV or placebo.

[0143] FIG. 100 illustrates the treatment-emergent adverse events leaving to death in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo

[0144] FIG. 101 illustrates an overview of treatment-emergent serious adverse events and adverse events of special interest in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo.

[0145] FIG. 102 illustrates adverse events of special interest in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN-COV, or placebo, that required medical attention at a healthcare facility.

[0146] FIG. 103 illustrates the mean pharmacokinetic parameters of mAb10933 and mAb10987 in serum, in patients treated with 1200 mg REGEN-COV, 2400 mg REGEN-COV, 8000 mg REGEN- COV, or placebo.DETAILED DESCRIPTION

[0147] Before the present invention is described, it is to be understood that this invention is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0148] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as usedherein, the expression "about 100" includes 99 and 101 and all values in between ( e.g ., 99.1, 99.2, 99.3, 99.4, etc.).

[0149] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entireties.Methods of Preventing and Treating SARS-CoV-2 Infections and COVID-19

[0150] The present invention provides methods for preventing and treating SARS-CoV-2 infections and COVID-19 in subjects in need thereof via administration of an antigen-binding molecule or molecules that bind a surface protein of SARS-CoV-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein. In some cases, the subject is a hospitalized COVID-19 patient. In some cases, the subject is an outpatient (i.e., an ambulatory patient) that has tested positive for a SARS-CoV-2 infection. In some cases, the subject is a human patient with laboratory-confirmed SARS-CoV-2 and one or more COVID-19 symptoms, such as fever, cough, or shortness of breath. In some cases, the subject is (a) a human COVID-19 patient requiring low-flow oxygen supplementation; (b) a human COVID-19 patient requiring high-intensity oxygen therapy but not on mechanical ventilation; or (c) a human COVID-19 patient requiring mechanical ventilation. In some cases, the subject is a non-hospitalized symptomatic COVID-19 human. In some cases, the subject is an uninfected human, e.g., an uninfected human that is in a group at high risk of exposure (such as healthcare workers or first responders) or an uninfected human with close exposure to a subject that has been infected by SARS-CoV-2 (such as a housemate or family member that has contracted COVID-19. In some cases, the subject is at high risk of complications from COVID-19 or who are more likely to be infected by SARS-CoV-2, such as elderly humans, immunocompromised humans, and humans who often do not respond well to vaccines. In some embodiments, the present invention provides methods for treating, preventing and reducing the severity or progression of a SARS-CoV-2 infection and / or COVID-19.

[0151] The present invention also includes use of antigen-binding molecules that bind a surface protein of SARS-CoV-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen binding fragments thereof discussed herein, for preventing and treating SARS-CoV-2 infections and COVID-19 and / or for treating, preventing and reducing the severity or progression of a SARS-CoV- 2 infection and / or COVID-19, or symptoms thereof. The present invention also includes use of antigen-binding molecules that bind a surface protein of SARS-Co-2, including the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof discussed herein, in the manufacture of a medicament for preventing and treating SARS-CoV-2 infections and COVID-19 and / or for treating, preventing and reducing the severity or progression of a SARS-CoV-2 infection and / or COVID-19. Where methods are discussed herein with reference to a combination of two anti-SARS-CoV-2 spike protein antibodies, such combinations include use of a first such antibody or antigen-binding fragment thereof in the manufacture of a medicament for use in combination with a second such antibody or antigen-binding fragment thereof, as well as use of the second such antibody or antigen-binding fragment thereof in the manufacture of a medicament for use in combination with the first such antibody.

[0152] As used herein, a therapeutic or prophylactic agent (e.g., an anti-SARS-CoV-2 spike glycoprotein antibody) that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample or delays the onset of the disorder or condition relative to the untreated control sample. The term "treating" as used herein includes amelioration or elimination of the condition once it has been established. In either case, prevention or treatment may be discerned in the diagnosis provided by a physician or other health care provider and the intended result of administration of the therapeutic or prophylactic agent.

[0153] In general, treatment or prevention of a disease or condition as described in the present disclosure is achieved by administering one or more anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragment thereof in an effective amount. An effective amount of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount of an agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual. A prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0154] In some embodiments, anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof may be used to treat, prevent, or reduce the progression of a SARS-CoV-2 infection or COVID-19. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof block the spike protein receptor binding domain (RBD) interaction with angiotensin-converting enzyme 2 (ACE2), leading to decreased infectivity of host cells.Blocking viral entry results in reductions in SARS-CoV-2 RNA replication, and corresponding viral shedding in affected tissues. Thus, in some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof will reduce viral shedding in the upper respiratorytract. In some embodiments, viral shedding is measured in samples collected from the upper respiratory tract in patients from 7 to 29 days after the start of dosing (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 days after the start of dosing). In some cases, a reduction from baseline in SARS-CoV-2 viral shedding is determined by RT-qPCR in nasopharyngeal swab samples, nasal samples, or saliva samples.

[0155] In some cases, the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof improve clinical status of a patient (e.g., a patient diagnosed with a SARS-CoV-2 infection or COVID-19). In some embodiments, an improvement in clinical status is based on a 7- point ordinal scale (rating clinical status from death [1] to not hospitalized [7]) used to assess changes in clinical status. Utilization of an ordinal scale that incorporates multiple clinical outcomes of interest (e.g., death, mechanical ventilation etc.) ordered by their clinical importance is an appropriate measure for assessing efficacy in trials of severe and / or critical patients with COVID-19. In some cases, administration of the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen binding fragments thereof improve the clinical status of a patient by at least 1 -point or 2-points. In some cases, administration of the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen binding fragments thereof lead to a reduction in rates of mortality and / or use of oxygen therapy, and / or increase ventilator-free days of such patients. As discussed above, improvements in clinical status can be assessed using the following ordinal scale:[1] Death[2] Hospitalized, requiring invasive mechanical ventilation or ECMO[3] Hospitalized, requiring non-invasive ventilation or high flow oxygen devices[4] Hospitalized, requiring supplemental oxygen[5] Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19-related or otherwise)[6] Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care[7] Not hospitalized.

[0156] In some cases, a subject, following administration of the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, exhibits less than 5 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions. In some cases, the less than 5 (e.g., less than 5, less than 4, less than 3, less than 2, or less than 1) COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions are exhibited by the subject within a period of from 7 to 42 (e.g., 21 to 42 days) following administration of a first dose of the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof. In some embodiments, the less than5 COVID-19 related visits are exhibited by the subject with a period of 29 days following administration of the first dose. In some cases, the subject exhibits less than 4 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions. In some cases, the subject exhibits less than 3 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions. In some cases, the subject exhibits less than 2 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions. In some cases, the subject exhibits no more than 1 COVID-19 related medically-attended visits, telemedicine visits, hospital admissions, and / or intensive care unit (ICU) admissions.

[0157] In some cases, a subject, following administration of the anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof, tests negative for SARS-CoV-2 within 2 days to 3 weeks following first administration of the therapeutic composition. In some cases, the negative test for SARS-CoV-2 is determined by RT-qPCR in nasopharyngeal swab samples, nasal samples, or saliva samples.

[0158] In any of the various embodiments discussed above or herein (e.g., combination prophylactic or therapeutic administration of mAb10933 and mAb10987), the result of administration of the anti-SARS-CoV-2-spike glycoprotein antibody or antibodies may be any one or more of the following:(a) a reduction in time-weighted average viral shedding (log10copies / mL) from baseline, as measured by RT-qPCR in nasopharyngeal (NP) swabs;(b) a reduction in time-weighted average viral shedding (log10copies / mL) from baseline, as measured by RT-qPCR in nasal swabs;(c) a reduction in time-weighted average viral shedding (log10copies / mL) from baseline, as measured by RT-qPCR in saliva samples;(d) an at least 1-point improvement in clinical status using the 7-point ordinal scale relative to baseline;(e) a reduction in COVID-19 related medically-attended visits relative to control (a COVID-19- related medically-attended visit is defined as follows: hospitalization, emergency room (ER) visit,urgent care visit, physician’s office visit, or telemedicine visit, with the primary reason for the visit being COVID-19);(f) a reduction in time to negative RT-qPCR in NP swabs with no subsequent positive RT-qPCR relative to control;(g) a reduction in incidence of hospitalization or days hospitalized relative to control;(h) a reduction in incidence of admission to ICU or days in ICU relative to control;(i) a reduction in incidence of mechanical ventilation or time on mechanical ventilation relative to control;(j) a reduction in duration of COVID-19 symptoms relative to control;(k) a reduction in time to negative RT-qPCR in all tested samples with no subsequent positive RT- qPCR in any tested samples (nasopharyngeal swabs, nasal swabs, saliva) relative to control;(l) a reduction in incidence of subsequent development of signs or symptoms of SARS-CoV-2 infection (strict term or broad term);(m) a reduction in time-weighted average daily viral load (e.g., a reduction through day 7 by 0.4 or more Iog10 copies / mL, a reduction through day 7 by 0.5 or more Iog10 copies / mL, or a reduction through day 7 by 0.6 or more Iog10 copies / mL, or a reduction through day 11 by 0.5 or more Iog10 copies / mL, a reduction through day 11 by 0.6 or more Iog10 copies / m, or a reduction through day 11 by 0.7 or more Iog10 copies / m; and(n) a reduction in time-weighted average viral load from baseline (Iog10 copies / mL).

[0159] In some embodiments, administration of the anti-SARS-CoV-2 spike glycoprotein antibodies can have a greater effect on subjects without an effective amount of existing antibodies in their blood against SARS-CoV-2 ( “seronegative” subjects) than on subjects with an effective amount of existing antibodies in their blood against SARS-CoV-2 (“seropositive” subjects). In the Examples provided herein, serostatus (i.e., seronegative, seroposiive, or undetermined) was determined by assessing for the presence of serum anti-SARS-CoV-2 antibodies: anti-spike [S1]IgA (Euroimmun IgA test), anti-spike [S1] IgG (Euroimmun IgG test), and anti-nucleocapsid IgG (Abbot IgG test). Study participants were grouped for analyses as seronegative (if all available tests were negative), seropositive (if any of the tests were positive), or sero-undetermined (missing or inconclusive results). A test was categorized as negative if the antibodies in the sample were below the lower limit of quantitation for the test. As described herein, the methods described herein can have a differential effect in seronegative subjects over a comparable population of seropositivesubjects (e.g., a greater reduction in viral load, faster time to symptom alleviation, fewer medically- attended visits post-administration).Antigen-Binding Molecules and Anti-SARS-Cov-2 Spike Glycoprotein Antibodies

[0160] The methods and uses of the present invention utilize antigen-binding molecules that bind a surface protein of SARS-CoV-2. In some embodiments, the antigen-binding molecules are anti- SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof.

[0161] The amino acid and nucleotide sequences of the variable regions, CDRs, and heavy chains and light chains of exemplary antibodies that bind to the SARS-CoV-2 spike protein are shown in Tables 1 and 2, below. Additional amino acid and nucleotide sequences of variable regions, CDRs, and heavy and light chains of exemplary antibodies and antigen binding fragments that bind to the SARS-CoV-2 spike protein and that are useful in the methods described herein are found in U.S. Patent No. 10,787,501, which is hereby incorporated by reference in its entirety.

[0162] Table 1 : Amino Acid Sequence Identifiers

[0163] Table 2: Nucleic Acid Sequence Identifiers

[0164] In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen binding fragment for use in the methods or uses discussed herein is an antibody or antigen-binding fragment comprising the six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) of any one or more of the antibodies listed in Table 1. In some cases, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen-binding fragment comprises the CDRs of a heavy chain variable region (HCVR) and light chain variable region pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81. Methods and techniques for identifyingCDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of the structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani etal., J Mol Biol 273:927-948 (1997); and Martin et al., PNAS (USA) 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within an antibody.

[0165] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains comprising the amino acid sequences, respectively, selected from the group consisting of SEQ ID NOs: 4-6-8- 12-14-16, 24-26-28-32-34-36, 44-46-48-52-34-54, and 75-77-79-83-85-87.

[0166] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody or antigen binding fragment comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2 / 10, 22 / 30, 42 / 50, and 73 / 81.

[0167] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody comprises a heavy chain (HC) and light chain (LC) pair comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 18 / 20, 38 / 40, 56 / 58, and 89 / 91.

[0168] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody binds to an epitope within the SARS-CoV-2 spike protein receptor binding domain (RBD) (amino acids 1-1273 of NCBI accession number (MN908947.3), SEQ ID NO: 59). In some cases, the antibody (e.g., mAb10989) binds to residues 467-513(DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVL) (SEQ ID NO: 60) of the RBD. In some cases, the antibody (e.g., mAb10987) binds to residues 432-452 (CVIAWNSNNLDSKVGGNYNYL) (SEQ ID NO: 61) of the RBD. In some cases, the antibody (e.g., mAb10933) binds to residues 467-510(DISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRV) (SEQ ID NO: 62) of the RBD.

[0169] In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10933. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10987. In some embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is mAb10989. In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequencesshown in Table 1) of mAb10933. In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10987. In various embodiments, the anti-SARS-CoV-2 spike glycoprotein antibody is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10989. The antibodies provided herein can be identified as “mAb” followed by a number or “REGN” followed by a number, interchangeably. For example, mAb10933 and REGN 10933 refer to the same antibody (amino acid sequences provided in Table 1 and nucleic acid sequences provided in Table 2). Similarly, mAb10987 and REGN 10987 are equivalent, mAb10989 and REGN 10989 are equivalent, and mAb10985 and REGN 10985 are equivalent. In addition, mAb10933 can be referred to as casirivimab and mAb10987 can be referred to as imdevimab. The combination of casirivimab and imdevimab is known as REGEN-COV.

[0170] In some embodiments, the methods and uses discussed herein include a composition comprising a first antigen-binding molecule (e.g., an antibody) that binds a first epitope on a surface protein of SARS-CoV-2, and a second antigen-binding molecule (e.g., an antibody) that binds a second epitope on a surface protein of SARS-CoV-2, wherein the first epitope and the second epitope are structurally non-overlapping. In some embodiments, the methods and uses discussed herein include a combination of two or more anti-SARS-CoV-2 spike glycoprotein antibodies or antigen-binding fragments thereof. In some cases, the two antibodies or antigen-binding fragments used in combination bind to structurally non-overlapping epitopes of the RBD. In some embodiments, the combination includes mAb10987 and mAb10933. In some embodiments, the combination includes mAb10987 and mAb10989. In some embodiments, the combination includes mAb10933 and mAb10987 and mAb10985. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike glycoprotein antibody that is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10933, and the second anti-SARS-CoV-2 spike glycoprotein antibody that is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10987, and optionally a third anti-SARS-CoV-2 spike glycoprotein antibody that is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10985. In various embodiments, the combination includes a first anti-SARS-CoV-2 spike glycoprotein antibody that is an antibody comprising the CDRs, the HCVR and LCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10989, and the second anti- SARS-CoV-2 spike glycoprotein antibody that is an antibody comprising the CDRs, the HCVR andLCVR, or the heavy chain and light chain (e.g., the amino acid sequences shown in Table 1) of mAb10987. In some embodiments, a combination of antigen-binding molecules (e.g., antibodies such as mAb10987 and mAb10933, mAb10987 and mAb10989, or mAb10987 and mAb10933 and mAb10985) can reduce the frequency of escape mutants (e.g., SARS-CoV-2 viruses that have one or more mutations in the S protein so as to reduce the efficacy of a treatment, for example by diminishing the binding of an antibody to the S protein). Escape variants were identified following two passages in cell culture of recombinant VSV encoding SARS-CoV-2 spike protein in the presence of mAb10933 (casirivimab) or mAb10987 (imdevimab) individually, but not following two passages in the presence of casirivimab and imdevimab together. This combination of antibodies also is effective against variant SARS-CoV-2 viruses. For example, the combination of mAb10933 and mAb10987 was evaluated for its ability to neutralize pseudotyped VSV expressing a SARS- CoV-2 variant known as B.1.1.7, also called the “UK variant.” This variant is rapidly expanding, and may have different effects than wild-type SARS-CoV-2, including more severe symptoms than the wild-type virus and potential resistance to vaccines and / or therapeutics. It is classified, in part, by the following mutations in the spike protein: HV 69-70 deletion, Y144 deletion, N501Y, A570D, P681H, T716I, S982A, and D1118H. Casirivimab and imdevimab, in combination, was shown to effectively neutralize the virus (Figure 29). Indeed, casirivimab and imdevimab individually and together retained neutralization activity against pseudovirus expressing all spike protein substitutions found in the B.1.1.7 lineage (UK origin) and against pseudovirus expressing only N501Y found in B.1.1.7 and other circulating lineages. Casivirimab and imdevimab together retained neutralization activity against pseudovirus expressing all spike protein substitutions, or individual substitutions K417N, E484K or N501Y, found in the B.1.1351 lineage (South Africa origin), and against K417T+E484K, found in the P.1 lineage (Brazil origin), although casirivimab alone, but not imdevimab, had reduced activity against pseudovirus expressing K417N or E484K, as indicated above. The E484K substitution is also found in the B.1.526 lineage (New York origin).

[0171] Table 3A: Casivirimab and imdevimab, individually and together, retained neutralization activity against the L452R substitution found in the B.1.427 / B.1.429 lineages (California origin).

[0172] Table 3B: Pseudovirus Neutralization Data for SARS-CoV-2 Variant Substitutions with Casirivimab and Imdevimab Together

[0173] Certain variants showed reduced susceptibility to casirivimab alone, including those with spike protein amino acid substitutions K417E (182-fold), K417N (7-fold), K417R (61 -fold), Y453F (>438- fold), L455F (80-fold), E484K (25-fold), F486V (>438-fold) and Q493K (>438-fold). Variants which showed reduced susceptibility to imdevimab alone included substitutions K444N (>755- fold), K444Q (>548-fold), K444T (>1,033- fold), and V445A (548-fold). Casirivimab and imdevimab together showed reduced susceptibility to variants with K444T (6-fold) and V445A (5-fold) substitutions. In neutralization assays using VSV pseudotyped with 39 different spike protein variants identified in circulating SARS-CoV-2, variants with reduced susceptibility to casirivimab alone included those with Q409E (4-fold), G476S (5-fold) and S494P (5-fold) substitutions, and variants with reduced susceptibility to imdevimab alone included one with N439K (463-fold) substitution. Additional substitutions that were tested in pseudovirus assays and had reduced activity to casirivimab alone included E484Q (9-fold) and Q493E (446-fold). Casirivimab andimdevimab together retained activity against all variants tested. In some embodiments, the present disclosure provides a method for treating SARS-CoV-2 infection comprising administering mAb10933 and mAb10987, wherein the SARS-CoV-2 is a variant SARS-CoV-2, e.g., comprising a HV 69-70 deletion, Y144 deletion, Q409E, K417E, K417N, K417R, N439K, Y453F, L455F,G476S, E484K, E484Q, F486V, Q493K, Q493E, S494P, N501Y, A570D, P681H, T716I, S982A, or D1118H, or any combination thereof. In the clinical trial of Example 2, interim data indicated only one variant (G446V) occurring at an allele fraction ≥15%, which was detected in 3 / 66 subjects who had nucleotide sequencing data, each at a single time point (two at baseline in subjects from placebo and 2,400 mg casirivimab and imdevimab groups, and one at Day 25 in a subject from the 8,000 mg casirivimab and imdevimab group). The G446V variant had reduced susceptibility to imdevimab of 135-fold compared to wild-type in a VSV pseudoparticle neutralization assay but retained susceptibility to casirivimab alone and casirivimab and imdevimab together.

[0174] In some embodiments, the methods and uses discussed herein include a composition comprising a first antigen-binding molecule (e.g., an antibody) that binds a first epitope on a surface protein of SARS-CoV-2, and a second antigen-binding molecule (e.g., an antibody) that binds a second epitope on a surface protein of SARS-CoV-2, wherein the first antigen-binding molecule and the second antigen-binding molecule are capable of simultaneously binding the surface protein of SARS-CoV-2.

[0175] in certain embodiments, one, two, three, four, or more antibodies, or antigen-binding fragments thereof can be administered in combination (e.g., concurrently or sequentially).Exemplary combinations include mAb10933 and mAb10987, mAb10989 and mAb10987, mAb10933 and mAb10989, mAb10933 and mAb10987 and mAb10985.

[0176] As used herein, "an antibody that binds SARS-CoV-2 spike protein" or an "anti-SARS- CoV-2 spike glycoprotein antibody" or an “anti-SARS-CoV-2 spike protein antibody” includes antibodies, and antigen-binding fragments thereof, that bind a soluble fragment of the SARS-CoV-2 spike protein and may also bind an epitope within the receptor binding domain (RBD) of the spike protein. Other antibodies that can be used alone or in combination with one another or with one or more of the antibodies disclosed herein for use in the context of the methods of the present disclosure include, e.g., LY-CoV555 (Eli Lilly); 47D11 (Wang et al Nature Communications Article No. 2251); B38, H4, B5 and / or H2 (Wu et al., 10.1126 / science.abc2241 (2020); STI-1499 (Sorrento Therapeutics); VIR-7831 and VIR-7832 (Vir Biotherapeutics).

[0177] The term "antibody” means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., SARS-CoV-2 spike protein). The term "antibody" includesimmunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1).The VHand VLregions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VHand VLis composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-SARS-CoV-2 spike protein antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0178] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0179] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g.monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen binding fragment," as used herein.

[0180] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VHdomain associated with a VLdomain, the VHand VLdomains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen binding fragment of an antibody may contain a monomeric VHor VLdomain.

[0181] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH- CH1-CH2; (V) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VHor VLdomain (e.g., by disulfide bond(s)).

[0182] As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

[0183] In certain embodiments of the invention, the anti-SARS-CoV-2 spike protein antibodies of the invention are human antibodies. The term "human antibody," as used herein, is intended toinclude antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0184] The antibodies of the invention may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody," as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et ai, Nucl Acids Res 20:6287-6295 (1992)) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VHand VLregions of the recombinant antibodies are sequences that, while derived from and related to human germline VHand VLsequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0185] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75- 80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.

[0186] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. Molecular Immunology 30:105 1993)) to levels typically observed using a human lgG1 hinge. The instant invention encompasses antibodieshaving one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0187] The antibodies of the invention may be isolated antibodies. An "isolated antibody," as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present invention. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0188] The present invention includes neutralizing and / or blocking anti-SARS-CoV-2 spike protein antibodies. A "neutralizing" or "blocking" antibody, as used herein, is intended to refer to an antibody whose binding to SARS-CoV-2 spike protein: (i) inhibits an activity of SARS-CoV-2 spike protein to any detectable degree, e.g., inhibits the ability of SARS-CoV-S to bind to a receptor such as ACE2, to be cleaved by a protease such as TMPRSS2, or to mediate viral entry into a host cell or viral reproduction in a host cell.

[0189] The anti-SARS-CoV-2 spike protein antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VHand / or VLdomains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, onlycertain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1 , CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0190] The present invention also includes anti-SARS-CoV-2 spike protein antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes anti-SARS- CoV-2 spike protein antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0191] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear.A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0192] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA,BLAST or Gap, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0193] As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson, W.R., Methods Mol Biol 24: 307-331 (1994), herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256: 1443-1445 (1992), herein incorporated by reference. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0194] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and amutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (see, e.g., Pearson, W.R., Methods Mol Biol 132: 185-219 (2000), herein incorporated by reference). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et ai, J Mol Biol 215:403-410 (1990) and Altschul et ai, Nucleic Acids Res 25:3389-402 (1997), each herein incorporated by reference.Specific Binding

[0195] The term "specifically binds" or the like, as used herein, means that an antigen-specific binding protein, or an antigen-specific binding domain, forms a complex with a particular antigen characterized by a dissociation constant (KD) of 50 nM or less, and does not bind other unrelated antigens under ordinary test conditions. "Unrelated antigens" are proteins, peptides or polypeptides that have less than 95% amino acid identity to one another. Methods for determining whether two molecules specifically bind one another are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antigen-specific binding protein or an antigen-specific binding domain, as used in the context of the present invention, includes molecules that bind a particular antigen (e.g., SARS-CoV-2 spike protein, SARS-CoV-2 spike protein RBD, or a specific epitope of the SARS-CoV-2 spike protein RBD) or a portion thereof with a KDof less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, or less than about 1 nM, as measured in a surface plasmon resonance assay.

[0196] The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0197] The term "KD", as used herein, means the equilibrium dissociation constant of a particular protein-protein interaction (e.g., antibody-antigen interaction). Unless indicated otherwise, the KDvalues disclosed herein refer to KDvalues determined by surface plasmon resonance assay at 25°C.Antibodies Comprising Heavy Chain Constant Region Variants

[0198] According to certain embodiments of the present invention, anti-SARS-CoV-2 spike protein antibodies are provided comprising an Fc domain comprising one or more mutations which enhance or diminish antibody binding to the FcRn receptor, e.g., at acidic pH as compared to neutral pH. For example, the present invention includes anti-SARS-CoV-2 spike protein antibodies comprising a mutation in the CH2 or a CH3 region of the Fc domain, wherein the mutation(s) increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Such mutations may result in an increase in serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / Wor T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T); or a modification at position 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., A, W, H, F or Y [N434A, N434W, N434H, N434F or N434Y]); or a modification at position 250 and / or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and / or 308 modification (e.g., 308F or 308P). In yet another embodiment, the modification comprises a 265A (e.g., D265A) and / or a 297A (e.g., N297A) modification.

[0199] For example, the present invention includes anti-SARS-CoV-2 spike protein antibodies comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (e.g., M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); 257I and 311l (e.g., P257I and Q311I); 257I and 434H (e.g., P257I and N434H); 376V and 434H (e.g., D376V and N434H); 307A, 380A and 434A (e.g., T307A, E380A and N434A); and 433K and 434F (e.g., H433K and N434F).All possible combinations of the foregoing Fc domain mutations, and other mutations within the antibody variable domains disclosed herein, are contemplated within the scope of the present invention.

[0200] In various embodiments, the anti-SARS-CoV-2 spike protein antibodies comprise a heavy chain constant region combining sequences derived from more than one immunoglobulin isotype. For example, a chimeric heavy chain constant region can comprise part or all of a CH2 sequence derived from a human lgG1 , human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human lgG1, human lgG2 or human lgG4. A chimeric heavy chain constant region can also contain a chimeric hinge region. For example, a chimeric hinge maycomprise an "upper hinge" sequence, derived from a human lgG1, a human lgG2 or a human lgG4 hinge region, combined with a "lower hinge" sequence, derived from a human lgG1, a human lgG2 or a human lgG4 hinge region. A particular example of a chimeric heavy chain constant region that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [lgG4 CH1] - [lgG4 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [lgG4 CH3] Another example of a chimeric heavy chain constant region that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [lgG1 CH1] - [lgG1 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [lgG1 CH3] These and other examples of chimeric heavy chain constant regions that can be included in any of the antibodies of the present invention are described in WO 2014 / 121087 (8550-WO). Chimeric heavy chain constant regions having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.

[0201] In various embodiments, the anti-SARS-CoV-2 spike protein antibodies comprise a heavy chain constant region including a hinge domain in which positions 233-236 within the hinge domain may be G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering. Optionally, the heavy chain constant region comprises from N-terminal to C-terminal the hinge domain, a CH2 domain and a CH3 domain. Optionally, the heavy chain constant region comprises from N-terminal to C-terminal a CH1 domain, the hinge domain, a CH2 domain and a CH3 domain. Optionally, the CH1 region, if present, remainder of the hinge region, if any, CH2 region and CH3 region are the same human isotype. Optionally, the CH1 region, if present, remainder of the hinge region, if any, CH2 region and CH3 region are human lgG1. Optionally, the CH1 region, if present, remainder of the hinge region, if any, CH2 region and CH3 region are human lgG2. Optionally, the CH1 region if present, remainder of the hinge region, if any, CH2 region and CH3 region are human lgG4. Optionally, the constant region has a CH3 domain modified to reduce binding to protein A. These and other examples of modified heavy chain constant regions that can be included in any of the antibodies of the present invention are described in WO 2016 / 161010 (10140W001).Epitope Mapping and Related Technologies

[0202] The present invention includes anti-SARS-CoV-2 spike protein antibodies which interact with one or more amino acids found within the SARS-CoV-2 spike protein (e.g., within the spike protein RBD). The epitope to which the antibodies bind may consist of a single contiguous sequence of 3 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acids located within the spike protein RBD. Alternatively, the epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences) located within the spike proteinRBD.

[0203] Various techniques known to persons of ordinary skill in the art can be used to determine whether an antibody "interacts with one or more amino acids" within a polypeptide or protein. Exemplary techniques include, e.g., routine cross-blocking assay such as that described Antibodies. Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutational analysis, peptide blots analysis (Reineke, Methods Mol Biol 248:443-463 (2004)), and peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer, Protein Science 9:487-496 (2000)). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen / deuterium exchange detected by mass spectrometry. In general terms, the hydrogen / deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein / antibody complex is transferred to water to allow hydrogen-deuterium exchange to occur at all residues except for the residues protected by the antibody (which remain deuterium-labeled). After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues which correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring, Analytical Biochemistry 267(2):252-259 (1999); Engen and Smith, Anal. Chem. 73:256A-265A (2001).

[0204] The present invention further includes anti-SARS-CoV-2 spike protein antibodies that bind to the same epitope as any of the exemplary antibodies mentioned above (e.g., mAb10933, mAb10987, or mAb10989). Likewise, the present invention also includes anti-SARS-CoV-2 spike protein antibodies that compete for binding to the SARS-CoV-2 spike protein with any of the specific exemplary antibodies described herein (e.g., mAb10933, mAb10987, or mAb10989).

[0205] One can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-SARS-CoV-2 spike protein antibody by using routine methods known in the art and exemplified herein. For example, to determine if a test antibody binds to the same epitope as a reference anti-SARS-CoV-2 spike protein antibody discussed herein, the reference antibody is allowed to bind to SARS-CoV-2 spike protein. Next, the ability of a test antibody to bind to SARS-CoV-2 spike protein is assessed. If the test antibody is able to bind to SARS-CoV-2 spike protein following saturation binding with the reference anti-SARS-CoV-2 spike protein antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-SARS-CoV-2 spike protein antibody. On the other hand, if the test antibody is not able to bind to SARS-CoV-2 spike protein following saturation binding with the reference anti- SARS-CoV-2 spike protein antibody, then the test antibody may bind to the same epitope as theepitope bound by the reference anti-SARS-CoV-2 spike protein antibody discussed herein. Additional routine experimentation ( e.g ., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, Biacore, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. In accordance with certain embodiments of the present invention, two antibodies bind to the same (or overlapping) epitope if, e.g., a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et a!., Cancer Res. 50:1495-1502 (1990)). Alternatively, two antibodies are deemed to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies are deemed to have "overlapping epitopes" if only a subset of the amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.Preparation of Human Antibodies

[0206] Methods for generating monoclonal antibodies, including fully human monoclonal antibodies are known in the art. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to SARS-CoV-2 spike protein.

[0207] Using VELOCIMMUNE™ technology, for example, or any other known method for generating fully human monoclonal antibodies, high affinity chimeric antibodies to SARS-CoV-2 spike protein are initially isolated having a human variable region and a mouse constant region.The antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. If necessary, mouse constant regions are replaced with a desired human constant region, for example wild-type or modified lgG1 or lgG4, to generate a fully human anti- SARS-CoV-2 spike protein antibody. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region. In certain instances, fully human anti-SARS-CoV-2 spike protein antibodies are isolated directly from antigen-positive B cells.Bioequivalents

[0208] The anti-SARS-CoV-2 spike protein antibodies and antibody fragments of the present invention encompass proteins having amino acid sequences that vary from those of the described antibodies but that retain the ability to bind SARS-CoV-2 spike protein. Such variant antibodies andantibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the anti-SARS-CoV-2 spike protein antibody-encoding DNA sequences of the present invention encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an anti-SARS-CoV-2 spike protein antibody or antibody fragment that is essentially bioequivalent to an anti-SARS-CoV-2 spike protein antibody or antibody fragment of the invention.

[0209] Two antibodies are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

[0210] In one embodiment, two antibodies are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0211] In one embodiment, two antibodies are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

[0212] In one embodiment, two antibodies are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

[0213] Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

[0214] Bioequivalent variants of anti-SARS-CoV-2 spike protein antibodies of the invention maybe constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include anti-SARS-CoV-2 spike protein antibody variants comprising amino acid changes which modify the glycosylation characteristics of the antibodies, e.g., mutations which eliminate or remove glycosylation.

[0215] In some embodiments, the antibodies disclosed herein lack fucose in its constant region glycosylation. Methods of measuring fucose in an antibody composition have been described in the art, e.g., U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), incorporated herein by reference. In some embodiments, fucose is undetectable in a composition comprising a population of antibody molecules. In some embodiments, an antibody lacking fucose has enhanced ADCC activity.

[0216] In some embodiments, antibodies that lack fucose can be produced using cell lines that are deficient in their ability to fucosylate proteins, i.e. , the ability to fucosylate proteins is reduced or eliminated. Fucosylation of glycans requires synthesis of GDP-fucose via the de novo pathway or the salvage pathway, both of which involve sequential function of several enzymes, leading to addition of a fucose molecule to the first N-acetylglucosamine (GlcNAc) moiety of the reducing end of a glycan. The two key enzymes of the de novo pathway responsible for production of GDP- fucose are GDP-D-mannose-4, 6-dehydratase (GMD) and GDP-keto-6-deoxymannose-3,5- epimerase, 4-reductase (FX). In the absence of fucose, these two de novo pathway enzymes (GMD and FX) convert mannose and / or glucose to GDP-fucose which is then transported into the Golgi complex where nine fucosyl-transferases (FUT1-9) act in concert to fucosylate the first GlcNAc molecule of a glycan. In the presence of fucose, however, the salvage pathway enzymes, fucose- kinase and GDP-fucose pyrophosphorylase, convert fucose into GDP-fucose.

[0217] Cell lines that are deficient in their ability to fucosylate proteins have been described in the art. In some embodiments, a cell line deficient in its ability to fucosylate proteins is a mammalian cell line (e.g., CHO cell lines, such as CHO K1, DXB-11 CHO, Veggie-CHO) comprising a mutation or genetic modification in one or more of endogenous FUT 1 to 9 genes resulting in a lack of one or more functional fucosyl-transferases. In some embodiments, the mammalian cell line comprises a mutation in an endogenous FUT8 gene (e.g., a FUT8 knock-out cell line in which the FUT8 gene has been disrupted resulting in a lack of a functional α1,6-fucosyltransferase in the cell line, as described in US Patent No. 7,214,775 (Kyowa Hakko Kogyo Co., Ltd.) and US Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd), incorporated herein by reference. In some embodiments, themammalian cell line comprises a mutation or genetic modification in an endogenous GMD gene resulting in a lack of a functional GMD in the cell line, e.g., a GMD knock-out cell line in which the GMD gene has been disrupted, described in e.g., US Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd), incorporated herein by reference. In some embodiments, the mammalian cell line comprises a mutation or genetic modification in an endogenous Fx gene resulting in a lack of a functional Fx protein. In some embodiments, the mammalian cell line is an Fx knock-out cell line in which the endogenous Fx gene has been disrupted (see, e.g., US Patent 7,737,725 (Kyowa Hakko Kirin Co., Ltd), incorporated herein by reference). In some embodiments, the mammalian cell line comprises a mutation in an endogenous Fx mutation that confers temperature sensitive phenotypes (as described in, e.g., U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), incorporated herein by reference). In some embodiments, the mammalian cell line deficient in its ability to fucosylate proteins is a cell line that has been selected based on resistance to certain lectins, e.g., the Lens culinaris lectin. See, e.g., U.S. Patent No. 8,409,838 (Regeneron Pharmaceuticals), incorporated herein by reference.Therapeutic Formulation and Administration

[0218] The anti-SARS-CoV-2 spike protein antibodies or antigen-binding fragments used in the methods and uses of the present invention may be formulated for administration in pharmaceutical compositions with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical compositions are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA, J Pharm Sci Technol 52:238- 311 (1998).

[0219] mAb10933 and mAb10987 are human lgG1 mAbs that bind simultaneously to different, non-overlapping epitopes on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Spike (S) glycoprotein. mAb10933 and mAb10987, the combination of which can be found in the antibody cocktail named REGN-COV2 or REGEN-COV, can be produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture and have approximatemolecular weights of 145.23 kDa and 144.14 kDa, respectively. The antibodies described herein (e.g., mAb10933 and mAb10987) can be formulated individually or co-formulated. For example, a co-formulated composition can be used to streamline administration (e.g., intravenously or subcutaneously), while individual formulations provide more flexibility in dosing. In particular embodiments, the two antibodies in the composition referred to as REGEN-COV (mAb10933 and mAb10987) can be co-formulated, or the two antibodies can be individually formulated and combined prior to administration.

[0220] In some embodiments, the mAb10933 and mAb10987 injection is a sterile, preservative- free, clear to slightly opalescent and colorless to pale yellow solution with a pH of 6.0. In some embodiments, each of mAb10933 and mAb10987 can be formulated as: 120 mg / mL of antibody, 10 mM histidine, 8% (w / v) sucrose, and 0.1% (w / v) polysorbate 80, pH 6.0. Two strengths are available for each antibody: 300 mg in 2.5 mL, and 1332 mg in 11.1 mL.ln some embodiments, mAb10933 and mAb10987 are each available as vials with 300 mg antibody (e.g., in a 2.5 mL solution) vial or 1332 mg antibody (e.g., in an 11.1 mL solution). Exemplary contents for each vial are shown below:300 mg vial• mAb10933: Each 2.5 mL of solution contains 300 mg of mAb10933, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.• mAb10987: Each 2.5 mL of solution contains 300 mg of mAb10987, L-histidine (1.9 mg), L-histidine monohydrochloride monohydrate (2.7 mg), polysorbate 80 (2.5 mg), sucrose (200 mg), and Water for Injection, USP. The pH is 6.0.1332 mg vial• mAb10933: Each 11.1 mL of solution contains 1332 mg of mAb10933, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.• mAb10987: Each 11.1 mL of solution contains 1332 mg of mAb10987, L-histidine (8.3 mg), L-histidine monohydrochloride monohydrate (12.1 mg), polysorbate 80 (11.1 mg), sucrose (888 mg), and Water for Injection, USP. The pH is 6.0.

[0221] The dose of antibody administered to a patient may vary depending upon the age and the size of the patient, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. When an antibody of the present invention is used for treating an adult patient, it may be advantageous to intravenously administer the antibody of the present invention normally at a single dose of about 0.01 to about 20 mg / kgbody weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 g / kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. Effective dosages and schedules for administering anti-SARS-CoV- 2 spike protein antibodies may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of dosages can be performed using well-known methods in the art (e.g., Mordenti et al., Pharmaceut Res 8:1351 (1991)).

[0222] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing an antibody or other therapeutic protein of the invention, receptor mediated endocytosis (see, e.g., Wu et al., J Biol Chem 262:4429-4432 (1987)). The antibodies and other therapeutically active components of the present invention may also be delivered by gene therapy techniques. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[0223] A pharmaceutical composition can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0224] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition as discussed herein. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (NovoNordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park IL), to name only a few.

[0225] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra ; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987)). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, Science 249:1527-1533 (1990).

[0226] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents.Combination Therapies

[0227] In some cases, the anti-SARS-CoV-2 spike protein antibodies can be administered with a further therapeutic agent. In some embodiments, the further therapeutic agent is an anti-viral drug or a vaccine. In some embodiments, the further therapeutic agent is selected from the group consisting of: an anti-inflammatory agent, an antimalarial agent, an antibody or antigen-binding fragment thereof that specifically binds TMPRSS2, and an antibody or antigen-binding fragment thereof that specifically binds to SARS-CoV-2 spike protein. In some cases, the antimalarial agent is chloroquine or hydroxychloroquine. In some cases, the anti-inflammatory agent is an antibody, such as sarilumab, tocilizumab, or gimsilumab. In some embodiments, the further therapeuticagent is a second antibody or antigen-binding fragment comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences of Table 1.

[0228] The further therapeutic agents may be administered to a subject or used prior to administration of an anti-SARS-CoV-2 spike protein antibody of the present invention. For example, a first component may be deemed to be administered / used "prior to" a second component if the first component is administered / used 1 week before, 72 hours before, 60 hours before, 48 hours before, 36 hours before, 24 hours before, 12 hours before, 6 hours before, 5 hours before, 4 hours before, 3 hours before, 2 hours before, 1 hour before, 30 minutes before, 15 minutes before, 10 minutes before, 5 minutes before, or less than 1 minute before administration / use of the second component. In other embodiments, the further therapeutic agents may be administered to a subject or used after administration of an anti-SARS-CoV-2 spike protein antibody of the present invention. For example, a first component may be deemed to be administered / used "after" a second component if the first component is administered / used 1 minute after, 5 minutes after, 10 minutes after, 15 minutes after, 30 minutes after, 1 hour after, 2 hours after, 3 hours after, 4 hours after, 5 hours after, 6 hours after, 12 hours after, 24 hours after, 36 hours after, 48 hours after, 60 hours after, 72 hours after administration / use of the second component. In yet other embodiments, the further therapeutic agents may be administered to a subject or used concurrent with administration of an anti-SARS-CoV-2 spike protein antibody of the present invention. "Concurrent" administration, for purposes of the present invention, includes, e.g., administration of an anti-SARS- CoV-2 spike protein antibody and an additional therapeutically active component to a subject in a single dosage form, or in separate dosage forms administered to the subject within about 30 minutes or less of each other. If administered in separate dosage forms, each dosage form may be administered via the same route (e.g., both the anti-SARS-CoV-2 spike protein and the additional therapeutically active component may be administered intravenously, subcutaneously, etc.). In any event, administering the components in a single dosage form, in separate dosage forms by the same route, or in separate dosage forms by different routes are all considered "concurrent administration," for purposes of the present disclosure. For purposes of the present disclosure, administration of an anti-SARS-CoV-2 spike protein antibody "prior to", "concurrent with," or "after" (as those terms are defined herein above) administration of a further therapeutic agent is considered administration of an anti-SARS-CoV-2 spike protein antibody "in combination with" the further therapeutic agent.Dosage

[0229] The amount of active ingredient (e.g., anti-SARS-CoV-2 spike protein antibodies, or other therapeutic agents given in combination with anti-SARS-CoV-2 spike protein antibodies) that can be administered to a subject is, generally, a therapeutically effective amount, as discussed elsewhere herein.

[0230] In some embodiments, a therapeutically effective amount can be from about 0.05 mg to about 20 g; e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, 1.5 g, about 1.6 g, about 1.7 g, about1.8 g, about 1.9 g, about 2 g, about 2.1 g, about 2.2 g, about 2.3 g, about 2.4 g, about 2.5 g, about2.6 g, about 2.7 g, about 2.8 g, about 2.9 g, about 3 g, about 3.1 g, about 3.2 g, about 3.3 g, about3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4 g, about 4.1 g, about4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, about 5 g, about 5.1 g, about 5.2 g, about 5.3 g, about 5.4 g, about 5.5 g, about 5.6 g, about 5.7 g, about 5.8 g, about 5.9 g, about 6 g, about 6.1 g, about 6.2 g, about 6.3 g, about 6.4 g, about 6.5 g, about 6.6 g, about 6.7 g, about 6.8 g, about 6.9 g, about 7 g, about 7.1 g, about 7.2 g, about 7.3 g, about 7.4 g, about 7.5 g, about 7.6 g, about 7.7 g, about 7.8 g, about 7.9 g, about 8 g, about 8.1 g, about 8.2 g, about 8.3 g, about 8.4 g, about 8.5 g, about 8.6 g, about 8.7 g, about 8.8 g, about 8.9 g, about 9 g, about 9.1 g, about 9.2 g, about 9.3 g, about 9.4 g, about 9.5 g, about 9.6 g, about 9.7 g, about 9.8 g, about 9.9 g, about 10 g, about 11 g, about 12 g, about 13 g, about 14 g, about 15 g, about 16 g, about 17 g, about 18 g, about 19 g, or about 20 g of the respective antibody. In somecases, the therapeutically effective amount is from 0.1 g to 3.5 g. In some cases, the therapeutically effective amount is from 0.5 g to 2 g. In some cases, the therapeutically effective amount is from 0.8 g to 1.6 g. In some cases, the therapeutically effective amount is from 1.0 g to 1.4 g. In some cases, the therapeutically effective amount is from 1 g to 7 g. In some cases, the therapeutically effective amount is from 3 g to 5 g. In some cases, the therapeutically effective amount is from 3.5 g to 4.5 g. In any of these embodiments, discussed above, the dose may represent the dose of a single antibody or, alternatively, the total dose of a combination of antibodies. For example, two different anti-SARS-CoV-2-spike glycoprotein antibodies may be co administered, in which the dose of each antibody represents one-half of the total dose administered.

[0231] In some embodiments, a combination of mAb10933 and mAb10987 are co-administered intravenously or subcutaneously at a total dose of from 300 mg to 2400 mg. In some cases, the total dose is from 100 mg to 5000 mg. In some embodiments, the total dose is from 200 mg to 400 mg, from 500 mg to 700 mg, from 1000 mg to 1400 mg, or from 2000 mg to 2800 mg. In some embodiments, the total dose is from 250 mg to 350 mg, from 550 mg to 650 mg, from 1150 mg to 1250 mg, or from 2300 mg to 2500 mg. In some cases, the total dose is 300 mg, 600 mg, 1200 mg or 2400 mg. In some cases, the total dose is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg,1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, or 3000 mg. In some embodiments, the total dose is 2400 mg, and each of mAb10933 and mAb10987 is administered at a dose of 1200 mg intravenously. In some embodiments, the total dose is 1200 mg, and each of mAb10933 and mAb10987 is administered at a dose of 600 mg intravenously. In some embodiments, the total dose is 600 mg, and each of mAb10933 and mAb10987 is administered at a dose of 300 mg intravenously. In some embodiments, the total dose is 300 mg, and each of mAb10933 and mAb10987 is administered at a dose of 150 mg intravenously. In some embodiments, the total dose is 1200 mg, and each of mAb10933 and mAb10987 is administered at a dose of 600 mg subcutaneously. In some embodiments, the total dose is 600 mg, and each of mAb10933 and mAb10987 is administered at a dose of 300 mg subcutaneously. In some embodiments, each individual antibody is administered at a dose of from 100 mg to 200 mg, from 200 mg to 400 mg, from 500 mg to 700 mg, or from 2300mg to 2500 g. In some cases, each individual antibody is administered at a dose of from 124 mg to 175 mg, from 250 mg to 350 mg, from 550 mg to 650 mg, or from 1150 mg to 1250 mg.

[0232] The amount of anti-SARS-CoV-2 spike protein antibody or other therapeutic agent contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the anti-SARS-CoV-2 spike protein antibodies may be administered to a patient at a dose of about 0.0001 to about 200 mg / kg of patient body weight (e.g. 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11.0 mg / kg, 11.5 mg / kg, 12.0 mg / kg, 12.5 mg / kg, 13.0 mg / kg, 13.5 mg / kg, 14.0 mg / kg, 14.5 mg / kg, 15.0 mg / kg, 15.5 mg / kg, 16.0 mg / kg, 16.5 mg / kg, 17.0 mg / kg, 17.5 mg / kg, 18.0 mg / kg, 18.5 mg / kg, 19.0 mg / kg, 19.5 mg / kg, 20.0 mg / kg, 20.5 mg / kg, 21.0 mg / kg, 21.5 mg / kg, 22.0 mg / kg, 22.5 mg / kg, 23.0 mg / kg, 23.5 mg / kg, 24.0 mg / kg, 24.5 mg / kg, 25.0 mg / kg, 25.5 mg / kg, 26.0 mg / kg, 26.5 mg / kg, 27.0 mg / kg, 27.5 mg / kg, 28.0 mg / kg, 28.5 mg / kg, 29.0 mg / kg, 29.5 mg / kg, 30.0 mg / kg, 30.5 mg / kg, 31.0 mg / kg, 31.5 mg / kg, 32.0 mg / kg, 32.5 mg / kg, 33.0 mg / kg, 33.5 mg / kg, 34.0 mg / kg, 34.5 mg / kg, 35.0 mg / kg, 35.5 mg / kg, 36.0 mg / kg, 36.5 mg / kg, 37.0 mg / kg, 37.5 mg / kg, 38.0 mg / kg, 38.5 mg / kg, 39.0 mg / kg, 39.5 mg / kg, 40.0 mg / kg, 40.5 mg / kg, 41.0 mg / kg, 41.5 mg / kg, 42.0 mg / kg, 42.5 mg / kg, 43.0 mg / kg, 43.5 mg / kg, 44.0 mg / kg, 44.5 mg / kg, 45.0 mg / kg, 45.5 mg / kg, 46.0 mg / kg, 46.5 mg / kg, 47.0 mg / kg, 47.5 mg / kg, 48.0 mg / kg, 48.5 mg / kg, 49.0 mg / kg, 49.5 mg / kg, 50.0 mg / kg, 50.5 mg / kg, 51.0 mg / kg, 51.5 mg / kg, 52.0 mg / kg, 52.5 mg / kg, 53.0 mg / kg, 53.5 mg / kg, 54.0 mg / kg, 54.5 mg / kg, 55.0 mg / kg, 55.5 mg / kg, 56.0 mg / kg, 56.5 mg / kg, 57.0 mg / kg, 57.5 mg / kg, 58.0 mg / kg, 58.5 mg / kg, 59.0 mg / kg, 59.5 mg / kg, 60.0 mg / kg, 60.5 mg / kg, 61.0 mg / kg, 61.5 mg / kg, 62.0 mg / kg, 62.5 mg / kg, 63.0 mg / kg, 63.5 mg / kg, 64.0 mg / kg, 64.5 mg / kg, 65.0 mg / kg, 65.5 mg / kg, 66.0 mg / kg, 66.5 mg / kg, 67.0 mg / kg, 67.5 mg / kg, 68.0 mg / kg, 68.5 mg / kg, 69.0 mg / kg, 69.5 mg / kg, 70.0 mg / kg, 70.5 mg / kg, 71.0 mg / kg, 71.5 mg / kg, 72.0 mg / kg, 72.5 mg / kg, 73.0 mg / kg, 73.5 mg / kg, 74.0 mg / kg, 74.5 mg / kg, 75.0 mg / kg, 75.5 mg / kg, 76.0 mg / kg, 76.5 mg / kg, 77.0 mg / kg, 77.5 mg / kg, 78.0 mg / kg, 78.5 mg / kg, 79.0 mg / kg, 79.5 mg / kg, 80.0 mg / kg, 80.5 mg / kg, 81.0 mg / kg, 81.5 mg / kg, 82.0 mg / kg, 82.5 mg / kg, 83.0 mg / kg, 83.5 mg / kg, 84.0 mg / kg, 84.5 mg / kg, 85.0 mg / kg, 85.5 mg / kg, 86.0 mg / kg, 86.5 mg / kg, 87.0 mg / kg, 87.5 mg / kg, 88.0 mg / kg, 88.5 mg / kg, 89.0 mg / kg, 89.5 mg / kg, 90.0 mg / kg, 90.5 mg / kg, 91.0 mg / kg, 91.5 mg / kg, 92.0 mg / kg, 92.5 mg / kg, 93.0 mg / kg, 93.5 mg / kg, 94.0 mg / kg, 94.5 mg / kg, 95.0 mg / kg, 95.5 mg / kg, 96.0 mg / kg, 96.5 mg / kg, 97.0 mg / kg, 97.5 mg / kg, 98.0 mg / kg, 98.5 mg / kg, 99.0 mg / kg, 99.5 mg / kg, 100.0 mg / kg, 100.5 mg / kg, 101.0 mg / kg, 101.5 mg / kg, 102.0 mg / kg, 102.5 mg / kg, 103.0 mg / kg, 103.5 mg / kg, 104.0 mg / kg, 104.5 mg / kg, 105.0 mg / kg, 105.5 mg / kg, 106.0 mg / kg, 106.5 mg / kg, 107.0 mg / kg, 107.5 mg / kg, 108.0 mg / kg, 108.5 mg / kg, 109.0 mg / kg, 109.5 mg / kg, 110.0mg / kg, 110.5 mg / kg, 111.0 mg / kg, 111.5 mg / kg, 112.0 mg / kg, 112.5 mg / kg, 113.0 mg / kg, 113.5 mg / kg, 114.0 mg / kg, 114.5 mg / kg, 115.0 mg / kg, 115.5 mg / kg, 116.0 mg / kg, 116.5 mg / kg, 117.0 mg / kg, 117.5 mg / kg, 118.0 mg / kg, 118.5 mg / kg, 119.0 mg / kg, 119.5 mg / kg, 120.0 mg / kg, 120.5 mg / kg, 121.0 mg / kg, 121.5 mg / kg, 122.0 mg / kg, 122.5 mg / kg, 123.0 mg / kg, 123.5 mg / kg, 124.0 mg / kg, 124.5 mg / kg, 125.0 mg / kg, 125.5 mg / kg, 126.0 mg / kg, 126.5 mg / kg, 127.0 mg / kg, 127.5 mg / kg, 128.0 mg / kg, 128.5 mg / kg, 129.0 mg / kg, 129.5 mg / kg, 130.0 mg / kg, 130.5 mg / kg, 131.0 mg / kg, 131.5 mg / kg, 132.0 mg / kg, 132.5 mg / kg, 133.0 mg / kg, 133.5 mg / kg, 134.0 mg / kg, 134.5 mg / kg, 135.0 mg / kg, 135.5 mg / kg, 136.0 mg / kg, 136.5 mg / kg, 137.0 mg / kg, 137.5 mg / kg, 138.0 mg / kg, 138.5 mg / kg, 139.0 mg / kg, 139.5 mg / kg, 140.0 mg / kg, 140.5 mg / kg, 141.0 mg / kg, 141.5 mg / kg, 142.0 mg / kg, 142.5 mg / kg, 143.0 mg / kg, 143.5 mg / kg, 144.0 mg / kg, 144.5 mg / kg, 145.0 mg / kg, 145.5 mg / kg, 146.0 mg / kg, 146.5 mg / kg, 147.0 mg / kg, 147.5 mg / kg, 148.0 mg / kg, 148.5 mg / kg, 149.0 mg / kg, 149.5 mg / kg, 150.0 mg / kg, 150.5 mg / kg, 151.0 mg / kg, 151.5 mg / kg, 152.0 mg / kg, 152.5 mg / kg, 153.0 mg / kg, 153.5 mg / kg, 154.0 mg / kg, 154.5 mg / kg, 155.0 mg / kg, 155.5 mg / kg, 156.0 mg / kg, 156.5 mg / kg, 157.0 mg / kg, 157.5 mg / kg, 158.0 mg / kg, 158.5 mg / kg, 159.0 mg / kg, 159.5 mg / kg, 160.0 mg / kg, 160.5 mg / kg, 161.0 mg / kg, 161.5 mg / kg, 162.0 mg / kg, 162.5 mg / kg, 163.0 mg / kg, 163.5 mg / kg, 164.0 mg / kg, 164.5 mg / kg, 165.0 mg / kg, 165.5 mg / kg, 166.0 mg / kg, 166.5 mg / kg, 167.0 mg / kg, 167.5 mg / kg, 168.0 mg / kg, 168.5 mg / kg, 169.0 mg / kg, 169.5 mg / kg, 170.0 mg / kg, 170.5 mg / kg, 171.0 mg / kg, 171.5 mg / kg, 172.0 mg / kg, 172.5 mg / kg, 173.0 mg / kg, 173.5 mg / kg, 174.0 mg / kg, 174.5 mg / kg, 175.0 mg / kg, 175.5 mg / kg, 176.0 mg / kg, 176.5 mg / kg, 177.0 mg / kg, 177.5 mg / kg, 178.0 mg / kg, 178.5 mg / kg, 179.0 mg / kg, 179.5 mg / kg, 180.0 mg / kg, 180.5 mg / kg, 181.0 mg / kg, 181.5 mg / kg, 182.0 mg / kg, 182.5 mg / kg, 183.0 mg / kg, 183.5 mg / kg, 184.0 mg / kg, 184.5 mg / kg, 185.0 mg / kg, 185.5 mg / kg, 186.0 mg / kg, 186.5 mg / kg, 187.0 mg / kg, 187.5 mg / kg, 188.0 mg / kg, 188.5 mg / kg, 189.0 mg / kg, 189.5 mg / kg, 190.0 mg / kg, 190.5 mg / kg, 191.0 mg / kg, 191.5 mg / kg, 192.0 mg / kg, 192.5 mg / kg, 193.0 mg / kg, 193.5 mg / kg, 194.0 mg / kg, 194.5 mg / kg, 195.0 mg / kg, 195.5 mg / kg, 196.0 mg / kg, 196.5 mg / kg, 197.0 mg / kg, 197.5 mg / kg, 198.0 mg / kg, 198.5 mg / kg, 199.0 mg / kg, 199.5 mg / kg, or 200.0 mg / kg).Administration Regimens

[0233] According to certain embodiments of the present invention, multiple doses of an active ingredient (e.g., an anti-SARS-CoV-2 spike protein antibody) may be administered to a subject over a defined time course. The methods according to this aspect of the invention comprise sequentially administering to a subject multiple doses of an active ingredient of the invention. As used herein, "sequentially administering" means that each dose of an active ingredient is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval( e.g ., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient a single initial dose of an active ingredient, followed by one or more secondary doses of the active ingredient, and optionally followed by one or more tertiary doses of the active ingredient.

[0234] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the active ingredient, e.g., anti-SARS-CoV-2 spike protein antibody of the invention or of a combination therapy of the invention, e.g., two different anti-SARS-CoV-2 spike protein antibodies. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the active ingredient, e.g., anti-SARS-CoV-2 spike protein antibody, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of the active ingredient, e.g., anti-SARS-CoV-2 spike protein antibody, contained in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").

[0235] In certain exemplary embodiments of the present invention, each secondary and / or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½,10, 10½, 11, 11 ½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of the active ingredient, e.g., an anti-SARS-CoV-2 spike protein antibody, which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

[0236] The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and / or tertiary doses of an active ingredient of the invention, e.g., an anti-SARS-CoV-2 spike protein antibody. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5,6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0237] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 12 weeks after the immediately preceding dose. In certain embodiments of the invention, the frequency at which the secondary and / or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

[0238] The present invention includes administration regimens in which 2 to 6 loading doses are administered to a patient a first frequency (e.g., once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by administration of two or more maintenance doses to the patient on a less frequent basis. For example, according to this aspect of the invention, if the loading doses are administered at a frequency of once a month, then the maintenance doses may be administered to the patient once every six weeks, once every two months, once every three months, etc.). In certain embodiments, a single dose is administered to the subject as part of a prophylactic or therapeutic course of treatment. In some embodiments, the dose or doses are administered to treat a high-risk adult or pediatric patient with diagnosed mild-to- moderate coronavirus disease (COVID-19).

[0239] In some embodiments, dosage in adults and in pediatric patients (12 years of age and older weighing at least 40 kg) is: o 600 mg of mAb10933 (casirivimab) and 600 mg of mAb10987 (imdevimab) administered together as a single intravenous infusion via pump or gravity (see Table 4A), or as a single subcutaneous injection, or as two subcutaneous injections; or o 1 ,200 mg of casirivimab and 1 ,200 mg of imdevimab administered together as a single intravenous infusion via pump or gravity (see Table 4B). Exemplary preparation instructions for mAb10933 + mAb10987 (casirivimab and imdevimab, respectively) are as follows:1. Remove the casirivimab and imdevimab vials from refrigerated storage and allow to equilibrate to room temperature for approximately 20 minutes before preparation. Do not expose to direct heat. Do not shake the vials.2. Inspect casirivimab and imdevimab vials visually for particulate matter and discoloration prior to administration. Should either be observed, the solution must be discarded, and freshsolution prepared. The solution for each vial should be clear to slightly opalescent, colorless to pale yellow.3. Obtain a prefilled IV infusion bag containing either 50 mL, 100 mL, 150 mL, or 250 mL of 0.9% Sodium Chloride Injection.4. If administering the 600 mg / 600 mg dose: o Withdraw 5 mL of casirivimab and 5 mL of imdevimab from each respective vial using two separate syringes (see Table 4A) and inject all 10 mL into a prefilled infusion bag containing 0.9% Sodium Chloride Injection (see Table 4A). Discard any product remaining in the vial.ORIf administering the alternative 1,200 mg / 1,200 mg dose: o Withdraw 10 mL of casirivimab and 10 mL of imdevimab from each respective vial using two separate syringes (see Table 4B) and inject all 20 mL into a prefilled infusion bag containing 0.9% Sodium Chloride Injection (see Table 4B). Discard any product remaining in the vial.5. Gently invert infusion bag by hand approximately 10 times. Do not shake.6. This product is preservative-free and therefore, the diluted infusion solution should be administered immediately.• If immediate administration is not possible, store the diluted casirivimab with imdevimab infusion solution in the refrigerator between 2°C to 8°C (36°F to 46°F) for no more than 36 hours or at room temperature up to 25°C (77°F) for no more than 4 hours. If refrigerated, allow the infusion solution to equilibrate to room temperature for approximately 30 minutes prior to administration.

[0240] Exemplary administration instructions are as follows:1. Gather the recommended materials for infusion: a. Polyvinyl chloride (PVC), Polyethylene (PE)-lined PVC, or Polyurethane (PU) infusion set b. In-line or add-on 0.2 micron polyethersulfone (PES) filter2. Attach the infusion set to the IV bag.3. Prime the infusion set.4. Administer as an IV infusion via pump or gravity over at least 60 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron polyethersulfone (PES) filter (see Table 4A or Table 4B).5. The prepared infusion solution should not be administered simultaneously with any other medication. The compatibility of mAb10933 and mAb10987 injection with IV solutions and medications other than 0.9% Sodium Chloride Injection is not known.6. After infusion is complete, flush with 0.9% Sodium Chloride Injection.7. Discard unused product.8. Clinically monitor patients during administration and observe patients for at least 1 hour after infusion is complete.

[0241] Table 4A: Recommended Dosing, Dilution and Administration Instructions for 600 mg Casirivimab with 600 mg Imdevimab for IV Infusion le ed

[0242] Table 4B: Recommended Dosing, Dilution and Administration Instructions for 1,200 mg Casirivimab with 1,200 mg Imdevimab for IV InfusionKits

[0243] The present invention further provides an article of manufacturing or kit, comprising a packaging material, container and a pharmaceutical agent contained within the container, wherein the pharmaceutical agent comprises at least one anti-SARS-CoV-2 spike glycoprotein antibody, and wherein the packaging material comprises a label or package insert showing indications and directions for use. In one embodiment, the kit may include two anti-SARS-CoV-2 spike glycoprotein antibodies, and the two antibodies may be contained in separate containers.EXAMPLES

[0244] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.Example 1. Clinical Evaluation of Anti-SARS-CoV-2 Spike Glycoprotein Antibodies in Hospitalized Adult Patients with COVID-19.

[0245] The below-described clinical study is an adaptive, phase 1 / 2 / 3, randomized, double- blinded, placebo-controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 in hospitalized adult patients with COVID-19. The safety, tolerability, and efficacy of mAb10989 will also be evaluated in the phase 1 portion of the study to enable further investigation in other clinical settings.

[0246] Study Objectives: The primary and secondary objectives of each phase of the study areset forth below.

[0247] Primary Objectives:Phase 1 Part A• To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo• To evaluate the virologic efficacy of mAb10933 + mAb10987 compared to placebo in reducing viral shedding of SARS-CoV-2Part B• To evaluate the safety and tolerability of mAb10989 compared to placebo• To evaluate the virologic efficacy of mAb10989 compared to placebo in reducing viral shedding of SARS-CoV-2Phase 2• To evaluate the virologic efficacy of mAb10933 + mAb10987 compared to placebo in reducing viral shedding of SARS-CoV-2• To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical statusPhase 3The primary objective of phase 3 is to evaluate and confirm the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical status.

[0248] Secondary Objectives:Phase 1 Part A• To evaluate additional indicators of virologic efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo in improving clinical outcomes• To characterize the pharmacokinetic (PK) profiles of mAb10933 and mAb10987 in serum• To assess the immunogenicity of mAb10933 and mAb10987 Part B• To evaluate additional indicators of virologic efficacy of mAb10989 compared to placebo• To evaluate the clinical efficacy of mAb10989 compared to placebo in improving clinical outcomes• To compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) results acquired with different sample types (naospharyngeal, nasal, and saliva)• To characterize the PK profile of mAb10989 in serum• To assess the immunogenicity of mAb10989 Phase 2• To evaluate additional indicators of virologic efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate additional indicators of clinical efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo• To characterize the concentrations of mAb10933 and mAb10987 in serum over time• To assess the immunogenicity of mAb10933 and mAb10987 Phase 3• To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo• To characterize the concentrations of mAb10933 and mAb10987 in serum over time• To assess the immunogenicity of mAb10933 and mAb10987

[0249] Study Design: This study was an adaptive, phase 1 / 2 / 3, randomized, double-blinded, placebo-controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 in hospitalized adult patients with COVID-19. The safety, tolerability, and efficacy of mAb10989 was evaluated in the phase 1 portion of the study to enable further investigation in other clinical settings. Eligible patients who were hospitalized for ≤72 hours at screening were enrolled in 1 of 4 cohorts based on disease severity at randomization. Phase 2 was initiated following independent data monitoring committee (IDMC) clearance of a phase 1 sentinel safety group, and after initiation, enrolled concurrently with phase 1. Once phase 2 was active, phase 1 continued to enroll to completion, but phase 2 enrollment did not require the completion of phase 1 enrollment.

[0250] Study Duration: The phase 1 portion of the study lasted up to 170 days. The phase 2 portion of the study lasted up to 58 days. The phase 3 portion of the study lasted up to 58 days.

[0251] Study Population: In order to evaluate potential differential treatment effects across the spectrum of hospitalized COVID-19 patients, the study was conducted and analyzed in four cohorts of hospitalized adult patients with COVID-19: Cohort 1A (Patients with COVID-19 symptoms but not requiring supplemental oxygen); Cohort 1 (Patients on low-flow oxygen supplementation); Cohort 2 (Patients requiring high-intensity oxygen therapy but not on mechanical ventilation); and Cohort 3 (Patients requiring mechanical ventilation).

[0252] Cohorts - Eligible patients were enrolled in 1 of 4 cohorts based on disease severity at randomization: Cohort 1A (Patients with COVID-19 symptoms but not requiring supplementaloxygen); Cohort 1 (02 saturation >93% on low-flow oxygen via nasal cannula, simple face mask, or other similar device); Cohort 2 (On high-intensity oxygen therapy* but not on mechanical ventilation - * High-intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of at least 10 L / min; use of a high flow device with at least 50% Fi02, or use of non-invasive ventilation to treat hypoxemia); and Cohort 3 (On mechanical ventilation).

[0253] Sample Size - The phase 1 portion of the study included up to 100 patients from cohort 1 only: Part A for mAb10933 + mAb10987: Approximately 20 patients per arm for a total of 60 patients across 3 treatment arms; and Part B for mAb10989: Approximately 20 patients per arm for a total of 40 patients across 2 treatment arms. The phase 2 portion of the study included approximately 1560 patients: Cohort 1A: Approximately 130 patients per arm for a total of 390 patients across 3 treatment arms; Cohort 1 : Approximately 130 patients per arm for a total of 390 patients across 3 treatment arms; Cohort 2: Approximately 130 patients per arm for a total of 390 patients across 3 treatment arms; and Cohort 3: Approximately 130 patients per arm for a total of 390 patients across 3 treatment arms. Sample size for phase 3 is estimated to be approximately 1350 (150 patients per arm across 3 treatment arms in each of the 3 cohorts). Finalization of the sample size and patient population for phase 3 is subject to change and will be determined after a full review of phase 2 data.

[0254] Inclusion Criteria: A patient must have met the following criteria to be eligible for inclusion in the study:1. Has provided informed consent (signed by study patient or legally acceptable representative);2. Male or female adult ≥18 years of age (or country’s legal age of adulthood) at randomization;3. Has SARS-CoV-2-positive molecular diagnostic test (by validated SARS-CoV-2 RT-PCR or other molecular diagnostic assay, using an appropriate sample such as NP, nasal, oropharyngeal [OP], or saliva) ≤72 hours prior to randomization and no alternative explanation for current clinical condition. A historical record of positive result from test conducted ≤72 hours prior to randomization is acceptable;4. Has symptoms consistent with COVID-19, with onset ≤10 days before randomization; and5. Hospitalized for COVID-19 illness for <72 hours with at least 1 of the following at randomization - patients meeting more than one criterion will be categorized in the most severely affected category: a. Cohort 1A: With COVID-19 symptoms but not requiring supplemental oxygen b. Cohort 1 : Maintains 02 saturation >93% on low-flow oxygen via nasal cannula, simple face mask, or other similar device c. Cohort 2: High-intensity oxygen therapy without mechanical ventilation, where high- intensity is defined as receiving supplemental oxygen delivered by 1 of the following devices:- Non-rebreather mask (with an Sp02 ≤96% while receiving an oxygen flow rate of at least 10 L / min)- High-flow device (e.g., AIRVO™ or Optiflow™) with at least 50% Fi02- Non-invasive ventilator, including continuous positive airway pressure (CPAP), to treat hypoxemia (excluding isolated use for sleep-disordered breathing) d. Cohort 3: On mechanical ventilation.

[0255] Exclusion Criteria: A patient who met any of the following criteria was excluded from the study:1. Phase 1 only: Patients maintaining 02 saturation >94% on room air;2. In the opinion of the investigator, unlikely to survive for >48 hours from screening;3. Receiving extracorporeal membrane oxygenation (ECMO);4. Has new-onset stroke or seizure disorder during hospitalization;5. Initiated on renal replacement therapy due to COVID-19;6. Has circulatory shock requiring vasopressors at randomization ( Patients who require vasopressors for sedation-related hypotension or reasons other than circulatory shock may be eligible in this study);7. Patients who have received convalescent plasma or IVIG in the past 5 months or plan to receive during the study period for any indication;8. Participation in a clinical research study, including any double-blind study, evaluating an investigational product within 30 days and less than 5 half-lives of the investigational product prior to the screening visit ( The use of remdesivir, hydroxychloroquine, or other treatments (except for COVID-19 convalescent plasma or IVIG) being used for COVID-19 treatments in the context of the local standard-of-care or an open-label study or compassionate use protocol is permitted);9. Any physical examination findings, history of illness, and / or concomitant medications that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study;10. Known allergy or hypersensitivity to components of study drug;11. Pregnant or breastfeeding women; or12. Continued sexual activity in women of childbearing potential (WOCBP)* or sexually active men who are unwilling to practice highly effective contraception prior to the initial dose / start of the first treatment, during the study, and for at least 6 months after the last dose.Highly effective contraceptive measures in women include:• Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable,implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening• Intrauterine device (IUD)• Intrauterine hormone-releasing system (IUS)• Bilateral tubal ligation• Vasectomized partner,† and / or• Sexual abstinenceMale study participants with WOCBP partners were required to use condoms unless they were vasectomized† or practice sexual abstinence.* WOCBP defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.† Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.§ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

[0256] Study Treatments: In phase 1, part A, patients received co-administered mAb10933 + mAb10987 combination therapy 2.4 g (1.2 g of mAb10933 plus 1.2 g of mAb10987) intravenously (IV) single dose, co-administered mAb10933 + mAb10987 combination therapy 8.0 g (4.0 g of mAb10933 plus 4.0 g of mAb10987) IV single dose, or placebo IV single dose. In phase I, part B, patients received mAb10989 monotherapy 1.2 g IV single dose, or placebo IV single dose. In phase 2, patients received co-administered mAb10933 + mAb10987 combination therapy 2.4 g (1.2g of mAb10933 plus 1.2 g of mAb10987) IV single dose, co-administered mAb10933 + mAb10987 combination therapy 8.0 g (4.0 g of mAb10933 plus 4.0 g of mAb10987) IV single dose, or placebo IV single dose. Treatment arms for phase 3 are determined after review of phase 2 data.

[0257] Endpoints: Primary, secondary, and exploratory endpoints are specified for each phase, as defined below.

[0258] Primary Endpoints Phase 1 (Cohort 1 Only)The primary endpoints for phase 1 (Part A and Part B) were:• Proportion of patients with treatment-emergent serious adverse events (SAEs) through day 169• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Time-weighted average change from baseline viral shedding (log10copies / mL) from day 1 to day 22, as measured by quantitative reverse transcription polymerase chain reaction (RT- qPCR) in nasopharyngeal (NP) swab samples (time-weighted average of change from baseline viral shedding from day 1 to day 22 will be calculated for each patient using the trapezoidal rule as the area under the curve for change from baseline at each time point divided by the time interval for the observation period).Phase 2The primary endpoints for phase 2 in each cohort were:Cohort 1A and Cohort 1• Time-weighted average change from baseline viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in nasopharyngeal (NP) swabs• Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 8 using the 7-point ordinal scaleCohort 2 and Cohort 3• Time-weighted average change from baseline viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in NP swabs• Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 22 using the 7-point ordinal scalePhase 3The primary endpoint for phase 3 in each cohort is:Cohort 1A and Cohort 1• Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 8 using the 7-point ordinal scaleCohort 2 and Cohort 3Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 22 using the 7-point ordinal scaleThe patient population (cohort 1 A, cohort 1 , cohort 2, and / or cohort 3) and the primary clinical efficacy endpoint(s) for phase 3 will be finalized after review of phase 2 data.

[0259] Secondary EndpointsPhase 1 (Cohort 1 Only)The secondary endpoints for phase 1 were:• Time-weighted average change from baseline viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in saliva samples• Time-weighted average change from baseline viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in nasal samples• Time to negative RT-qPCR in all tested samples with no subsequent positive RT-qPCR in any tested samples (NP swabs, saliva, or nasal swabs)• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in NP swabs• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in saliva samples• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in nasal swabs• Correlation and concordance with respect to RT-qPCR results over time between different sample types (NP, nasal, and saliva)• Time-weighted average change from baseline in viral shedding (Iog10 copies / mL) from day 1 to post-baseline study days (eg, day 5, 7, 15, and 29)Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 8 using the 7-point ordinal scale• Proportion of patients with at least 2-point improvement in clinical status from day 1 (time of randomization) to day 8 using the 7-point ordinal scale• Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 29 or discharge using the 7-point ordinal scale• Proportion of patients with at least 2-point improvement in clinical status from day 1 (time of randomization) to day 29 or discharge using the 7-point ordinal scale• Time to no longer requiring oxygen supplementation by day 29• Days of supplemental oxygen use up to day 29• Proportion of patients initiating high-intensity oxygen therapy up to day 29 or discharge• Days of high-intensity oxygen therapy up to day 29• Proportion of patients initiating mechanical ventilation up to day 29 or discharge• Days of mechanical ventilation up to day 29• Ventilator-free days up to day 29• Days of hospitalization up to day 29• Proportion of patients re-admitted to hospital after discharge through the end of study• Proportion of patients admitted into an intensive care unit (ICU) up to day 29• Days of ICU stay up to day 29• All-cause mortality up to day 29• All-cause mortality through the end of study• Overall survival• Proportion of patients with treatment-emergent SAEs through day 29• Concentrations of mAb10987, mAb10933, and mAb10989 in serum and corresponding PK parameters• Immunogenicity, as measured by anti-drug antibodies (ADAs) to mAb10933, mAb10987, and mAb10989Phase 2The secondary endpoints for phase 2 were:Cohort 1A and Cohort 1 only• Proportion of patients with at least 2-point improvement in clinical status from day 1 (time of randomization) to day 8 using the 7-point ordinal scaleCohort 2 and Cohort 3 only• Proportion of patients with at least 2-point improvement in clinical status from day 1 (time of randomization) to day 22 using the 7-point ordinal scaleCohort 1A, Cohort 1, Cohort 2, and Cohort 3• Time to negative RT-qPCR in NP swabs with no subsequent positive RT-qPCR• Change from baseline in viral shedding at each visit through day 29, as measured by RT-qPCR in NP swabs• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to post-baseline study days (e.g., day 5, 7, 15, and 29)• Proportion of patients with at least 1 -point improvement in clinical status from day 1 (time of randomization) to day 29 or discharge using the 7-point ordinal scale• Proportion of patients with at least 2-point improvement in clinical status from day 1 (time of randomization) to day 29 or discharge using the 7-point ordinal scale• Time to no longer requiring oxygen supplementation by day 29 (only cohort 1, cohort 2, and cohort 3)• Days of supplemental oxygen use up to day 29• Proportion of patients initiating high-intensity oxygen therapy up to day 29• Days of high-intensity oxygen therapy up to day 29• Proportion of patients initiating mechanical ventilation up to day 29 or discharge• Days of mechanical ventilation up to day 29• Ventilator-free days up to day 29• Days of hospitalization up to day 29• Proportion of patients re-admitted to hospital after discharge through the end of study• Proportion of patients admitted into an ICU up to day 29• Days of ICU stay up to day 29• All-cause mortality up to day 29• All-cause mortality through the end of study• Overall survival• Proportion of patients with treatment-emergent SAEs through day 29• Proportion of patients with treatment-emergent SAEs through day 57• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Concentrations of mAb10933 and mAb10987 in serum over time• Immunogenicity, as measured by ADAs to mAb10933 and mAb10987 Phase 3The patient population (cohort 1A, cohort 1, cohort 2, and / or cohort 3) and the secondary clinical efficacy endpoint(s) for phase 3 are finalized after review of complete phase 2 data.Other possible secondary endpoints for phase 3 included:• Proportion of patients with treatment-emergent SAEs through day 57• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Concentrations of mAb10933 and mAb10987 in serum over time• Immunogenicity, as measured by ADAs to mAb10933 and mAb10987

[0260] Exploratory EndpointsThe exploratory endpoints included:• Proportion of patients with treatment failure having mutations in the gene encoding the SARS-CoV-2 S protein through day 29• Change and percentage change in neutrophil-lymphocyte ratio (NLR) at each visit through day 29• Change and percentage change in D-dimer at each visit through day 29• Change and percentage change in ferritin at each visit through day 29• Change and percentage change in C-reactive protein (CRP) at each visit through day 29• Change and percentage change in lactate dehydrogenase (LDH) at each visit through day 29

[0261] Procedures and Assessments: Efficacy - nasopharyngeal (all phases), saliva (phase 1 only), and / or nasal swabs (phase 1 only) for SARS-CoV-2 RT-PCR, and clinical and oxygen status; Safety - recorded serious adverse events and adverse events of special interest. Nasal swab, saliva sample, and (in phase 1) nasopharyngeal samples were used to collect secretions from patients to determine presence or absence of SARS-CoV-2 virus and to measure viral shedding. Samples were used for RT-qPCR analysis. Samples may additionally be used for exploratory viral RNA sequencing (nasopharyngeal, nasal swab, saliva) and / or viral culture (nasopharyngeal, nasal swab).Statistical Plan:

[0262] Phase 1 - The sample size is a total of 60 patients for phase 1 part A and 40 for part B. The sample size allows preliminary estimation of the incidences of SAE, AESIs, and grade 3 or 4 TEAEs in treatment arms relative to placebo.

[0263] The primary efficacy endpoint in phase 1 was the time-weighted average change from baseline in viral shedding (log10copies / mL) in NP swab samples from day 1 to day 22. Assuming a standard deviation of 2.1 log10copies / mL, a sample size of 20 patients per arm in phase 1 should have at least 80% power to detect a difference of 1.91 log10copies / mL between the treatment arm and placebo group, using a two-sample t-test at a 2-sided significance of a=0.05.

[0264] Phase 2 - The sample size for phase 2 was based on the time-weighted average change from baseline in viral shedding (log10copies / mL) in NP swab samples from day 1 to day 22. Assuming a -23% dropout rate (including missing data at baseline) and standard deviation of 2.1 log10copies / mL, a sample size of 130 patients per arm (ie, 100 patients per arm with available data) across 3 treatment arms within each of the 3 cohorts should have 80% power to detect a difference of 0.84 log10copies / mL between each treatment arm and placebo in a cohort, using a 2-sample t- test at a 2-sided significance of a=0.05. If a standard deviation of 3.8 log10copies / mL is assumed, the detectable difference at 80% power would be 1.51 log10copies / mL

[0265] For the clinical endpoint of proportion of patients with at least 1 -point improvement in clinical status from baseline to day 22, the minimum detectable difference (MDD) between treatment arm and placebo — based on a chi-square test of equal proportions — for a sample size of 100 per arm (130 per arm assuming -23% dropout rate) will be as follows:• In cohorts 1A and 1, the MDD will be 13.7% assuming the response rate in the placebo group is 51% (ie, 64.7% in anti-SARS-CoV-2 S protein mAb versus 51% in placebo). The assumed response rate in the placebo group is similar to the rate observed for remdesivir.In cohorts 2 and 3, the MDD will be 13.3% assuming the response rate in placebo group is 57.1% (ie, 70.4% in anti-SARS-CoV-2 S protein mAb versus 57.1% in placebo). The assumed response rate in the placebo group is similar to the rate observed in sarilumab COVID-19 phase 2 / 3 study (6R88-COV-2040) with an advanced population similar to cohorts 2 and 3 in this study.

[0266] Phase 3 - The study will continue to enroll additional patients seamlessly into the phase 3 portion of the study, until an adaptation decision on the primary endpoint and final sample size for phase 3 is made based on the complete phase 2 data analysis. An initial sample size of total 1350 patients is estimated for the phase 3 portion of the study (150 per arm across 3 treatment arms in 3 cohorts). For example, for cohort 3, a sample size of 450 patients (150 patients per arm) will provide 90% power using a chi-square test to detect a treatment difference of 15.9% in the proportion of patients alive and off mechanical ventilation at day 22, assuming a 68.2% rate in the placebo group.

[0267] Results - Analysis of Phase 1 / 2 / 3 clinical trial (see FIG. 19) of the antibody cocktail, casirivimab and imdevimab (mAb10933 and mAb10987, respectively), in hospitalized COVID-19 patients requiring low-flow oxygen was prospectively designed to focus on patients who had not yet mounted their own immune response to SARS-CoV-2 (i.e. , did not have antibodies at baseline: seronegative), as evidence (see Example 2) suggested these patients were at greater risk. In addition, among subjects treated with placebo, patients who had mounted an immune response at baseline (seropositive patients) had much lower viral levels at baseline compared to patients who had not mounted an immune response at baseline (seronegative patients) and achieved viral loads below the lower level of quantitation (“LLQ”) sooner even without treatment. See FIG. 16. In addition, among hospitalized patients with COVID-19 on low flow supplemental oxygen, seropositive patients had lower cumulative incidence of death or mechanical ventilation compared to seronegative patients. See FIG. 17. Clinical outcomes in Cohort 1 were worse in patients who were seronegative at baseline or who had high viral load at baseline. See FIG. 18. The primary clinical objective of this initial analysis was to determine if there was sufficient efficacy in these patients to warrant continuing the trial (i.e., futility analysis). The results passed the futility analysis (p<0.3 single-sided), as seronegative patients treated with the antibody cocktail had a lower risk of death or receiving mechanical ventilation (hazard ratio (HR): 0.78; 80% Cl: 0.51-1.2). The benefit was driven by results starting one week post-treatment, when the risk of dying or receiving mechanical ventilation was reduced by approximately half with antibody cocktail treatment, basedon a post-hoc analysis.

[0268] Cohort 1 was analyzed for prevalence of seronegativity in both the full analysis set (FAS; randomized and dosed patients) and the modified full analysis set (mFAS; patients testing positive for SARS-CoV-2 via a nasopharyngeal qualitative test at baseline), and seronegative prevlance was similar in both the FAS and the mFAS groups. See FIG. 20. Seronegative patients (n=217) had much higher viral loads than those who had already developed their own antibodies (seropositive) to SARS-CoV-2 at the time of randomization. See FIG. 16. As hypothesized, there as a stronger anti-viral effect with the antibody cocktail compared to placebo in patients who had not mounted their own immune response (seronegative at baseline), patients treated with the antibody cocktail had more brisk viral reductions compared to placebo, and the cocktail reduced viral load faster compared to placebo at all baseline viral load thresholds. See FIGS. 21-24. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by - 0.54 Iog10 copies / mL, and through day 11 by -0.63 Iog10 copies / mL (nominal p=0.002 for combined doses). At day 5, the relative reduction compared to placebo was -1.1 Iog10 copies (nominal p=0.002 for combined doses). In seropositive patients (n=270) the clinical and virologic benefit of the antibody cocktail was limited (clinical endpoint HR: 0.98; time-weighted-average viral load reduction by day 7 of -0.20 Iog10 copies / mL for combined doses). Treatment with the cocktail resulted in similar viral load reductions in hospitalized patients and outpatients, and the most pronounced difference was observed between patients treated with the cocktail and those receiving placebo in seronegative patients, which is consistent with the data of Example 2 (FIGS. 25-28).

[0269] The clinical and virological analyses include data from hospitalized patients who were on low-flow oxygen (defined as maintaining oxygen saturation of >93% via nasal cannula, simple facemask, or similar device), including 217 who were seronegative when they entered the trial and 270 who were seropositive; although seronegative patients comprised less than half of the trial population, based on placebo rates they account for approximately two-thirds of the deaths in the absence of antibody cocktail treatment. Patients were randomized to receive the antibody cocktail (either 8,000 mg high dose or 2,400 mg low dose) or placebo, in addition to standard-of-care therapies, with 67% receiving remdesivir and 74% receiving systemic corticosteroids. Similar clinical and virologic efficacy was observed for the high and low doses of the antibody cocktail.

[0270] Both antibody cocktail doses were well-tolerated. In the overall trial population, the incidence of serious adverse events was 21% for high dose, 20% for low dose and 24% for placebo. Infusion reactions were more common with the high dose of the antibody cocktail (2.7% high dose, 0.9% low dose, 1.4% placebo) and there were two discontinuations due to infusion- related reactions, both of which occurred in the high dose group.Example 2. Clinical Evaluation of Anti-SARS-CoV-2 Spike Glycoprotein Antibodies in Ambulatory Patients with COVID-19.

[0271] The below-described clinical study is an adaptive, phase 1 / 2 / 3, randomized, double- blinded, placebo-controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 combination therapy (which together, can be referred to as REGN-COV2 or REGEN-COV), or alternatively mAb10989 monotherapy in adult outpatients (i.e., ambulatory patients) with COVID-19 or asymptomatic SARS-CoV-2 infection.

[0272] Study Objectives: The primary and secondary objectives of each phase of the study are set forth below.

[0273] Exemplary Use: An exemplary use that could be authorized based on the results (including interim results) from this Example is as follows:

[0274] This exemplary use applies to intravenous infusion of REGEN-COV, wherein mAb10933 and mAb10987 are administered together. REGEN-COV should be administered as soon as possible after positive viral test for SARS-CoV-2 and within 7 days of symptom onset in adults and pediatric patients 12 years of age and older weighing at least 40 kg who are at high risk for progressing to severe COVID-19 and / or hospitalization. COVID-19 illnesses can range from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. People of all ages with severe, long-lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example, and other conditions including obesity, seem to be at higher risk of being hospitalized for COVID-19. Older age, with or without other conditions, also places people at higher risk of being hospitalized for COVID-19.

[0275] This exemplary authorization is for the use of REGEN-COV for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40kg, and who are at high risk for progressing to severe COVID-19 and / or hospitalization.

[0276] The following medical conditions or other factors may place adults and pediatric patients (age 12-17 years and weighing at least 40 kg) at higher risk for progression to severe COVID-19: o Older age (for example age ≥65 years of age) o Obesity or being overweight (for example, adults with BMI >25 kg / m2, or if age 12-17, have BMI ≥85th percentile for their age and gender based on CDC growth charts, https: / / www.cdc.gov / growthcharts / clinical_charts.htm)o Pregnancy o Chronic kidney disease o Diabetes o Immunosuppressive disease or immunosuppressive treatment o Cardiovascular disease (including congenital heart disease) or hypertension o Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension) o Sickle cell disease o Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies) o Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))

[0277] Other medical conditions or factors (for example, race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and authorization of REGEN- COV under the EUA is not limited to the conditions listed above. For additional information on medical conditions and factors associated with increased risk for progression to severe COVID-19, see the CDC website: www.cdc.gov / coronavirus / 2019-ncov / need-extra-precautions / people-with- medical-conditions.html. Healthcare providers should consider the benefit-risk for an individual patient.

[0278] Limitations of an Authorized Use:• In this exemplary use, REGEN-COV should not be used in patients:- who are hospitalized due to COVID-19, OR- who require oxygen therapy due to COVID-19, OR- who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.However, alternative authorized uses contemplate the use of REGEN-COV in patients who can be hospitalized due to COVID-19, and / or who require oxygen therapy due to COVID-19, and / or who require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity.

[0279] Primary Objectives:Phase 1 Part ATo evaluate the safety and tolerability of mAb10933 + mAb10987 compared to placebo• To evaluate the virologic efficacy of mAb10933 + mAb10987 compared to placebo in reducing viral shedding of SARS-CoV-2Part B• To evaluate the safety and tolerability of mAb10989 compared to placebo• To evaluate the virologic efficacy of mAb10989 compared to placebo in reducing viral shedding of SARS-CoV-2Phase 2To evaluate the virologic efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo in reducing viral shedding of SARS-CoV-2.Phase 3To evaluate the clinical efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo.

[0280] Secondary Objectives:Phase 1 Part A• To evaluate additional indicators of virologic efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the clinical efficacy of mAb10933 + mAb10987 compared to placebo• To compare quantitative reverse transcription polymerase chain reaction (RT-qPCR) results acquired with different sample types (nasopharyngeal [NP], nasal, and saliva)• To characterize the pharmacokinetic (PK) profiles of mAb10933 and mAb10987 in serum• To assess the immunogenicity of mAb10933 and mAb10987 Part B• To evaluate additional indicators of virologic efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the clinical efficacy of mAb10989 compared to placebo• To compare RT-qPCR results acquired with different sample types (NP, nasal, and saliva)• To characterize the PK profile of mAb10989 in serum• To assess the immunogenicity of mAb10989 Phase 2• To evaluate additional indicators of virologic efficacy of mAb10933 + mAb10987 compared to placebo• To evaluate the clinical efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo• To evaluate the safety and tolerability of mAb10933 + mAb10987 and mAb10989 compared to placebo• To characterize the concentrations of mAb10933, mAb10987, and mAb10989 in serum• To assess the immunogenicity of mAb10933, mAb10987, and mAb10989 Phase 3• To evaluate the virologic efficacy of mAb10933 + mAb10987 and mAb10989 compared to placebo in reducing viral shedding of SARS-CoV-2• To evaluate the safety and tolerability of mAb10933 + mAb10987 and mAb10989 compared to placebo• To characterize the concentrations of mAb10933, mAb10987, and mAb10989 in serum To assess the immunogenicity of mAb10933, mAb10987, and mAb10989

[0281] Study Design: This is an adaptive, phase 1 / 2 / 3, randomized, double-blinded, placebo- controlled master protocol to evaluate the efficacy, safety, and tolerability of mAb10933 + mAb10987 combination therapy and mAb10989 monotherapy in adult outpatients (i.e., ambulatory patients) with COVID-19 or asymptomatic SARS-CoV-2 infection. To have been eligible, adult patients must have had laboratory-confirmed SARS-CoV-2 and COVID-19 symptoms but must not have been previously hospitalized or currently hospitalized. In phase 1, only patients with COVID-19 were enrolled. In phase 2, symptomatic patients and asymptomatic patients were enrolled into separate cohorts.Phase 1

[0282] In phase 1 part A, randomization was limited to mAb10933 + mAb10987 low dose, mAb10933 + mAb10987 high dose, and placebo. In part B, randomization was limited to mAb10989, and placebo. On day 1, eligible patients in part A were randomized to a single intravenous (IV) administration of mAb10933 + mAb10987 (low dose), mAb10933 + mAb10987 (high dose), mAb10989, or placebo.

[0283] Patients were then be sequestered for the first 48 hours after dosing, during which time they were closely monitored for serious adverse events (SAEs) and adverse events of special interest (AESIs). On day 3, patients could return home, if medically appropriate, after completing the day’s assessments. After completing assessments on day 7, all patients were sent home, if medically appropriate. Throughout the study, safety information (SAEs and AESIs) were collected, as was information about any medically-attended visits related to COVID-19. Nasopharyngeal (NP swab), nasal swab, and saliva samples were collected to assess viral shedding. The study ended on day 29, when patients had final assessments conducted in person including NP swab, nasalswab, and / or saliva sample collection (as feasible) and blood draws for PK, anti-drug antibody (ADA), and exploratory analyses.Phase 2On day 1 , eligible patients were randomized 1 : 1 : 1 : 1 to a single dose of mAb10933 + mAb10987 (low dose), mAb10933 + mAb10987 (high dose), mAb10989, or placebo. After infusion of study drug, patients were observed for 2 hours and, if no SAEs or AESIs were observed, were sent home. Nasopharyngeal swabs were collected every other day for the first 2 weeks and then twice weekly thereafter. Blood samples were collected periodically. Information regarding treatment-emergent SAEs, AESIs, and medically-attended related to COVID-19 were recorded throughout the study.On day 29, patients had final assessments, including nasopharyngeal swab collection and blood draws for PK, ADA, and exploratory analysis.

[0284] Study Duration: The duration of the study was 30 days for each patient.

[0285] Study Population: This study enrolled adult, non-hospitalized patients who had a positive diagnostic test for SARS-CoV-2.

[0286] Sample Size - Phase 1 enrolled until up to 100 patients are randomized. Phase 2 enrolled until approximately 1300 patients are randomized. It was estimated that 704 patients (176 patients per arm) would be required for phase 3.

[0287] Inclusion Criteria: A patient must have met the following criteria to be eligible for inclusion in the study:1. Is male or female ≥18 years of age (or country’s legal age of adulthood) at randomization;2. Has SARS-CoV-2-positive molecular diagnostic test (by validated SARS-CoV-2 RT-PCR or other molecular diagnostic assay, using an appropriate sample such as NP, nasal, oropharyngeal [OP], or saliva) ≤72 hours prior to randomization. A historical record of positive result from test conducted ≤72 hours prior to randomization is acceptable;3. Meets one of the following two criteria: a. Symptomatic Cohort (All Phases): Has symptoms consistent with COVID-19 as determined by the investigator with onset ≤7 days before randomizationOr b. Asymptomatic Cohort (Phase 2): Meets all of the following:• Has no symptoms consistent with COVID-19 (as determined by the investigator) occurring at any time <2 months prior to randomization• Has no positive SARS-CoV-2 test results from a sample collected >7 days prior to randomization• Has no known contact (of any duration) with an individual who has confirmed COVID-19 or confirmed positive SARS-COV-2 test >14 days prior to randomization4. Maintains O2 saturation ≥93% on room air;5. Is willing and able to provide informed consent signed by study patient or legally acceptable representative; and6. Is willing and able to comply with study procedures, including providing samples for viral shedding testing after discharge.

[0288] Exclusion Criteria: A patient who met any of the following criteria was excluded from the study:1. Has been admitted to a hospital prior to randomization, or is hospitalized (inpatient) at randomization, due to COVID-19;2. Has participated, or is participating, in a clinical research study evaluating COVID-19 convalescent plasma, monoclonal antibodies against SARS-CoV-2, or intravenous immunoglobulin (IVIG) within 3 months or less than 5 half-lives of the investigational product (whichever is longer) prior to the screening visit;3. Prior, current, or planned future use of COVID-19 convalescent plasma, mAbs against SARS CoV 2, intravenous immunoglobulin (IVIG) (any indication), systemic corticosteroids (any indication), or any Emergency Use Authorization (EUA)-approved treatments in the past 30 days or less than 5 half-lives of the investigational product (whichever is longer) prior to the screening visit;4. Has known allergy or hypersensitivity to components of study drug;5. Has been discharged, or is planned to be discharged, to a quarantine center;6. Pregnant or breastfeeding women; or7. Continued sexual activity in women of childbearing potential (WOCBP)* or sexually active men who are unwilling to practice highly effective contraception prior to the initial dose / start of the first treatment, during the study, and for at least 6 months after the last dose.Signs and symptoms of hypersensitivity including infusion related reactions may include: fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash including urticaria, pruritus, myalgia, and dizziness.Highly effective contraceptive measures in women include:• Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening,• Intrauterine device (IUD),• Intrauterine hormone-releasing system (IUS),• Bilateral tubal ligation,• Vasectomized partner,†and / or• Sexual abstinenceMale study participants with WOCBP partners are required to use condoms unless they are vasectomized†or practice sexual abstinence* WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.† Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

[0289] Study Treatments: Co-administered mAb10933 + mAb10987 combination therapy, 2.4 g (1.2 g each of mAb10933 and mAb10987) IV single dose, Co-administered mAb10933 + mAb10987 combination therapy, 8.0 g (4.0 g each of mAb10933 and mAb10987) IV single dose, mAb10989 monotherapy, 1.2 g IV single dose, or placebo IV single dose.

[0290] Endpoints: Primary, secondary, and exploratory endpoints were specified for each phase, as defined below.

[0291] Primary EndpointsPhase 1The primary endpoints for phase 1 were:Part A and B• Proportion of patients with treatment-emergent serious adverse events (SAEs) through day 29• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to day 22, as measured by quantitative reverse transcription quantitative polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab samples.Phase 2The primary endpoint for phase 2 was time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in NP swab samples. Phase 3The primary endpoint for phase 3 was proportion of patients with ≥1 COVID-19 related medically-attended visit through day 29.

[0292] Secondary EndpointsPhase 1Virologic• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in saliva samples• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in nasal swab samples• Time to negative RT-qPCR in all tested samples with no subsequent positive RT-qPCR in any tested samples (NP swabs, saliva, or nasal swabs)• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in NP swabs• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in saliva samples• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in nasal swabs• Correlation and concordance of RT-qPCR results across different sample types (NP, nasal, and saliva)• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to post-baseline study days (e.g., day 5, 7, 15, and 29)Clinical• Proportion of patients with ≥1 COVID-19 related medically-attended visit through day 29; COVID-19 related medically-attended visit will be defined as: hospitalization with the primary reason for hospitalization being COVID-19, or an outpatient visit (including a visitto the ER, UCC, doctor’s office, or telemedicine visit) with the primary reason for the visit being COVID-19• Proportion of patients with ≥2 COVID-19 related medically-attended visits through day 29• Total number of COVID-19 related medically-attended visits through day 29• Proportion of patients admitted to a hospital due to COVID-19 by day 29• Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 by day 29PK / ADA• Concentrations of mAb10933, mAb10987, and mAb10989 in serum and corresponding PK parameters• Immunogenicity as measured by anti-drug antibodies (ADA) to mAb10933, mAb10987, and mAb10989Phase 2The secondary endpoints for phase 2 were:Virologic• Time to negative RT-qPCR in NP swabs with no subsequent positive RT-qPCR• Change from baseline in viral shedding at each visit through day 29, as measured by RT-qPCR in NP samples• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to post-baseline study days (eg, day 5, 7, 15, and 29)Clinical• Proportion of patients with ≥1 COVID-19 related medically-attended visit through day 29• Proportion of patients with ≥2 COVID-19 related medically-attended visits through day29• Total number of COVID-19 related medically-attended visits through day 29• Proportion of patients admitted to a hospital due to COVID-19 by day 29• Proportion of patients admitted to an ICU due to COVID-19 by day 29• Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 by day 29• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29• Days of hospitalization due to COVID-19• Proportion of patients with all-cause mortality by day 29• Proportion of patients with treatment-emergent SAEs through day 29• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Time to first onset of any symptom of COVID-19• Duration of symptoms consistent with COVID-19 PK / ADA• Concentrations of mAb10933, mAb10987, and mAb10989 in serum• Immunogenicity as measured by anti-drug antibodies (ADA) to mAb10933, mAb10987, and mAb10989Phase 3The secondary endpoints for phase 3 were:Virologic• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to day 22, as measured by RT-qPCR in NP swabs• Time to negative RT-qPCR in NP swabs with no subsequent positive RT-qPCR• Change from baseline in SARS-CoV-2 viral shedding at each visit through day 29, as measured by RT-qPCR in NP swabs• Time-weighted average change from baseline in viral shedding (log10copies / mL) from day 1 to post-baseline study days (eg, day 5, 7, 15, and 29)Clinical• Proportion of patients with ≥2 COVID-19 related medically-attended visits through day 29• Total number of COVID-19 related medically-attended visits through day 29• Proportion of patients with ≥1 outpatient or telemedicine visit due to COVID-19 by day 29• Proportion of patients admitted to a hospital due to COVID-19 by day 29• Proportion of patients admitted to an ICU due to COVID-19 by day 29• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29• Days of hospitalization due to COVID-19• Proportion of patients with all-cause mortality by day 29• Proportion of patients with treatment-emergent SAEs through day 29• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29PK / ADA• Concentrations of mAb10933, mAb10987, and mAb10989 in serum• Immunogenicity as measured by anti-drug antibodies to mAb10933, mAb10987, and mAb10989

[0293] Exploratory EndpointsThe exploratory endpoints for phase 1 and phase 2 were:• Proportion of patients with treatment failure having mutations in the gene encoding the SARS-CoV-2 S protein through day 29• Change and percentage change in neutrophil-lymphocyte ratio (NLR) at each visit through day 29• Change and percentage change in D-dimer at each visit through day 29• Change and percentage change in ferritin at each visit through day 29• Change and percentage change in C-reactive protein (CRP) at each visit through day 29• Change and percentage change in lactate dehydrogenase (LDH) at each visit through day 29• Change in SE-C19 item scores over time• Change in PGIS score over time• PGIC score at day 29• Proportion of patients admitted to an ICU due to COVID-19 by day 29 (phase 1 only)• Proportion of patients requiring mechanical ventilation due to COVID-19 by day 29

[0294] Procedures and Assessments: Efficacy - nasopharyngeal swabs (all phases), nasal swabs (phase 1 only), and saliva samples (phase 1 only) for SARS-CoV-2 RT-qPCR, and medically-attended COVID-19 visit details; Safety - record serious adverse events and adverse events of special interest, blood collection for safety labs, and vital signs. Nasal swab and saliva samples were used to collect secretions from patients to determine presence or absence of SARS- CoV-2 virus and to measure viral shedding.Statistical Plan:

[0295] Primary Efficacy Analysis - The primary efficacy variable for phase 1 and phase 2 was time-weighted average change from baseline in viral shedding from day 1 to day 22, as measured by RT-qPCR in NP swab samples. The estimant for the primary hypothesis was the difference in means between each of the anti-S SARS-CoV-2 mAb treatments and placebo in the primary efficacy variable in the FAS. The primary efficacy variable was calculated using trapezoidal rule based on observed data and was analyzed using an Analysis of Covariance (ANCOVA) model with treatment group and randomization strata as fixed effects and baseline viral shedding as covariate.For phase 2, analysis was performed for each cohort separately (symptomatic and asymptomatic) and for both cohorts combined. The least squares means estimates for the time-weighted average mean change from baseline in viral shedding for each treatment group, as well as the difference between each anti-spike mAb treatment arm and placebo (in phase 2, for each cohort separately and for both cohorts combined), was presented along with the corresponding p-value, standard error, and associated 95% confidence interval. The phase 3 primary efficacy variable was the proportion of patients with medically attended visits due to worsening COVID-19 symptoms and signs and was compared between groups using stratified Cochran-Mantel-Haenszel test at two- sided 0.05 level. P-values and 95% confidence intervals for the treatment difference are presented below.

[0296] Safety Analysis - Safety data including serious adverse events and adverse events of special interest, vital signs, and laboratory tests are listed and summarized by treatment group.

[0297] Results - The seamless Phase 1 / 2 / 3 trial described above showed a significantly reduced SARS-CoV-2 viral load and time to alleviate symptoms in non-hospitalized patients with COVID-19, when treated with a combination of mAb10933 and mAb10987 (REGN-COV-2). REGEN-COV also significantly reduced COVID-19-related medically-attended visits. The randomized, double-blind trial measured the effect of adding REGEN-COV to usual standard-of-care, compared to adding placebo to standard-of-care.

[0298] The final analysis of the phase 1 / 2 portion included 799 patients: 275 (group-1) and 524 (group-2). Patients were randomized (1:1:1) to placebo, 2.4g of the mAb10933+mAb10987 antibody cocktail (also referred to as REGEN-COV), or 8.0g REGEN-COV, and characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive / negative). Efficacy was assessed in patients with a positive baseline RT-qPCR result; safety was assessed in all patients. Prespecified hierarchical analyses of virologic endpoints in group-2 were performed to confirm previously reported descriptive analyses from group-1. The proportion of patients with ≥1 Covid-19-related medically-attended visit (MAV) through day 29 was assessed in group-1+2.

[0299] Time-weighted average reduction in viral load (Iog10 copies / mL) through day 7 was significantly greater with REGEN-COV (combined 2.4g+8.0g dose groups) vs placebo in patients with baseline viral load >107copies / mL (prespecified primary endpoint): -0.68 (95% Cl, -0.94 to - 0.41; P<0.0001). Across all baseline viral loads, this change was -0.73 (P<0.0001) in serum antibody-negative patients and -0.36 (P=0.0003) in the overall population. Proportions of patients with ≥1 Covid-19-related MAV were 2.8% (12 / 434) with REGEN-COV vs 6.5% (15 / 231) with placebo (P=0.024; relative risk reduction=57%), with greater relative risk reductions in MAVs in patients with ≥1 risk factor for hospitalization (72%) or who were serum antibody-negative (65%).Adverse events were similar across groups.

[0300] Trial Design Summary: Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g REGEN-COV (1.2g each of casirivimab and imdevimab), or 8.0 g REGEN-COV (4.0g each of casirivimab and imdevimab) (Figure 5). The 29-day phase 2 trial included a screening / baseline period (days -1 to 1), a follow-up period (days 2 to 25), and an end-of-study visit (day 29). The phase 1 and phase 2 portions of the trial were identical, except for additional pharmacokinetic analyses in phase 1.

[0301] Patients: Eligible patients were ≥18 years of age and non-hospitalized, with a confirmed SARS-CoV-2-positive nasopharyngeal (NP) PCR test result ≤72 hours and symptom onset ≤7 days before randomization. Randomization was stratified by country and by the presence or absence of ≥1 risk factor for severe Covid-19: age >50 years, obesity (BMI >30), immunosuppression, and chronic cardiovascular, metabolic, liver, kidney, or lung disease. All patients were assessed for the presence or absence of anti-SARS-CoV-2 antibodies: anti-spike [S1] IgA, anti-spike [S1] IgG, and anti-nucleocapsid IgG. Because these results were not available at randomization, patients underwent randomization regardless of their baseline serum antibody status and were then subsequently grouped for analyses as serum antibody-negative (if all available tests are negative), serum antibody-positive (if any of the tests are positive), or unknown status (missing or inconclusive results). The demographic and baseline medical characteristics of the patients are shown in Table 5A, below.

[0302] Table 5A. Demographic and Baseline Medical Characteristics* (N=799; Full Analysis Set)

[0303] Intervention: At baseline (day 1), mAb10933 (casirivimab) and mAb10987 (imdevimab) (diluted in a 250-ml normal saline solution for co-administration) or saline placebo was administered intravenously over a period of 1 hour.Endpoints

[0304] The primary virologic endpoint and two key secondary clinical endpoints were prespecified in this phase 1 + phase 2 (collectively referred to as phase 1 / 2) analysis and tested hierarchically as described in Table 5B.The primary virologic endpoint was defined as the time-weighted mean change in viral load (Iog10 copies per milliliter) from baseline (day 1) through day 7. The key secondary clinical endpoints were the proportion of patients with at least one Covid-19- related medically-attended visit (MAV) through day 29 and the proportion of patients with at least oneCovid- 19- related MAV consisting of only hospitalization or emergency room (ER) visit or urgent care visit. A MAV was defined as a hospitalization or ER, urgent care, or physician office / telemedicine visit that was confirmed by the investigator to be related to Covid- 19.

[0305] Table 5B. Phase 2 Primary Analysis of Virologic and Clinical Endpoints

[0306] Safety endpoints for the phase 1 / 2 portion of the trial included adverse events that occurred or worsened during the observation period (only in phase 1; grade 3 and 4 only), serious adverse events (SAEs), and adverse events of special interest (AESIs): grade ≥2 hypersensitivity or infusion-related reactions.Statistical Analysis

[0307] The statistical analysis plan for the presented analysis was finalized prior to database lock and unblinding of the additional 524-patient phase 2 dataset. The full analysis set (FAS) included patients with Covid-19 symptoms who underwent randomization. Patients with a positive SARS-CoV-2 nasopharyngeal (NP) PCR test ≤72 hr of randomization (baseline) but who tested negative by the central lab qualitative PCR at baseline (limit of detection, 714 copies per milliliter) were excluded from analyses of virologic and clinical endpoints in a modified full analysis set (mFAS). Subgroup analyses by serology status and baseline viral load were prespecified in the statistical analysis plan. Safety was assessed in patients in the FAS who received study drug (active or placebo).

[0308] To confirm the virologic efficacy seen in analysis group 1 (patients 1 through 275), analyses of virologic endpoints were conducted using data from patients 276 through 799, inclusive (524 patients; analysis group 2). Analyses of clinical endpoints and safety, however, utilized data from all available patients, inclusive of the first 275 patients (patients 1 through 799; analysis group 1+2).

[0309] The virologic efficacy endpoint was calculated as discussed below. The key secondary clinical endpoints were analyzed using Fisher’s exact test. Analyses of virologic and clinical endpoints were conducted at a two-sided a=0.05 utilizing a hierarchical testing strategy to control for type I error. Statistical analyses were performed with SAS software, version 9.4 or higher (SAS Institute).Baseline Characteristics

[0310] 799 patients underwent randomization in the phase 1 / 2 portion of the trial. In the pooled799-patient group, 266, 267, and 266 patients were assigned to receive low-dose REGEN-COV, high-dose REGEN-COV, or placebo, respectively (Figure 6). Among the 799 patients (analysis group 1+2), 87 (10.9%) tested negative in the central lab SARS-CoV-2 NP RT-qPCR assay at baseline and 47 (5.9%) were without central lab baseline viral load data; consequently, the modifiedfull analysis (mFAS) set comprised 665 patients. Similarly, among the 524 patients in analysis group 2 (primary virologic efficacy analysis), the mFAS set comprised 437 patients.

[0311] Of the 799 randomized patients, the median age was 42.0 years, 47% were male, 9% identified as Black or African American, 50% identified as Hispanic or Latino (Table 5A). 483 (60.5%) patients had ≥1 risk factor for hospitalization due to Covid-19, including obesity (37.3%), age >50 years (29.3%), cardiovascular disease (20.5%), or chronic metabolic disease (13.1%). Baseline characteristics were similar between the 275-patient analysis group 1 and 524-patient analysis group 2 (Table 5C).

[0312] Table 5C. Phase 1 / 2 Demographic and Baseline Medical Characteristics* (N=524; Full Analysis Set)

[0313] At randomization, 408 (51.1%) patients were serum antibody-negative, 304 (38.0%) were serum antibody-positive, and 87 (10.9%) were serum antibody-unknown. Median baseline viral load was 5.48 Iog10 copies / mL (47 of 799 with missing baseline data); 256 (32.0%) patients had baseline viral load >107 copies / mL. The mean time from symptom onset to randomization was 3.4 days in the overall trial population: 3.2 days in serum antibody-negative patients; 3.6 days in serum antibody-positive patients; 2.9 days patients with viral load >107 copies / mL; and 3.8 days in patients with viral load ≤107 copies / mL. Among 408 patients with ≥1 risk factor for hospitalization, 336 (82.3%) were serum antibody-negative or had viral load >104 copies / mL.Natural History

[0314] The natural history of Covid-19 among placebo- treated patients in this analysis confirmed that the presence of endogenous antibodies against SARS-CoV-2 at baseline is an importantindicator of viral and clinical outcomes. Patients in the placebo arm who were serum antibody negative at baseline had higher median viral loads at baseline compared to those who were serum antibody-positive (7.73 Iog10 copies / ml vs 3.88 Iog10 copies / ml), and they took substantially longer to bring their viral levels to LLQ or to undetectable (Figures 7 and 8). Similarly, for clinical outcomes, placebo patients who were serum antibody-negative at baseline had substantially higher rates of Covid-19-related MAVs (9.7%; 12 / 124) than placebo patients who were serum antibody positive at baseline (2.4%; 2 / 83). As the endogenous immune response was associated with baseline viral titers, there was the expected association of Covid-19-related MAV risk with baseline viral load as well as with presence of risk factors: MAVs occurred in 0% (0 / 55) of patients with baseline viral load ≤104 copies / mL vs 8.5% (15 / 176) with baseline viral load >104 copies / mL and MAVs occurred in 2.2% (2 / 89) of patients with no risk factors vs 9.2% (13 / 142) with ≥1 risk factor (Figure 9).

[0315] Virolooic Efficacy

[0316] Prespecified comparisons for the virologic efficacy endpoint were assessed hierarchically in the 524-patient analysis group 2 who were confirmed SARS-CoV-2- positive by NP RT-qPCR at baseline (mFAS; n=437) (Tables 5B and 5D). REGEN-COV treatment significantly reduced viral load through day 7 vs placebo in all the prespecified virologic efficacy comparisons (Table 5D; FIG. 10A, FIG. 10B, and FIG. 11). In the first comparison, among patients with baseline viral load >107copies / mL, the least-squares mean difference between REGEN-COV treatment (combined 2.4g and 8.0g doses) versus placebo in the time-weighted average (TWA) daily change in viral load through day 7 was -0.68 Iog10 copies / mL (95% Cl, -0.94 to -0.41; P<0.0001) (Table 5D). Similarly, the least-squares mean difference in TWA daily change from baseline with REGEN-COV treatment vs placebo was -0.73 Iog10 copies / mL (95% Cl, -0.97 to -0.48; P<0.0001) in patients who were serum antibody-negative at baseline (n=256), while it was -0.36 Iog10 copies / mL (95% Cl, -0.56 to - 0.16; P=0.0003) in the overall modified full analysis set (n=437). These data indicate that reductions in viral load observed with the antibody cocktail treatment were primarily driven by effects in serum antibody-negative patients, as previously observed (Table 5D; Fig. 10A, FIG. 10B, and FIG. 11). Treatment effects were similar with the low-dose and high-dose antibody cocktail across all the virologic efficacy endpoint comparisons (Table 5D). Results from additional key virologic endpoints are provided in Table 5E, FIG. 12, and FIG. 13.

[0317] Table 5D. Key Virologic and Clinical End Points

[0318] Table 5E. Change from Baseline in Viral Load (log10copies / mL) at Each Visit in Patients With No or >1 Risk Factors for Hospitalization

[0319] The virologic efficacy endpoint of time-weighted average (TWA) daily change from baseline (day 1) through day 7 was calculated for each patient as the area under the concentration time curve with the use of the linear trapezoidal rule (area under the curve for change from baseline divided by the time interval of the observation period), and analyzed using an analysis of covariancemodel with treatment group, country, and risk factor (no risk factor versus at least one risk factor) as fixed effects and baseline viral load and treatment by baseline interaction as covariates.Clinical Efficacy

[0320] There were two clinical efficacy endpoints prespecified for hierarchical testing: the proportion of patients with at least one Covid- 19- related medically-attended visits (MAV) and the proportion of patients with at least one Covid- 19-related MAV consisting of only hospitalization or ER or urgent care visits (Tables 5B and 5D). Both endpoints were assessed through day 29 in the pooled 799-patient group (analysis group 1+2) who were confirmed SARS-CoV-2- positive by NP RT-qPCR at baseline (mFAS; n=665). Overall, 67% of the Covid-19- related MAVs were hospitalizations or emergency room (ER) visits (30% and 37%, respectively), 26% physician office visits / telemedicine, and 7% urgent care visits. Descriptions of Covid-19 related MAVs are included in Table 5F.

[0321] Table 5F. Description of Covid-19-related MAVs*

[0322] The proportion of patients in the REGEN-COV treatment group (combined 2.4g and 8.0g doses) with ≥1 Covid-19-related MAV was 2.8% (12 of 434) compared to 6.5% (15 of 231) in the placebo group, which represents a relative reduction of 57% (absolute difference vs. placebo, -3.7percentage points; 95% Cl, -7.9% to -0.3%; P=0.024) (Table 5D). Treatment effects observed with REGEN-COV were more pronounced in baseline serum antibody-negative patients (3.4% vs 9.7% placebo; 65% relative reduction) (Table 5G). For the final hierarchical endpoint, the proportion of patients with Covid-19- related hospitalization or ER or urgent care visits was numerically lower in the REGENCOV group (vs placebo) but the difference did not reach statistical significance (Table 5D). Post-hoc analyses demonstrated a reduction in the proportion of antibody cocktail treated patients (combined dose group) who were hospitalized or died (0.7% [3 of 434] vs 2.2% [5 of 231]; relative reduction of 68%) and in those who were hospitalized or had an ER visit (1.8% [8 of 434] vs 4.3% [10 of 231]; relative reduction of 58%) (Table 5H).

[0323] Table 5G. Proportion of Patients with >1 Covid-19-related MAVs by Baseline Serum Antibody Status

[0324] Table 5H. Proportion of Patients Who Were Hospitalized, Visited the ER, and / or Died

[0325] Additional post hoc analyses investigated the effects of the antibody cocktail treatment on MAVs in various high-risk subgroups. The proportion of patients with ≥1 risk factors for hospitalization (n=408) who had Covid-19-related MAVs in the REGEN-COV group (combined dose) vs the placebo group was: 2.6% vs 9.2% (absolute difference vs. placebo, -6.5 percentage points; 95% Cl, -17 to 4; 72% relative reduction) (FIG. 14A, FIG. 14B, and FIG. 14C; Table 5I). The proportion of patients with ≥1 risk factor who were baseline serum antibody-negative and had a viral load >104 copies / mL (n=217) who had Covid-19-related MAVs in the REGEN-COV group (combined doses) vs the placebo group was: 2.1% vs 13.2% (absolute difference vs. placebo, -11.0 percentage points; 95% Cl, -21 to -3; 84% relative reduction) (Table 5J). The majority (59%) of patients who experienced a MAV had a viral load of ≥4 Iog10 copies / ml around the time of the medically-attended visit (Table 5F; FIG. 15A, FIG. 15B, and FIG. 15C). As with virologic endpoints, no meaningful differences in clinical outcomes were observed between low dose and high dose treatments.

[0326] Table 5I. Proportion of Patients with >1 Covid-19-related MAVs in Those With No or >1 Risk Factors for Hospitalization

[0327] Table 5J. Proportion of Patients with >1 Covid-19-related MAVs in Those Who Are SerumAntibody-Negative & High-Risk & Have a Viral Load >104

[0328] The proportions of patients with medically attended visits due to worsening Covid-19 was compared between the REGEN-COV combined dose group and placebo as well as between each REGEN-COV treatment arm and placebo using Fisher’s exact test at a two-sided alpha level of 0.05. A similar analysis was performed for the proportion of patients with Covid-19-related hospitalization or emergency room or urgent care visits as well as proportions of patients with each type of medically attended visit.Safety

[0329] Serious Adverse Events (SAEs) were experienced by 4 of 258 patients (1.6%) in the REGEN-COV 2.4 g group, 2 of 260 patients (0.8%) in the REGEN-COV 8.0 g group, and a higher number of patients (i.e., 6 of 262 patients [2.3%]) in the placebo group (Tables 5K and 5L). Allserious adverse events were considered to be due to advanced or progressive Covid-19 disease and / or associated concomitant clinical conditions and were not evaluated to be related to the study drug treatment.

[0330] Adverse Events of Special Interest (AESIs) - grade ≥2 infusion-related reactions and hypersensitivity reactions - that occurred or worsened during the safety observation period were reported in no patients in the 2.4 g group, 4 (1.5%) patients in the 8.0 g group, and 2 (0.8%) patients in the placebo group, (Tables 5K and 5L).

[0331] Table 5K. Overview of Serious Adverse Events and Adverse Events of Special Interest in the Safety Population

[0332] Table 5L. Treatment-Emergent Serious Adverse Events and Adverse Events of Special Interest Reported in Subjects Receiving REGEN-COV

[0333] Pharmacokinetics: The mean concentrations for casirivimab and imdevimab increased in a dose-proportional manner and were consistent with linear pharmacokinetics for single intravenous doses (Table 5M). The mean±SD day 29 concentrations of casirivimab and imdevimab in serum were 79.7±34.6 mg per liter and 65.2±28.1 mg / L, respectively, for the low (1.2 g) doses and 250±97.4 and 205±82.7 mg / L, respectively, for the high (4.0 g) doses (Table 5M).

[0334] Table 5M. Mean Concentrations of REGN10933 and REGN10987 in Serum

[0335] Serum for drug concentration analysis was collected from all patients at pre-dose (at the screening or baseline visit), day 1 at the end of the infusion, and day 29. Additional serum collections were on days 3, 5, 7, and 15 for Phase 1 patients only. The human serum concentrations of REGN 10933 (casirivimab) and REGN 10987 (imdevimab) were measured using validated immunoassays which employ streptavidin microplates from Meso Scale Discovery (MSD, Gaithersburg, MD, USA). The methods utilized two anti-idiotypic monoclonal antibodies, each specific for either mAb10933 or mAb10987, as the capture antibodies. Captured mAb10933 and mAb10987 were detected using two different, non-competing anti-idiotypic monoclonal antibodies, each also specific for either mAb10933 or mAb10987. The bioanalytical methods specifically quantitated the levels of each anti-SARS-CoV-2 spike mAb separately, with no interference from the other antibody. The assay had a lower limit of quantitation (LLOQ) of 0.156 μg / mL for each analyte in the undiluted serum sample.

[0336] Discussion

[0337] The findings from this final phase 1 / 2 analysis of REGEN-COV antibody cocktail for the treatment of outpatients with Covid-19 confirmed and extended the findings from the first 275 patients. To better understand the natural history of Covid-19 in outpatients, data from placebo patients in this trial were described. These data confirms previous findings that patients who had not yet mounted their own immune response at baseline (i.e., were serum antibody-negative at baseline) had median viral loads at baseline that were almost 3 log copies / mL higher compared to patients who were serum antibody-positive, and took longer to reach low or undetectable levels. Similar to other viral infections, such as HIV, ebola virus disease, and influenza, high viral loadappears to be a predictor of disease progression in Covid-19, as evidenced by the fact that Covid- 19-related MAVs were enriched in placebo patients with baseline viral loads >104copies / ml. The data also indicate that risk factors for severe disease, such as older age and obesity, may help to predict outpatients who are most likely to have a subsequent Covid-19-related MAV. For example, 9.2% (13 / 142) of placebo patients with ≥1 risk factors had a MAV compared to 2.2% (2 / 89) of placebo patients without any risk factors. In this trial, >80% of patients with risk factors were serum antibody-negative or had a viral load >104copies / mL. In the absence of a rapid serology test or quantitative PCR assay to identify at-risk patients, identifying patients with risk factors for hospitalization may help identify outpatients most likely to benefit from early treatment with the antibody cocktail.

[0338] The prespecified hierarchical analysis described herein prospectively and with high statistical significance confirmed the virologic efficacy of REGEN-COV, and revealed similar virologic efficacy with both the 2.4 g and 8.0 g doses of the antibody cocktail. The reduction in viral load was greatest in the first 5 days after treatment, in patients who were serum antibody-negative or had high viral load at baseline. Treatment had no apparent additional virologic benefit in patients who had already mounted an effective endogenous antibody response to the infection (serum antibody-positive). The reduction in the viral load after treatment with either dose of REGEN-COV was accompanied by a significant reduction in the proportion of patients requiring a subsequent Covid-19- related medically-attended visits, the majority (67%) of which were hospitalizations or ER visits. REGEN-COV antibody cocktail led to a relative reduction in MAVs by 57% (6.5% in placebo vs 2.8% in the combined dose group; P=0.0240). Interestingly, the reduction in the proportion of patients with MAVs treated with REGEN-COV compared to placebo occurs only after the first week of treatment. One possible explanation for this finding is that medical visits occurring in the first week are not modifiable despite accelerated clearance of the virus. For example, among patients treated with the antibody cocktail, all three hospitalizations occurred in the first three days after treatment when viral loads were still ≥4 Iog10 copies / mL but no hospitalizations occurred after day 7 (Table 5F;FIG. 15A, FIG. 15B, and FIG. 15C). In contrast, among patients treated with placebo, 3 of the 5 hospitalizations occurred after Day 7, when viral loads continued to be high (≥4 Iog10 copies / mL). These data support early identification and rapid treatment of outpatients with Covid-19 in order to optimize the efficacy of REGEN-COV treatment.

[0339] A low incidence of serious adverse events, infusion-related reactions, and hypersensitivity reactions was observed. Similar to the results reported previously, concentrations of each antibody in serum at day 29 were well above the predicted neutralization target concentration based on in vitro and preclinical data.

[0340] The clinical evidence from this trial suggests that treatment had the greatest benefit when given to high-risk patients who present early after diagnosis when they were most likely to have high viral load and may not have yet mounted their own immune response. Moreover, there were no adverse findings observed in patients who were serum antibody-positive at baseline. Early treatment of Covid-19 outpatients is crucial and, if unable to rapidly determine viral load or serum antibody status, the risk-benefit assessment supports treatment to prevent MAVs in high-risk patients.

[0341] Phase 3 trial plan

[0342] Patient population for Cohort 1 - the patient population for Cohort 1 of the Phase 3 portion of the study was adult (≥18 years old) male and female patients with:• SARS-CoV-2-positive antigen or molecular diagnostic test (by validated SARS CoV-2 antigen, RT-PCR, or other molecular diagnostic assay) ≤72 hours prior to randomization and• symptoms consistent with COVID-19, as determined by the investigator, with onset ≤7 days before randomization and• ≥1 risk factor for severe COVID-19

[0343] Risk factors are defined as follows: a. Age >50 years b. Obesity, defined as body mass index (BMI) >30 kg / m2 c. Cardiovascular disease, including hypertension d. Chronic lung disease, including asthma e. Type 1 or type 2 diabetes mellitus f. Chronic kidney disease, including those on dialysis g. Chronic liver disease h. Pregnancy / . Immunosuppressed (examples include cancer treatment, bone marrow or organ transplantation, immune deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anaemia, thalassemia, and prolonged use of immune-weakening medications).

[0344] Primary and key secondary endpoint for Cohort 1 :

[0345] For cohort 1, the primary endpoint was COVID-19-related medically-attended visits (MAVs) through day 29. A COVID-19-related medically-attended visit was defined as follows: hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with the primary reason for the visit being COVID-19. A patient with multiple medically- attended visits was counted as having 1 event.

[0346] The key pre-specified secondary endpoint was the cumulative incidence of COVID-19- related hospitalizations or emergency room visits through day 29.

[0347] Other key pre-specified secondary endpoints included various types of COVID-19-related MAVs, and related outcomes.

[0348] The virologic data collectively provide definitive evidence that mAb10933 + mAb10987 markedly enhances SARS-CoV-2 viral clearance. Moreover, data from a pooled phase 1 / 2 analysis indicated that the viral load reduction translated into clinical benefit by significantly reducing COVID- 19-related MAVs, defined as hospitalizations, ER visits, urgent care visits, or physician office or telemedicine visits for COVID-19. Specifically, a prespecified and multiplicity-controlled analysis of pooled phase 1 / 2 data (n=799) showed a statistically significant reduction in MAVs in the mAb10933 + mAb10987 treated groups compared to placebo (2.8% combined dose groups vs 6.5% placebo; p=0.0240). Most of the MAVs occurred in patients who were higher risk, defined as seronegative at baseline, had higher baseline viral load, or had at least 1 pre-existing risk factor for severe COVID-19 (eg, age >50 years old, obesity, co-morbid conditions). In exploratory analyses, treatment with mAb10933 + mAb10987 showed the greatest benefit in these high-risk groups, with reductions in the proportion of patients with MAVs compared to placebo of 62% (3.2% combined treatment vs 8.5% placebo) for those with baseline viral loads >104 copies / mL, 65% (3.4% combined treatment vs 9.7% placebo) for those who were seronegative at baseline, and 72% (2.6% combined treatment vs 9.2% placebo) for those who had at least 1 risk factor for severe COVID-19. Considering the clinical benefits observed in phase 2, phase 3 will focus on confirming the clinical benefit of mAb10933 + mAb10987 in reducing MAVs for high-risk patients, thereby demonstrating the clinical benefit of reducing viral burden.

[0349] The sample size of the phase 3 Cohort 1 was estimated to be approximately 5400 patients. Cohort 1 continued until at least 80 patients with hospitalizations or ER visits were observed in patients enrolled into the primary analysis population (patients in mFAS with at least 1 risk factor) and the total number of patients with hospitalizations or ER visits during the study in the primary analysis population is more than 120.

[0350] The primary efficacy endpoint for phase 3 cohort 1 was the cumulative incidence of COVID 19 related MAVs through day 29 in the mFAS (randomized and treated PCR-positive patients with at least 1 risk factor at baseline).

[0351] Analyses were performed for the phase 3 cohort 1 key secondary endpoint, cumulative incidence of COVID- 19- related hospitalization / ER visit through day 29, based on the time to first hospitalization / ER visit.

[0352] For phase 3, planned virologic analyses were descriptive. The time-weighted average change from baseline in viral load (Iog10 copies / mL) from day 1 to post-baseline visit timepoints was analyzed using the same method as the phase 2 primary virologic endpoint based on mFAS for seronegative patients and seropositive patients separately for patients that underwent an intensive sampling schedule. Proportion endpoints based on observed virologic data were compared between groups using similar method as the proportion clinical endpoints. The analyses were performed for seronegative mFAS as well as for mFAS.

[0353] To assess the time course of treatment effect in viral load, the change from baseline in viral load (Iog10 copies / mL) at each visit for seronegative mFAS and mFAS was analysed using a mixed effect model for repeated measures (MMRM) with terms for baseline, randomization strata, treatment, visit, treatment by baseline interaction, baseline by visit interaction, and treatment by visit interaction.

[0354] The phase 3 portion of the study assessed 2 dose levels of mAb10933 + mAb10987, 1200 mg and 2400 mg, in a 1:1 ratio (600 mg and 1200 mg per mAb, respectively). In the phase 1 and 2 results, the 2400 mg and 8000 mg doses of mAb10933 + mAb10987 demonstrated similar virologic and clinical efficacy as assessed by MAVs, and both doses had similar and acceptable safety profiles. Given the similarities between the 2400 mg and 8000 mg doses, the 2400 mg dose was studied in this phase 3 study as the highest dose, along with lower doses.

[0355] Pediatric patients aged 0 to <18 years can be included in the phase 3 portion of the study as a separate cohort (cohort 2) to assess the safety, PK, immunogenicity, and efficacy of mAb10933 + mAb10987. Both patients that are symptomatic with COVID-19 or asymptomatic patients that are SARS-CoV-2 positive at baseline can be included in this cohort. Pediatric patients that have a risk factor for severe COVID-19 can be included in cohort 2.

[0356] Pediatric patients in cohort 2 can be randomized in a 1:1:1 allocation ratio to receive a single intravenous (IV) dose of mAb10933 + mAb10987 combination therapy at a low dose, a high dose, or placebo. However, the mAb10933 + mAb10987 treatment arms can be tiered according to body weight, as defined in Table 6, below.

[0357] Dose selection in the pediatric population (<18 years of age) can utilize a body weight tiered flat dose approach for both the high and low doses. For each weight-tiered dose targeting the higher dose in adults (2400 mg), the goal is to select doses that are predicted by population PK modelling to ensure that the fifth percentile of concentration in serum 28 days after dosing (C28) is similar to, or greater than, the observed fifth percentile of C28 in adults for the 2400 mg dose. An additional consideration is to ensure that predicted Cmax and AUCO-28 for each weight-tiered dose do not exceed values previously achieved in adults. Both mAb10933 and mAb10987 havedemonstrated linear PK, and as such, the same 50% reduction employed in selecting the lower adult dose in phase 3 (2400 mg to 1200 mg) was applied to each of the pediatric body weight tiered flat doses targeting the 1200 mg adult dose (Table 6).

[0358] Table 6: mAb10933 + mAb10987 IV Doses for Each Weight Group,Phase 3 Cohort 2 (Ages 0 to <18 Years)

[0359] The primary objective for the patients in cohort 2 is safety, with MAVs as a descriptive secondary objective.

[0360] The primary endpoints for cohort 2 is safety / tolerability and drug concentrations in serum over time:• Proportion of patients with treatment-emergent serious adverse events (SAEs) through day 29• Proportion of patients with infusion-related reactions (grade ≥2) through day 4• Proportion of patients with hypersensitivity reactions (grade ≥2) through day 29• Concentrations of mAb10933 and mAb10987 in serum over time• Immunogenicity, as measured by antidrug antibody (ADA) and neutralising antibodies (NAbs) to mAb10933 and mAb10987

[0361] Up to approximately 180 pediatric patients in cohort 2 (60 per treatment arm) would allow 45 patients to be randomized to each PK-ADA sampling schedule.Phase 3 adult data: summary

[0362] An objective of the confirmatory Phase 3 trial (FIG. 31 and FIG. 32) was to prospectively demonstrate clinically significant effect on risk of COVID-19 hospitalization or all-cause death in high- risk outpatients and confirm safety. This trial also prospectively evaluated potential benefit on symptom duration. The seamless design began comparing 8000 mg and 2400 mg versus placebo, and was amended to evaluate 2400 mg and 1200 mg versus placebo based on the final analysis of the phase 1 / 2 portion, which showed that the 8000 mg and 2400 mg doses were indistinguishable basedon antiviral and clinical endpoints (and that clinical events were largely occurring in high-riskpatients). Data comparing 8000 mg to placebo was converted to descriptive analysis. A formal hierarchical analysis first evaluated the 2400 mg dose versus concurrent placebo (in patients with ≥1 risk factor from original and amended portions, n = ~2700) and then evaluated 1200 mg dose versus concurrent placebo (in patients with ≥1 risk factor, n = -1500. A companion dose ranging virology study in outpatients further evaluated REGEN-COV doses from 2400 mg to 300 mg IV (and 1200 mg to 600 mg subcutaneous) for anti-viral efficacy (Example 7). Key results are shown below.

[0363] Table 7: Key Results from Phase 3 Outpatient Trial1 3

[0364] In the Phase 3 trial in 4567 high-risk patients, mAb10933 + mAb10987 (REGEN-COV) significantly reduced COVID-19 hospitalization or all-cause death, and shortened time to symptoms resolution by 4 days, confirming the clinical benefits seen in Phase 1 / 2. Additionally, REGEN-COV administered as a 1200 mg or 2400 mg single IV infusion significantly reduced the proportion of patients with COVID-19-related hospitalization or all-cause death in those who were SARS-CoV-2 PCR+ at baseline and had ≥1 risk factor for severe COVID-19. There was a similar treatment effect with the two dose levels: 2400 mg vs placebo (PBO), 71.3% reduction (1.3% vs 4.6%; p<0.0001); 1200 mg vs PBO, 70.4% reduction (1.0% vs 3.2%; p=0.0024). There was a greater reduction in COVID-19 hospitalization or all-cause death after study day 3 (89.2%, 2400mg vs PBO, p<0.0001; 71.7%, 1200 mg vs PBO, p=0.0101); with early events less modifiable. See FIG. 35, FIG. 36, and FIG. 37. Effects were more pronounced in patients with high viral loads and / or seronegativity at baseline, but meaningful risk reductions were seen in seropositive patients. There was also a significant reduction in viral load at day 7 across subgroups, with consistency between 2400 mgand 1200 mg doses (FIG. 43, FIG. 44, FIG. 52, FIG. 53, FIG. 54, FIG. 55, FIG. 56, and FIG. 58). Administration of REGEN-COV resulted in faster symptom resolution at both doses: 2400 mg vs PBO, median 10 vs 14 days; p<0.0001; 1200 mg vs PBO, median 10 vs 14 days; p<0.0001 (FIG.38, FIG. 39). A summary of these data are shown in FIG. 33. Moreover, serious adverse events (including fatal events) were more frequent in the placebo (PBO) group compared to REGEN-COV dose groups (4.0% PBO vs 1.4% combined REGEN-COV groups) (FIG. 40, FIG. 41, FIG. 42). Demographics for this study are shown in FIG. 34.Phase 3 adult data: full results and discussion

[0365] In the phase 1 / 2 portion of this adaptive phase 1-3 randomized, placebo-controlled master protocol, REGEN-COV demonstrated efficacy in outpatients, where it was shown to rapidly reduce viral load and the need for medical attention related to Covid-19. In fact, on February 19th, 2021, an independent data monitoring committee (IDMC) recommended stopping enrollment of patients into the placebo group of the phase 3 portion of this master protocol because of clear efficacy of REGEN-COV.

[0366] The phase 3 portion of this adaptive, randomized, master protocol, included 4,057 COVID- 19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV and followed for 29 days. The prespecified hierarchical analysis compared the REGEN-COV 2400mg dose versus concurrent placebo, followed by the 1200mg dose versus concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients.

[0367] Both REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71% reduction, 1.0% vs 3.2%, p<0.0024; 70% reduction, 1.3% vs 4.6%, respectively; p<0.0001). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including serum antibody-positive patients. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0% vs 1.1% and 1.3% in the 1200mg and 2400mg groups, respectively) and infusion-related reactions were infrequent (<2 patients in all groups).

[0368] Treatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load.

[0369]

[0370] Trial Design - This was an adaptive, multicenter, randomized, double-blind, placebo- controlled, phase 1 / 2 / 3 master protocol in Covid-19 outpatients (NCT04425629). The phase 3portion comprised 3 cohorts: Cohort 1 (≥18 years), Cohort 2 (<18 years), and Cohort 3 (pregnant at randomization). Initially, phase 3 patients were randomized 1:1:1 to receive placebo, REGEN-COV 2400mg (1200mg each of casirivimab and imdevimab) IV, or REGEN-COV 8000mg (4000mg each antibody) IV (FIG. 81). Based upon phase 1 / 2 results that showed the 8000mg and 2400mg doses had similar antiviral and clinical efficacy and that most clinical events occurred in high-risk patients, the trial was subsequently amended on November 14th, 2020 to revise the population and the doses. As a result of the amendment, subsequent patients enrolled had ≥1 risk factor for severe Covid-19 and were randomized 1:1:1 to receive placebo, REGEN-COV 1200mg (600mg each antibody) IV, or REGEN-COV 2400mg (1200mg each antibody) IV. On February 19th, 2021, per IDMC recommendation, patients were no longer randomized to receive placebo. The phase 3 analysis presented here is comprised of Cohort 1 patients (≥18 years) randomized to REGEN-COV 2400mg or 1200mg with their concurrent placebo groups serving as a control.

[0371] Eligible patients (Cohort 1) were ≥18 years of age and non-hospitalized, with a confirmed local SARS-CoV-2-positive diagnostic test result ≤72 hours and onset of any Covid-19 symptom ≤7 days before randomization. Randomization into the initial phase 3 portion was stratified by country and presence of risk factors for severe Covid-19. In the amended phase 3 portion, only patients with ≥1 risk factor for severe Covid-19 were eligible. All patients were assessed at baseline for anti- SARS-CoV-2 antibodies: anti-spike [S1] IgA, anti-spike [S1] IgG, and anti-nucleocapsid IgG. Because assay results were not available at randomization, patients were subsequently grouped for the purposes of virologic and subgroup analyses as serum antibody-negative (if all available tests were negative), serum antibody-positive (if any available test was positive), or other (inconclusive / unknown results).

[0372] At baseline (day 1), REGEN-COV (diluted in normal saline solution for co-administration) or saline placebo was administered intravenously. Hospitalizations were assessed to be related to Covid-19 by the investigator. The Symptoms Evolution of COVID-19 (SE-C19) instrument, an electronic diary, assessed 23 Covid-19 symptoms daily. Quantitative virologic analysis of nasopharyngeal (NP) swab samples and serum antibody testing were conducted in a central laboratory and were previously described.

[0373] The prespecified primary and two key secondary endpoints were tested hierarchically (FIG. 89). The primary endpoint was the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death through day 29. The two key secondary clinical endpoints were (1) the proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death from day 4 through day 29 and (2) the time to Covid-19 symptoms resolution. Time to Covid-19 symptoms resolution was defined as time from randomization to the first day during which the subject scored “no symptom’ (score of0) on all of the symptoms except cough, fatigue, and headache, which could have been “mild / moderate symptom” (score of 1) or “no symptom” (score of 0). Safety endpoints for the phase 3 portion of the trial included serious adverse events (SAEs) that occurred or worsened during the observation period and adverse events of special interest (AESIs): grade ≥2 hypersensitivity reactions and infusion-related reactions and treatment-emergent adverse events requiring medical attention at a healthcare facility.

[0374] The statistical analysis plan for the presented analysis was finalized prior to database lock and unblinding of phase 3 Cohort 1; the primary analysis did not include patients from the previously reported phase 1 / 2 portion of the trial. The full analysis set (FAS) included all randomized symptomatic patients. Efficacy analyses were performed based on a modified FAS (mFAS) defined as all randomized patients with a positive SARS-CoV-2 central lab-determined RT- qPCR test at baseline and with ≥1 risk factor for severe Covid-19. Safety was assessed in treated patients in the FAS. The proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death was compared between each dose group and placebo using the stratified Cochran-Mantel- Haenszel (CMH) test with country as a stratification factor. P-values from the stratified CMH test and 95% confidence intervals (Cls) for the relative risk reduction using the Farrington-Manning method are presented. Time to Covid-19 symptoms resolution was assessed in patients with a baseline total severity score >3 and analyzed using the stratified log-rank test with country as a stratification factor. Median times and associated 95% Cls were derived from the Kaplan-Meier method. The hazard ratio and 95% Cl were estimated by the Cox regression model. Analyses of the primary and key clinical endpoints were conducted at a two-sided a=0.05 utilizing a hierarchical testing strategy to control for type I error (FIG. 89). Statistical analyses were performed with SAS software, version 9.4 or higher (SAS Institute).Results (Trial Population)

[0375] Phase 3 patients were enrolled between September 24th, 2020 and January 17th, 2021. Initially, in the original phase 3 portion, a total of 3088 patients, with or without risk factors for severe Covid-19, underwent randomization to receive a single dose of either placebo, REGEN-COV 8000mg or REGEN-COV 2400mg. Subsequently, in the amended phase 3 portion, an additional 2519 patients with ≥1 risk factor were randomized to receive a single dose of either placebo, REGEN-COV 2400mg or REGEN-COV 1200mg (FIG. 76). Patients had a median follow-up duration of 45 days, with 96.6% of patients having >28 days follow-up.

[0376] The primary efficacy population included those with ≥1 risk factors for severe Covid-19 and baseline central laboratory test positive for SARS-CoV-2 (mFAS) (FIG. 76). Among the mFAS population (n=4057), demographic and baseline medical characteristics were balanced between theplacebo and REGEN-COV groups (FIG. 78). The median age was 50 years (interquartile range [IQR, 38-59]), 52% male, 14% ≥65 years, 28% Hispanic, and 61% obese. The most common risk factor were obesity (58%), age ≥50 years (52%), and cardiovascular disease (36%); 3% of patients were immunosuppressed or on immunosuppressive medications (FIG. 90). Similar demographic and baseline medical characteristics were observed in the overall full analysis set (n=5607) and in the REGEN-COV 8000mg group (FIG. 91).

[0377] The median NP viral load was 6.98 log10copies / mL (IQR 5.45-7.85) and the majority of patients (69%) were SARS-CoV-2 serum antibody negative at baseline (FIG. 78); these high viral loads and lack of endogenous immune response at baseline indicated that the enrolled individuals were early in the course of their infection. NP viral load and serum antibody-negative status were similar across treatment groups. Patients had a median of 3 days (IQR 2-5) of Covid-19 symptoms at randomization and this was well-balanced across treatment groups.Results (Natural History)

[0378] There was an association between Covid-19-related hospitalization or all-cause death risk with baseline viral load: hospitalization / deaths occurred in a greater proportion of patients with high viral load compared to those with lower viral load at baseline (baseline viral load >106copies / mL: 6.3% [55 / 876] and 4.2% [20 / 471 ] in the concurrent placebo groups for 2400mg and 1200mg, respectively; baseline viral load ≤106copies / mL: 1.3% [6 / 457] and 1.5% [4 / 273] of patients in the concurrent placebo groups for 2400mg and 1200mg, respectively) (FIG. 92).

[0379] Patients in the placebo group who were serum antibody-negative at baseline had higher median viral loads at baseline compared to those who were serum antibody-positive (7.45 log10copies / ml vs 4.96 log10copies / ml) and they took longer to bring their viral levels to below the lower limit of quantification (LLQ) (FIG. 82).

[0380] Baseline serum antibody status of placebo patients was not predictive of subsequent Covid-19- related hospitalizations or all-cause death, as these rates were similar in patients who were serum antibody-negative and antibody-positive (antibody negative: 5.3% [49 / 930] and 3.5% [18 / 519] of patients in the concurrent placebo groups for 2400mg and 1200mg, respectively; antibody-positive: 4.0% [12 / 297] and 3.7% [6 / 164] in the concurrent placebo groups for 2400 and 1200mg, respectively). However, placebo patients who were serum antibody-positive and subsequently required hospitalization or died had high viral loads at baseline and day 7, similar to patients who were serum antibody-negative who required hospitalization or died, arguing that some serum antibody-positive patients may have an ineffective innate antibody response (FIG. 93). Efficacy (Primary Endpoint)

[0381] REGEN-COV 2400mg and 1200mg similarly reduced Covid-19-related hospitalization or all-cause death by 71.3% (1.3% vs 4.6% placebo; 95% Cl: 51.7%, 82.9%; p<0.0001) and 70.4% (1.0% vs 3.2% placebo; 95% Cl: 31.6%, 87.1%; p<0.0024), respectively (FIG. 79, FIG. 77A, FIG. 77B, FIG. 94). Similar reductions in Covid-19-related hospitalizations or all-cause deaths were observed across subgroups, including in patients who were serum antibody-positive at baseline (FIG. 79, FIG. 83A, FIG. 83B, and FIG. 83C).Efficacy (Key Secondary Endpoints)

[0382] The reduction in the proportion of patients with Covid-19-related hospitalization or death was observed starting approximately 1 to 3 days after treatment with REGEN-COV (FIG. 77A, FIG. 77B, FIG. 79). After these first 1 to 3 days, patients in the placebo group continued to experience Covid- 19- related hospitalization or death events during the study period (46 / 1340 [3.4%]), while very few events occurred in the 2400mg or 1200mg REGEN-COV treatment groups (5 / 1351 [0.4%] and 5 / 735 [0.7%], respectively) (FIG. 79, FIG. 84A, FIG. 84B).

[0383] The median time to resolution of Covid-19 symptoms was 4 days sooner than placebo in both REGEN-COV dose groups (10 days vs 14 days; p<0.0001 each for 2400mg and 1200mg) (FIG. 79 and FIG. 77C). The more rapid resolution of Covid-19 symptoms with either dose of REGEN-COV was evident by day 3. Both REGEN-COV doses were associated with similar improvements in symptoms resolution across subgroups (FIG. 85).

[0384] All REGEN-COV dose levels (1200mg, 2400mg, and 8000mg) led to similar and rapid declines in viral load compared to placebo (FIG. 86A, FIG. 86B. FIG. 86C, FIG. 87, FIG. 88A, FIG. 88B, and FIG. 88C).Efficacy (Other Secondary Endpoints)

[0385] REGEN-COV treatment was associated with a lower proportion of patients with Covid-19- related hospitalization (FIG. 95). Among patients that were hospitalized due to Covid-19, those in the REGEN-COV group had shorter hospital stays and a lower rate of admission to an intensive care unit (FIG. 96).

[0386] REGEN-COV treatment was associated with a lower proportion of patients with Covid-19- related hospitalization, emergency room visits, or all-cause death through Day 29 (FIG. 97) and a lower proportion requiring any medically-attended visit for worsening Covid-19 (hospitalization, emergency room visit, urgent care visit or physician office / telemedicine visit) or all-cause death(FIG. 95, FIG. 98, and FIG. 99).Safety

[0387] Serious adverse events (SAEs) were experienced by more patients in the placebo group (4.0%) compared to the REGEN COV dose groups: 1.1% 1200mg, 1.3% 2400mg and 1.7%8000mg (FIG. 80). More patients experienced treatment emergent adverse events (TEAEs) that resulted in death in the placebo group (5 patients, 0.3%) compared to the REGEN-COV dose groups: 1 (0.1%) in 1200mg, 1 (<0.1%) in 2400mg, and 0 in 8000mg (FIG. 80 and FIG. 100). Most adverse events were consistent with complications of Covid-19 (FIG. 101 and FIG. 102) and the majority were not considered to be related to study drug. Few patients experienced infusion-related reactions (0 in placebo; 2, 1, and 3 patients in 1200mg, 2400mg, and 8000mg) and hypersensitivity reactions (1 in placebo and 1 in 2400mg) (Figure 91). A similar safety profile was observed between REGEN-COV doses, with no discernable imbalance in safety events. No safety signals were observed in safety laboratory parameters collected through day 29.Pharmacokinetics

[0388] The mean concentrations of casirivimab and imdevimab in serum on day 29 increased in a dose-proportional manner and were consistent with linear pharmacokinetics (FIG. 103). The mean day 29 concentrations of casirivimab and imdevimab in serum were 46.4±SD22.5 and 38.3±SD19.6 mg / L, respectively, for the 1200mg dose and 73.2±SD27.2 and 60.0±SD22.9 mg / L, respectively, for the 2400mg dose; the mean estimated half-life was 28.8 days for casivirimab and 25.5 for imdevimab (FIG. 103).Discussion

[0389] Previous Phase 1 / 2 data showed that, in outpatients with Covid-19, REGEN-COV robustly lowered viral load, reduced the need for medical attention, and despite a small number of events, was highly suggestive of a reduced risk for hospitalization. These clinical outcomes data now definitively prove that early treatment with REGEN-COV in outpatients with risk factors for severe Covid-19 can dramatically lower the risk of hospitalization or all-cause death. Both 1200mg IV and 2400mg IV doses of REGEN-COV led to -70% reduction (vs placebo) in Covid-19 hospitalization or all-cause death over 28 days after treatment. In those who were hospitalized, REGEN-COV treatment also led to shorter duration of hospitalization and a lower proportion of patients requiring intensive care. In addition, REGEN-COV, at both doses, resulted in more rapid resolution of Covid- 19 symptoms by a median of 4 days. Therefore, a single dose of REGEN-COV in outpatients with Covid-19 has the potential to improve patient outcomes and substantially reduce the health care burden experienced during this pandemic by reducing morbidity and mortality, including hospitalizations and intensive care. Furthermore, REGEN-COV can substantially speed recovery from Covid-19, which represents an additional benefit for patients, as there is a growing body of evidence that suggests that some patients, including those with mild symptoms, will have a variably prolonged course of recovery.

[0390] Without wishing to be bound by theory, we previously hypothesized that, while host factors play a role in the disease course, the morbidity and mortality of SARS-CoV-2 result from high viral burden and early treatment with an anti-spike monoclonal antibody cocktail could markedly ameliorate this risk. In the placebo group, we found that patients with hospitalizations or all-cause death had markedly higher viral loads at baseline and were slower to clear virus, independent of baseline serological status. Patients in the placebo group who had mounted their own endogenous antibody response to SARS-CoV-2 (serum antibody-positive) had similar rates of hospitalizations or death compared to patients who were serum antibody-negative, suggesting that some serum antibody-positive patients had an ineffective immune response. Furthermore, placebo patients who were serum antibody-positive and had a Covid-19-related hospitalization or who died, also had high baseline viral load levels similar to patients who were serum antibody-negative who also had these events, supporting high viral load as a key driver of severe Covid-19. Moreover, this study also demonstrated that there is clinical benefit of REGEN-COV, regardless of baseline serum antibody status, making serological testing at the time of Covid-19 diagnosis less critical for clinical treatment decisions. This is important given the prevalence of vaccine utilization, which will result in baseline serum antibody-positive status that may not effectively prevent severe infection in some patients (as appears to be the case for certain patients with ineffective natural immunity in this trial) or due to emerging variants of concern (VOCs).

[0391] Both 1200mg and 2400mg doses of REGEN-COV had similar antiviral and clinical efficacy, suggesting that we are well above the minimally effective dose. Both doses rapidly reduced viral loads with faster time to viral clearance compared to placebo. In addition to providing clinical benefit to the individual patient receiving REGEN-COV, the rapid anti-viral effect is likely to be associated with a public health benefit through reduced risk of viral transmission and containment of SARS- CoV-2 VOCs.

[0392] A low incidence of serious adverse events and hypersensitivity and infusion-related reactions was observed. Concentrations of each antibody in serum at day 29 were well above the predicted neutralization target concentration based on in vitro and preclinical data.

[0393] The emergence of resistant variants of SARS-CoV-2 during treatment with an antiviral agent(s) or via circulation within the global community will continue to be a challenge for the success of Covid-19 therapeutics and vaccines. Although in vitro studies or in vivo animal studies using recombinant viruses demonstrate that combinations of non-competing antibodies, such as REGEN-COV, are able to suppress the emergence of resistant variants, questions remain about the relevance of those studies to natural human infection. We therefore recently investigated and reported the genetic diversity of the entire spike protein across samples from 1,000 outpatientsenrolled into either the outpatient REGEN-COV trial described in this Example or a separate, hospitalized Covid-19 REGEN-COV trial (described in Example 1). The analysis of 4,882 samples from these 1,000 patients treated with REGEN-COV or placebo demonstrated that REGEN-COV protects against the selection of resistant variants, as evidenced by a similar number of receptor binding domain (RBD) variants found in placebo-treated patients compared to those treated with 1200mg and 2400mg doses of REGEN-COV (15 RBD variants in placebo versus 12 in 1200mg and 12 in 2400mg dose in REGN-COV treated group). Three of these RBD variants were found in only the REGEN-COV-treated groups but were identified at baseline or soon after treatment (<5 days) and did not increase in frequency over time, suggesting the occurrence of these variants was not due to treatment pressure.

[0394] REGEN-COV antibody cocktail at the 2400mg dose received Emergency Use Authorization (EUA) from the US FDA in November 2020 for the treatment of mild-to-moderate Covid-19. On April 8, 2021, the NIH treatment guidelines recommended the use of 2400mg REGEN-COV for the treatment of high-risk outpatients with Covid-19, with preferential use of REGEN-COV in areas where VOCs are common. The clinical evidence from this clinical outcomes trial, the largest randomized, controlled phase 3 Covid-19 outpatient treatment trial to date, indicates that 1200mg of REGEN-COV is well-tolerated, can significantly reduce Covid-19-related hospitalizations or death, can speed time to recovery, and is unlikely to promote the emergence of treatment-resistant SARS-CoV-2 variants. With this definitive phase 3 data demonstrating a profound reduction in the risk of hospitalization or all-cause death, together with an acceptable safety profile, physicians should consider treating every high risk, SARS-CoV-2 positive individual.

[0395] Supplement Details

[0396] The Symptoms Evolution of COVID-19 (SE-C19) instrument was an electronic diary that was completed daily from Day 1 to Day 29. The SE-C19 was initially developed based on the CDC symptom list and available published literature specific to patients with COVID-19. It included a list of 23 symptoms feverish, chills, sore throat, cough, shortness of breath or difficulty breathing, nausea, vomiting, diarrhea, headache, red or watery eyes, body aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, pressure or tight chest, chest pain, stomachache, rash, sneezing, sputum or phlegm, runny nose). Patients indicated which of the 23 symptoms they experienced in the last 24 hours and then rated each symptom selected at its worst moment in that period on a scale of mild, moderate or severe. In parallel to the main clinical trial, patient and clinician interviews were performed to confirm the content validity of the newly developed SE-C19 and psychometric validation was conducted using blinded phase 1 / 2 data to explore the reliability and validity of the measure and refine a symptom endpoint. The results indicated 19 of the original23 items being most valid, reliable and relevant to outpatients with COVID-19 (i.e., sneezing, rash, vomiting and confusion were excluded) and refinement of the response options to three-categories (0 - none, 1 - mild / moderate, 2 - severe). The detailed, rigorous scientific methods implemented and results of these additional studies will be published independently.

[0397] Missing data for virology endpoints was handled as follows: Analysis-positive polymerase chain reaction (PCR) results below the lower limit of quantification (LLOQ) of 714 copies / ml (2.85 Iog10 copies / ml) were imputed as half the LLOQ (357 copies / ml) and negative PCR results were imputed as 0 log10copies / ml (1 copy / ml). Patients with missing baseline symptom assessment were not included in the analysis of the symptom resolution endpoint. Patients who do not experience resolution of symptoms will be censored at the last observation time point. Patients who died or had COVID-19-related hospitalization prior to day 29 were censored at day 29.

[0398] Prior to protocol amendment 6, serum for drug concentration analysis was collected from all patients randomized to 2.4 g IV, 8.0 g IV, or placebo at pre-dose (at the screening or baseline visit), day 1 at the end of the infusion, and day 29. After protocol amendment 6, serum for drug concentration analysis was collected from patients randomized to 1 2g IV, 2.4g IV, or placebo in a PK sub-study at pre-dose (at the screening or baseline visit), day 29, and day 120. The human serum concentrations of REGN 10933 (casirivimab) and REGN 10987 (imdevimab) were measured using validated immunoassays which employ streptavidin microplates from Meso Scale Discovery (MSD, Gaithersburg, MD, USA). The methods utilized two anti-idiotypic monoclonal antibodies, each specific for either REGN 10933 or REGN 10987, as the capture antibodies. Captured REGN 10933 and REGN 10987 were detected using two different, non-competing anti-idiotypic monoclonal antibodies, each also specific for either REGN 10933 or REGN 10987. The bioanalytical methods specifically quantitated the levels of each anti-SARS-CoV-2 spike monoclonal antibody separately, with no interference from the other antibody. The assay has an LLOQ of 0.156 μg / ml for each analyte in the undiluted serum sample.Example 3. Clinical Evaluation of Anti-SARS-CoV-2 Spike Glycoprotein Antibodies for Prevention of SARS-CoV-2 Infection and COVID-19 in At-Risk Subjects.

[0399] The below-described clinical study is a randomized, double-blind, placebo-controlled phase 3 study to assess the safety, and efficacy of anti-Spike SARS-CoV-2 monoclonal antibodies in first responders, healthcare workers, and other adult individuals at risk of exposure to SARS-CoV-2 in geographic areas of ongoing COVID-19 outbreaks.

[0400] Study Objectives: For analysis of endpoints, there are 2 defined cohorts based on the subjects’ SARS-CoV-2 infection status at baseline, as measured by central lab SARS-CoV-2 RT-qPCR (quantitative reverse transcription polymerase chain reaction): negative (cohort A) or positive (cohort B).

[0401] A strict definition of COVID-19 signs and symptoms (i.e., strict-term) is utilized for the primary endpoint, which include: fever (≥ 38°C) PLUS ≥1 respiratory symptoms (sore throat, cough, shortness of breath), OR ≥2 respiratory symptoms, OR 1 respiratory symptom PLUS ≥2 non- respiratory symptoms (chills, nausea, vomiting, diarrhea, headache, conjunctivitis, myalgia, arthralgia, loss of taste or smell, fatigue or general malaise). A broader definition (i.e., broad-term) including the signs / symptoms in the strict definition and additional non-specific symptoms (feverish, sore throat, cough, shortness of breath, chills, nausea, vomiting, diarrhea, headache, red or watery eyes, body aches, loss of taste / smell, fatigue, loss of appetite, confusion, dizziness, pressure / tightness in chest, chest pain, stomach ache, rash, sneezing, runny nose, or sputum / phlegm) is used for secondary endpoints.Objectives are for subjects who are seronegative at baseline unless noted otherwise.

[0402] Cohort A: SARS-CoV-2 RT-qPCR Negative at Baseline Cohort A Primary Efficacy Objectives• To evaluate the efficacy of mAb10933) + mAb10987 compared to placebo in preventing symptomatic SARS-CoV-2 infection (strict-term) confirmed by RT-qPCR• To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing symptomatic (strict-term or broad-term) and asymptomatic SARS-CoV-2 infection confirmed by RT qPCRCohort A Primary Safety Objective• To evaluate the safety and tolerability of mAb10933 + mAb10987 following subcutaneous (SC) administration compared to placeboCohort A Secondary Objectives• To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing symptomatic SARS-CoV-2 infection (broad-term) confirmed by RT qPCR• To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing asymptomatic SARS-CoV-2 infection confirmed by RT-qPCR• To evaluate the impact of mAb10933 + mAb10987 compared to placebo on the duration of signs and symptoms in subjects with symptomatic SARS CoV-2 infection confirmed by RT-qPCR• To evaluate the impact of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 RT- qPCR test results• To evaluate the impact of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 infection:o On health care utilization o On absenteeism from daily responsibilities• To characterize the drug concentration-time profiles of mAb10933 and mAb10987 in serum and selected pharmacokinetic (PK) parameters• To assess the immunogenicity of mAb10933 and mAb10987• To evaluate the safety and tolerability of mAb10933 + mAb10987 following SC administration in seropositive subjects• To estimate the incidence and severity of symptomatic SARS-CoV-2 infection over time, including the period following study drug treatment, in mAb10933 + mAb10987 treated seronegative and seropositive subjects compared to placebo treated subjects

[0403] Cohort B: SARS-CoV-2 RT-qPCR Positive at BaselineCohort B Secondary Objectives• To evaluate the efficacy of mAb10933 + mAb10987 compared to placebo in preventing development of: o Symptomatic SARS-CoV-2 infection (strict-term) o Symptomatic SARS-CoV-2 infection (broad-term)• To evaluate the impact of mAb10933 + mAb10987 compared to placebo on the duration of signs and symptoms in subjects with symptomatic SARS CoV-2 infection confirmed by RT-qPCR• To evaluate the impact of mAb10933 + mAb10987 compared to placebo on SARS CoV-2 RT- qPCR test results• To evaluate the impact of mAb10933 + mAb10987 compared to placebo in SARS CoV-2 infection: o On health care utilization o On absenteeism from daily responsibilities• To characterize the concentration-time profiles of mAb10933 and mAb10987 in serum and selected PK parameters• To assess the immunogenicity of mAb10933 and mAb10987• To evaluate the safety and tolerability of mAb10933 + mAb10987 following SC administration in both seronegative and seropositive subjects• To estimate the incidence and severity of symptomatic SARS-CoV-2 infection over time, including the period following study drug treatment, in mAb10933 + mAb10987 treated seronegative and seropositive subjects compared to placebo-treated subjects

[0404] Study Design: This is a phase 3 randomized, double-blind, placebo-controlled study in first responders, healthcare workers, and other adult individuals at risk of exposure to SARS-CoV-2in geographic areas of ongoing COVID-19 outbreaks. Approximately 6000 subjects are enrolled. Subjects are randomized in a 1:1:1 ratio into 1 of the 3 treatment groups. Randomization is performed by site and stratified by local molecular diagnostic assay for SARS-CoV-2 from respiratory sample (negative, positive, or undetermined), on-site LFIA serology test for SARS-CoV- 2 (seropositive, seronegative, or undetermined), and age ≥50 year (yes vs no).

[0405] Cohort allocation is based on central lab baseline SARS-CoV-2 RT-qPCR for data analysis: cohort A (negative) and cohort B (positive). Approximately 5000 subjects are enrolled in cohort A and cohort B is capped to 1000 subjects. For the purpose of the study analysis, cohort A and cohort B are independent. Since this is an event driven study, the sponsor may decide to close enrollment of cohort B once cohort A is fully enrolled and / or the necessary number of events are accrued in cohort A for the primary efficacy analysis.

[0406] Enrollment in this study is carried out in 2 phases:1. Sentinel group of approximately 30 subjects, irrespective of allocation to cohort A or cohort B: Subjects will be monitored for safety on-site for a minimum of 4 hours after administration of the first dose of study drug and then daily via visits to the study site or phone calls for the first 4 days (96 hours). Because mAb10933 + mAb10987 already have cleared a sentinel safety group at higher doses administered IV, the sentinel group in this study will focus on safety evaluation for injection site reactions and hypersensitivity reactions. Blinded safety data up to day 4 assessments from a pooled ~30 subjects enrolled in the SC administered mAb10933 + mAB10987 prophylaxis program (from either this study or pooled with an accompanying post-exposure prophylaxis study in household contacts (Example 4), which comprise a sentinel safety cohort) are reviewed before progressing with enrollment of additional study subjects.2. Following a conclusion of the blinded safety data review that the study may proceed, the study resumes enrollment.

[0407] Study Duration: For each subject, the study comprises 3 periods: an up to 3-day screening / baseline period, a 4-month efficacy enhancement period (EAP), and a 7-month follow-up period after the end of the EAP.

[0408] Study Population: The study population comprises asymptomatic, healthy adult first responders, healthcare workers, and other individuals at risk of exposure to SARS-CoV-2. Enrollment of “other individuals” at risk of SARS CoV-2 infection should occur only in geographic areas where there is widespread COVID-19 and high attack rates. The decision to include such subject population(s) in the study will be based on review of epidemiologic data.

[0409] Cohorts and Sample Size - Cohort A: Approximately 5000 subjects with negative baseline rapid SARS-CoV-2 RT-PCR; Cohort B: Up to 1000 subjects with positive baseline rapidSARS CoV-2 RT-PCR.

[0410] Inclusion Criteria: A subject must meet the following criteria to be eligible for inclusion in the study:1. 18 years of age and above at the signing of informed consent;2. In a population at high risk for exposure to SARS-CoV-2, including but not limited to the following: a. Active first responders and / or healthcare workers including but not limited to physicians, nurses, nurses’ aides, respiratory therapists, and members of law enforcement, firefighter, emergency medical technician or paramedic at risk of exposure to the SARS- CoV-2;OR b. Other individuals deemed to be at risk for SARS-CoV-2 infection (including but not limited to industry workers; meat packers; nursing home residents and workers; people congregating in places of worship; college students, teachers and workers) in geographic areas with an active COVID-19 outbreak. The decision to include such subject population(s) in the study will be based on review of epidemiologic data by the Sponsor and other collaborating parties;3. Is judged by the investigator to be in good health based on medical history and physical examination at screening / baseline;4. Willing and able to comply with study visits and study-related procedures;5. Provides signed informed consent.

[0411] Exclusion Criteria: A subject who meets any of the following criteria will be excluded from the study:1. Subject reported history of prior positive SARS-CoV-2 RT-PCR test or positive SARS-CoV-2 serology test at any time before the screening visit;2. Active respiratory or non-respiratory symptoms suggestive or consistent with COVID-19;3. History of respiratory illness with signs / symptoms of COVID-19, in the opinion of the investigator, within the prior month to screening;4. History of clinically significant illness or presenting any concern, as assessed by the investigator that may confound the results of the study or poses an additional risk to the subject by their participation in the study;5. Hospitalization (i.e. , >24 hours) for any reason within 30 days of the screening visit;6. Cancer requiring treatment currently or in the past 1 year, except for non-melanoma skin cancer or cervical / anus in-situ;7. Has a history of significant multiple and / or severe allergies (e.g., latex gloves), or has had an anaphylactic reaction to prescription or non-prescription drugs or food. This is to avoid potential confounding of the safety data and not due to a particular safety risk;8. Treatment with another investigational drug in the last 30 days or within 5 half-lives of the investigational drug, whichever is longer, prior to the screening visit;9. Received investigational or approved SARS-CoV-2 vaccine;10. Received investigational or approved passive antibodies for SARS-CoV-2 infection prophylaxis (e.g., convalescent plasma or sera, monoclonal antibodies, hyperimmune globulin);11. Use of hydroxychloroquine / chloroquine, remdesivir, intravenous immunoglobulin (IVIG) or other anti-SARS viral agents within 2 months prior to screening;12. Member of the clinical site study team and / or immediate fam...